FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Moir, S Fauci, AS AF Moir, Susan Fauci, Anthony S. TI Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals SO IMMUNOLOGICAL REVIEWS LA English DT Review DE B cells; HIV; memory; differentiation; immune activation ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-FOLLICULAR-HELPER; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN MONOCLONAL-ANTIBODIES; CXC CHEMOKINE RECEPTOR-5; CHRONIC VIRAL-INFECTION; TUMOR-NECROSIS-FACTOR; NEUTRALIZING ANTIBODIES; LYMPHOID-TISSUE; DISEASE PROGRESSION AB Human immunodeficiency virus (HIV) disease is associated with dysregulation and dysfunction involving all major lymphocyte populations, including B cells. Such perturbations occur early in the course of infection and are driven in large part by immune activation resulting from ongoing HIV replication leading to bystander effects on B cells. While most of the knowledge regarding immune cell abnormalities in HIV-infected individuals has been gained from studies conducted on the peripheral blood, it is clear that the virus is most active and most damaging in lymphoid tissues. Here, we discuss B-cell perturbations in HIV-infected individuals, focusing on the skewing of B-cell subsets that circulate in the peripheral blood and their counterparts that reside in lymphoid tissues. This review also highlights recent advances in evaluating HIV-specific B-cell responses both in the memory B-cell compartment, as well as in circulating antibody-secreting plasmablasts and the more differentiated plasma cells residing in tissues. Finally, we consider how knowledge gained by investigating B cells in HIV-infected individuals may help inform the development of an effective antibody-based HIV vaccine. C1 [Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIH, Bldg 10,Room 6A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX This work was funded by the Intramural Research Program of NIAID, NIH. The authors have no conflicts of interest to disclose. NR 183 TC 58 Z9 58 U1 0 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 207 EP 224 DI 10.1111/imr.12067 PG 18 WC Immunology SC Immunology GA 164EE UT WOS:000320390900012 PM 23772622 ER PT J AU Mascola, JR Haynes, BF AF Mascola, John R. Haynes, Barton F. TI HIV-1 neutralizing antibodies: understanding nature's pathways SO IMMUNOLOGICAL REVIEWS LA English DT Review DE monoclonal antibodies (mAbs); broadly neutralizing antibodies (BNAbs); unmutated ancestor (UA); B-cell lineages; immune tolerance ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; B-CELL RESPONSES; RECOMBINANT GLYCOPROTEIN-120 VACCINE; GP120 ENVELOPE GLYCOPROTEIN; CROSS-CLADE NEUTRALIZATION; 2ND HYPERVARIABLE REGION; DEFICIENCY SYNDROME AIDS; HTLV-III LAV; SUBTYPE-B AB The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus-1 (HIV-1) and its ability to escape a myriad of host immune responses. In addition, conserved vulnerable regions on the HIV-1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV-1-infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV-1-infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination. C1 [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Human Vaccine Inst, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Human Vaccine Inst, Durham, NC USA. RP Mascola, JR (reprint author), 40 Convent Dr, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU Vaccine Research Center, NIAID, NIH; NIH, NIAID Center for HIV/AIDS Vaccine immunology-Immunogen Design [UM1 AI100645]; Collaboration for AIDS Vaccine Discovery grants FX We thank Tony Moody and Rebecca Lynch for their review and suggestions for this manuscript. Supported by the intramural research program of the Vaccine Research Center, NIAID, NIH and by the NIH, NIAID Center for HIV/AIDS Vaccine immunology-Immunogen Design UM1 AI100645 and by Collaboration for AIDS Vaccine Discovery grants to B. F. H. The authors have no conflicts of interest to declare. NR 211 TC 180 Z9 184 U1 6 U2 73 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 225 EP 244 DI 10.1111/imr.12075 PG 20 WC Immunology SC Immunology GA 164EE UT WOS:000320390900013 PM 23772623 ER PT J AU Martin, MP Carrington, M AF Martin, Maureen P. Carrington, Mary TI Immunogenetics of HIV disease SO IMMUNOLOGICAL REVIEWS LA English DT Review DE HLA; KIR; CTL; NK cells; GWAS; host genetic variation ID IMMUNODEFICIENCY-VIRUS TYPE-1; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; GENOME-WIDE ASSOCIATION; CD8(+) T-CELLS; EXPOSED UNINFECTED INDIVIDUALS; HLA-C EXPRESSION; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTORS; HUMAN MONOCLONAL-ANTIBODIES AB Host genetic factors are a major contributing factor to the inter-individual variation observed in response to human immunodeficiency virus (HIV) infection and are linked to resistance to HIV infection among exposed individuals, as well as rate of disease progression and the likelihood of viral transmission. Of the genetic variants that have been shown to affect the natural history of HIV infection, the human leukocyte antigen (HLA) class I genes exhibit the strongest and most consistent association, underscoring a central role for CD8+ T cells in resistance to the virus. HLA proteins play important roles in T-cell-mediated adaptive immunity by presenting immunodominant HIV epitopes to cytotoxic T lymphocytes (CTLs) and CD4+ T cells. Genetic and functional data also indicate a function for HLA in natural killer cell-mediated innate immunity against HIV by interacting with killer cell immunoglobulin-like receptors (KIR). We review the HLA and KIR associations with HIV disease and discuss the mechanisms underlying these associations. C1 [Martin, Maureen P.; Carrington, Mary] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, NCI Frederick, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Carrington, M (reprint author), NCI Frederick, Bldg 560,Rm 21-89B Miller Dr, Frederick, MD 21702 USA. EM carringm@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Arman Bashirova for helpful comments. The authors have no conflicts of interest to declare. NR 207 TC 38 Z9 38 U1 0 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 245 EP 264 DI 10.1111/imr.12071 PG 20 WC Immunology SC Immunology GA 164EE UT WOS:000320390900014 PM 23772624 ER PT J AU Swaminathan, S Murray, DD Kelleher, AD AF Swaminathan, Sanjay Murray, Daniel D. Kelleher, Anthony D. TI miRNAs and HIV: unforeseen determinants of host-pathogen interaction SO IMMUNOLOGICAL REVIEWS LA English DT Review DE miRNA; HIV-1; CD4+T cell; monocytes; cytokines; biomarkers ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNA-BINDING PROTEIN; IN-VIVO DELIVERY; CD4(+) T-CELLS; MESSENGER-RNA; MICRORNA EXPRESSION; CELLULAR MICRORNA; CIRCULATING MICRORNAS; SILENCING PATHWAY; POLYMERASE-II AB Our understanding of the complexity of gene regulation has significantly improved in the last decade as the role of small non-coding RNAs, called microRNAs (miRNAs), has been appreciated. These 19-22 nucleotide RNA molecules are critical regulators of mRNA translation and turnover. The miRNAs bind via a protein complex to the 3 untranslated region (3 UTR) of mRNA, ultimately leading to mRNA translational inhibition, degradation, or repression. Although many mechanisms by which human immunodeficiency virus-1 (HIV-1) infection eventually induces catastrophic immune destruction have been elucidated, the important role that miRNAs play in HIV-1 pathogenesis is only now emerging. Accumulating evidence demonstrates that changes to endogenous miRNA levels following infection is important: in maintaining HIV-1 latency in resting CD4+ T cells, potentially affect immune function via changes to cytokines such as interleukin-2 (IL-2) and IL-10 and may predict disease progression. We review the roles that both viral and host miRNAs play in different cell types and disease conditions that are important in HIV-1 infection and discuss how miRNAs affect key immunomodulatory molecules contributing to immune dysfunction. Further, we discuss whether miRNAs may be used as novel biomarkers in serum and the potential to modulate miRNA levels as a unique approach to combating this pathogen. C1 [Swaminathan, Sanjay] Sci Applicat Int Corp SAIC Frederick Inc, Lab Human Retrovirol, Appl & Dev Res Directorate ADD, Frederick Natl Lab Canc Res, Frederick, MD USA. [Murray, Daniel D.; Kelleher, Anthony D.] St Vincents Ctr Appl Med Res, Immunovirol Lab, Darlinghurst, NSW 2010, Australia. [Murray, Daniel D.; Kelleher, Anthony D.] Univ New S Wales, Kirby Inst, Kensington, NSW 2033, Australia. RP Kelleher, AD (reprint author), St Vincents Ctr Appl Med Res, Immunovirol Lab, Kirby Inst, 405 Liverpool St, Darlinghurst, NSW 2010, Australia. EM t.kelleher@amr.org.au OI Swaminathan, Sanjay/0000-0001-5315-6445 FU Australian Government Department of Health and Ageing; National Health and Medical Research Council; Australian Postgraduate Research Scholarship FX This study was supported by the Australian Government Department of Health and Ageing, the National Health and Medical Research Council via a Program Grant, Project Grants, and a practitioner fellowship (to A. D. K.) and an Australian Postgraduate Research Scholarship (to D. M.). The authors report no conflicts of interest. NR 123 TC 17 Z9 17 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 265 EP 280 DI 10.1111/imr.12077 PG 16 WC Immunology SC Immunology GA 164EE UT WOS:000320390900015 PM 23772625 ER PT J AU Klatt, NR Chomont, N Douek, DC Deeks, SG AF Klatt, Nichole R. Chomont, Nicolas Douek, Daniel C. Deeks, Steven G. TI Immune activation and HIV persistence: implications for curative approaches to HIV infection SO IMMUNOLOGICAL REVIEWS LA English DT Review DE AIDS; immunodeficiency diseases; cell activation; cell differentiation; cell proliferation; inflammation ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMACYTOID DENDRITIC CELLS; TISSUE FACTOR EXPRESSION; INNATE LYMPHOID-CELLS; CHRONIC SIV INFECTION; NATURAL-KILLER-CELL; MICROBIAL TRANSLOCATION; VIRAL REPLICATION AB Despite complete or near-complete suppression of human immunodeficiency virus (HIV) replication with combination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persist indefinitely. Untangling the association between the virus and the host immune environment during therapy might lead to novel interventions aimed at either curing the infection or preventing the development of inflammation-associated end-organ disease. Chronic inflammation and immune dysfunction might lead to HIV persistence by causing virus production, generating new target cells, enabling infecting of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms from function. Chronic HIV production or replication might contribute to persistent inflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that a vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence. C1 [Klatt, Nichole R.] Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Chomont, Nicolas] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. [Douek, Daniel C.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94110 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, Sch Med, Dept Med, San Francisco Gen Hosp, Bldg 80,1001 Potrero Ave, San Francisco, CA 94110 USA. EM sdeeks@php.ucsf.edu FU National Institute of Allergy and Infectious Diseases [R01 AI087145, K24 AI069994]; DARE: Delaney AIDS Research Enterprise (DARE) [U19AI096109]; American Foundation for AIDS Research (amfAR); Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R01 AI087145, K24 AI069994), the DARE: Delaney AIDS Research Enterprise (DARE; U19AI096109), the American Foundation for AIDS Research (amfAR), and the Intramural Program of the National Institute of Allergy and Infectious Diseases. The authors have no conflicts of interest to declare. NR 238 TC 86 Z9 87 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 326 EP 342 DI 10.1111/imr.12065 PG 17 WC Immunology SC Immunology GA 164EE UT WOS:000320390900019 PM 23772629 ER PT J AU Wilson, EMP Sereti, I AF Wilson, Eleanor M. P. Sereti, Irini TI Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs SO IMMUNOLOGICAL REVIEWS LA English DT Review DE IRIS; monocytes; macrophages; AIDS; T cells; cytokines ID RECONSTITUTION INFLAMMATORY SYNDROME; HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RECOVERY; CHRONIC HIV-INFECTION; SUSTAINED VIROLOGICAL SUPPRESSION; RANDOMIZED CONTROLLED-TRIAL; LYMPHOID-TISSUE STRUCTURE; WHITE-NOSE SYNDROME; RISK-FACTORS; HIV-1-INFECTED PATIENTS AB Antiretroviral therapy (ART) is a life-saving intervention in human immunodeficiency virus (HIV) infection. Immune restoration after ART dramatically reduces the incidence and severity of opportunistic diseases and death. On some occasions, immune restoration may be erratic, leading to acute inflammatory responses (known as immune reconstitution inflammatory syndrome) shortly after ART initiation, or incomplete, with residual inflammation despite chronic treatment, leading to non-infectious morbidity and mortality. We propose that ART may not always restore the perfect balance of innate and adaptive immunity in strategic milieus, predisposing HIV-infected persons to complications of acute or chronic inflammation. The best current strategy for fully successful immune restoration is early antiretroviral therapy, which can prevent acquired immunodeficiency syndrome (AIDS)-associated events, restrict cell subset imbalances and dysfunction, while preserving structural integrity of lymphoid tissues. Future HIV research should capitalize on innovative techniques and move beyond the static study of T-cell subsets in peripheral blood or isolated tissues. Improved targeted therapeutic strategies could stem from a better understanding of how HIV perturbs the environmental niches and the mobility and trafficking of cells that affect the dynamic cell-to-cell interactions and determine the outcome of innate and adaptive immune responses. C1 [Wilson, Eleanor M. P.; Sereti, Irini] NIAID, HIV Pathogenesis Unit, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), 10 Ctr Dr,Bldg 10,Room 11B-07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov OI Wilson, Eleanor/0000-0002-4855-514X FU NIAID/NIH FX This study was supported by the Intramural Research Program of NIAID/NIH. The authors have no conflicts of interest to declare. NR 131 TC 20 Z9 20 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 343 EP 354 DI 10.1111/imr.12064 PG 12 WC Immunology SC Immunology GA 164EE UT WOS:000320390900020 PM 23772630 ER PT J AU Ittiprasert, W Miller, A Su, XZ Mu, JB Bhusudsawang, G Ukoskit, K Knight, M AF Ittiprasert, Wannaporn Miller, Andre Su, Xin-zhuan Mu, Jianbing Bhusudsawang, Ganlayarat Ukoskit, Kitipat Knight, Matty TI Identification and characterisation of functional expressed sequence tags-derived simple sequence repeat (eSSR) markers for genetic linkage mapping of Schistosoma mansoni juvenile resistance and susceptibility loci in Biomphalaria glabrata SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Expressed sequence tags; Genetic linkage mapping; Resistance; Susceptibility; Biomphalaria glabrata; Schistosoma mansoni ID FIBRINOGEN-RELATED PROTEINS; SNAIL HOST; INFECTION; HEMOCYTES; GENOME; COMPATIBILITY; CONSTRUCTION; INVERTEBRATE; MODEL; BURST AB Biomphalaria glabrata susceptibility to Schistosoma mansoni has a strong genetic component, offering the possibility for investigating host-parasite interactions at the molecular level, perhaps leading to novel control approaches. The identification, mapping and molecular characterisation of genes that influence the outcome of parasitic infection in the intermediate snail host is, therefore, seen as fundamental to the control of schistosomiasis. To better understand the evolutionary processes driving disease resistance/susceptibility phenotypes, we previously identified polymorphic random amplification of polymorphic DNA and genomic simple sequence repeats from B. glabrata. In the present study we identified and characterised polymorphic expressed simple sequence repeats markers (Bg-eSSR) from existing B. glabrata expressed sequence tags. Using these markers, and with previously identified genomic simple sequence repeats, genetic linkage mapping for parasite refractory and susceptibility phenotypes, the first known for B. glabrata, was initiated. Data mining of 54,309 expressed sequence tag, produced 660 expressed simple sequence repeats of which dinucleotide motifs (TA)(n) were the most common (37.88%), followed by trinucleotide (29.55%), mononucleotide (18.64%) and tetranucleotide (10.15%). Penta- and hexanucleotide motifs represented <3% of the Bg-eSSRs identified. While the majority (71%) of Bg-eSSRs were monomorphic between resistant and susceptible snails, several were, however, useful for the construction of a genetic linkage map based on their inheritance in segregating F2 progeny snails derived from crossing juvenile BS-90 and. NMRI snails. Polymorphic Bg-eSSRs assorted into six linkage groups at a logarithm of odds score of 3. Interestingly, the heritability of four markers (Prim1_910, Prim1_771, Prim6_1024 and Prim7_823) with juvenile snail resistance were, by t-test, significant (P < 0.05) while an allelic marker, Prim24_524, showed linkage with the juvenile snail susceptibility phenotype. On the basis of our results it is possible that the gene(s) controlling juvenile resistance and susceptibility to S. mansoni infection in B. glabrata are not only on the same linkage group but lie within a short distance (42 cM) of each other. (C) 2013 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. C1 [Ittiprasert, Wannaporn; Miller, Andre; Knight, Matty] Biomed Res Inst, Rockville, MD 20852 USA. [Su, Xin-zhuan; Mu, Jianbing] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Bhusudsawang, Ganlayarat; Ukoskit, Kitipat] Thammasat Univ, Fac Sci & Technol, Pathum Thani, Thailand. RP Knight, M (reprint author), Biomed Res Inst, 12111 Parklawn Dr, Rockville, MD 20852 USA. EM matty_knight@gwu.edu OI Su, Xinzhuan/0000-0003-3246-3248 FU National Institute of Allergy and Infectious Diseases, National Institute of Health, USA [R01-AI063480]; Intramural Research Program of the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institute of Health FX This work was supported by a grant from the National Institute of Allergy and Infectious Diseases, National Institute of Health, USA, R01-AI063480 and the Intramural Research Program of the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institute of Health. We are grateful to Ms Frances Barnes for technical support and to Dr. Fred Lewis for his helpful editing of the manuscript. We also thank Drs. Nithya Raghavan and Peter FitzGerald for their guidance with the determination of SSR sequences for B. glabrata in GenBank. NR 53 TC 5 Z9 5 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD JUL PY 2013 VL 43 IS 8 BP 669 EP 677 DI 10.1016/j.ijpara.2013.03.007 PG 9 WC Parasitology SC Parasitology GA 175MA UT WOS:000321233600007 PM 23643514 ER PT J AU Kaur, G Behrsing, H Parchment, RE Millin, MD Teicher, BA AF Kaur, Gurmeet Behrsing, Holger Parchment, Ralph E. Millin, Myrtle Davis Teicher, Beverly A. TI Analyses of the combination of 6-MP and dasatinib in cell culture SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE 6-mercaptopurine; dasatinib; combination index; isobologram; response surface ID DRUG-COMBINATION; IN-VITRO; INVITRO CULTIVATION; EXPERIMENTAL-DESIGN; BREAST CARCINOMA; HUMAN TUMORS; LUNG-CANCER; LINES; MODEL; P53 AB A major tenet of cancer therapeutics is that combinations of anticancer agents with different mechanisms of action and different toxicities may be effective treatment regimens. Evaluation of additivity/synergy in cell culture may be used to identify drug combination opportunities and to assess risk of additive/synergistic toxicity. The combination of 6-mercaptopurine and dasatinib was assessed for additivity/synergy using the combination index (CI) method and a response surface method in six human tumor cell lines including MCF-7 and MDA-MB-468 breast cancer, NCI-H23 and NCI-H460 non-small cell lung cancer, and A498 and 786-O renal cell cancer, based on two experimental end-points: ATP content and colony formation. Clonal colony formation by human bone marrow CFU-GM was used to assess risk of enhanced toxicity. The concentration ranges tested for each drug were selected to encompass the clinical C-max concentrations. The combination regimens were found to be additive to sub-additive by both methods of data analysis, but synergy was not detected. The non-small cell lung cancer cell lines were the most responsive among the tumor lines tested and the renal cell carcinoma lines were the least responsive. The bone marrows CFU-GM were more sensitive to the combination regimens than were the tumor cell lines. Based upon these data, it appears that the possibility of enhanced efficacy from combining 6-mercaptopurine (6-MP) and dasatinib would be associated with increased risk of severe bone marrow toxicity, so the combination is unlikely to provide a therapeutic advantage for treating solid tumor patients where adequate bone marrow function must be preserved. C1 [Kaur, Gurmeet] Frederick Natl Lab Canc Res, Div Canc Treatment & Diag, Dev Therapeut Program, Mol Pharmacol Branch, Frederick, MD 21702 USA. [Behrsing, Holger; Parchment, Ralph E.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Dev Res Directorate, Lab Invest Toxicol, Frederick, MD 21702 USA. [Millin, Myrtle Davis] NCI, Toxicol & Pharmacol Branch, Rockville, MD 20852 USA. [Teicher, Beverly A.] NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Mol Pharmacol Branch, Rockville, MD 20852 USA. RP Kaur, G (reprint author), Frederick Natl Lab Canc Res, Div Canc Treatments & Diag, Dev Therapeut Program, Mol Pharmacol Branch, 1050 Boyles St,Bldg 321 Room 122, Frederick, MD 21702 USA. EM kaurgu@mail.nih.gov FU Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 55 TC 1 Z9 1 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2013 VL 43 IS 1 BP 13 EP 22 DI 10.3892/ijo.2013.1930 PG 10 WC Oncology SC Oncology GA 172RR UT WOS:000321023100002 PM 23652925 ER PT J AU Hasan, UA Zannetti, C Parroche, P Goutagny, N Malfroy, M Roblot, G Carreira, C Hussain, I Muller, M Taylor-Papadimitriou, J Picard, D Sylla, BS Trinchieri, G Medzhitov, R Tommasino, M AF Hasan, Uzma A. Zannetti, Claudia Parroche, Peggy Goutagny, Nadege Malfroy, Marine Roblot, Guillaume Carreira, Christine Hussain, Ishraq Mueller, Martin Taylor-Papadimitriou, Joyce Picard, Didier Sylla, Bakary S. Trinchieri, Giorgio Medzhitov, Ruslan Tommasino, Massimo TI The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; HISTONE DEACETYLASE INHIBITORS; CERVICAL-CANCER; IMMUNE FUNCTIONS; GENE-EXPRESSION; MOUSE MODEL; ESTROGEN; TLR9; RECOGNITION; SKIN AB Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-kappa Bp50-p65 and ER alpha induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-kappa B and ER alpha in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor. C1 [Hasan, Uzma A.; Carreira, Christine; Sylla, Bakary S.; Tommasino, Massimo] Int Agcy Res Canc, Infect & Canc Biol Grp, F-69008 Lyon, France. [Hasan, Uzma A.; Zannetti, Claudia; Parroche, Peggy; Roblot, Guillaume] Univ Lyon, Ecole Normale Super, INSERM U1111, CIRI,Hosp Civils Lyon,CNRS UMR5308, F-69000 Lyon, France. [Goutagny, Nadege; Malfroy, Marine] Ctr Leon Berard, UMR INSERM CNRS 1052 5286, CRCL, F-69008 Lyon, France. [Hussain, Ishraq] SK Alusteng, Div Vet Biochem FVSc & AH, Kashmir 190006, India. [Mueller, Martin] DKFZ, Programme Infect & Canc, D-69120 Heidelberg, Germany. [Taylor-Papadimitriou, Joyce] Kings Coll London, Sch Med, Guys Hosp, Breast Canc Biol Grp, London SE1 9RT, England. [Picard, Didier] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Medzhitov, Ruslan] Yale Univ, Sch Med, New Haven, CT 06510 USA. RP Hasan, UA (reprint author), Int Agcy Res Canc, Infect & Canc Biol Grp, F-69008 Lyon, France. EM uzma.hasan@inserm.fr; tommasinom@iarc.fr RI hasan, uzma/G-3247-2013; OI Hussain, Ishraq/0000-0001-8449-1617 FU EMBO Fellowship Program; La Ligue Regionale de la Loire contre le Cancer; la Fondation pour la Recherche Medicale; l'Association Research sur la Cancer; CLARA Procan Axe II innate sensors platform, Lyon FX This study was supported by the EMBO Fellowship Program (U.A. Hasan), La Ligue Regionale de la Loire contre le Cancer (U.A. Hasan), la Fondation pour la Recherche Medicale (U.A. Hasan), l'Association Research sur la Cancer (U.A. Hasan), and CLARA Procan Axe II innate sensors platform, Lyon (M. Tommasino). NR 85 TC 32 Z9 32 U1 2 U2 16 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 JUL 1 PY 2013 VL 210 IS 7 BP 1369 EP 1387 DI 10.1084/jem.20122394 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 170NY UT WOS:000320860700006 PM 23752229 ER PT J AU Yang, JJ Zhang, RH Lu, GM Shen, Y Peng, L Zhu, C Cui, M Wang, WD Arnaboldi, P Tang, M Gupta, M Qi, CF Jayaraman, P Zhu, HF Jiang, B Chen, SH He, JCJ Ting, AT Zhou, MM Kuchroo, VK Morse, HC Ozato, K Sikora, AG Xiong, HB AF Yang, Jianjun Zhang, Ruihua Lu, Geming Shen, Yu Peng, Liang Zhu, Chen Cui, Miao Wang, Weidong Arnaboldi, Paul Tang, Meng Gupta, Monica Qi, Chen-Feng Jayaraman, Padmini Zhu, Hongfa Jiang, Bo Chen, Shu-hsia He, John Cijiang Ting, Adrian T. Zhou, Ming-Ming Kuchroo, Vijay K. Morse, Herbert C., III Ozato, Keiko Sikora, Andrew G. Xiong, Huabao TI T cell-derived inducible nitric oxide synthase switches off T(H)17 cell differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; KAPPA-B ACTIVATION; HELPER-CELLS; TH17 CELLS; TGF-BETA; EXPERIMENTAL STROKE; TYROSINE NITRATION; INFLAMMATION; RECEPTOR AB ROR gamma t is necessary for the generation of T(H)17 cells but the molecular mechanisms for the regulation of T(H)17 cells are still not fully understood. We show that activation of CD4(+) T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced T(H)17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dose-dependently reduced the percentage of IL-17-producing CD4(+) T cells. NO mediates nitration of tyrosine residues in ROR gamma t, leading to the suppression of ROR gamma t-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses. C1 [Yang, Jianjun; Zhang, Ruihua; Lu, Geming; Shen, Yu; Peng, Liang; Cui, Miao; Arnaboldi, Paul; Jayaraman, Padmini; Jiang, Bo; Chen, Shu-hsia; He, John Cijiang; Ting, Adrian T.; Sikora, Andrew G.; Xiong, Huabao] Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY 10029 USA. [Jayaraman, Padmini; Sikora, Andrew G.] Mt Sinai Sch Med, Dept Otolaryngol Head & Neck Surg, New York, NY 10029 USA. [Zhu, Hongfa] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Zhou, Ming-Ming] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. [Zhu, Chen; Kuchroo, Vijay K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Wang, Weidong] Cornell Univ, Weill Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10021 USA. [Tang, Meng] Southeast Univ, Sch Publ Hlth, Minist Educ, Key Lab Environm Med & Engn, Nanjing 210009, Jiangsu, Peoples R China. [Gupta, Monica; Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Programs Genom Differentiat, Bethesda, MD 20892 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. RP Xiong, HB (reprint author), Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY 10029 USA. EM Huabao.Xiong@mssm.edu OI Morse, Herbert/0000-0002-9331-3705; Arnaboldi, Paul/0000-0002-4005-4412 FU National Institutes of Health (NIH) [P01 DK072201, R56AI091871]; Broad Medical Research Program of The Broad Foundation; National Natural Science Foundation of China [30972504]; National Important Project on Scientific Research of China [2011CB933404]; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX H. Xiong was supported by the National Institutes of Health (NIH) funding (P01 DK072201 and R56AI091871) and The Broad Medical Research Program of The Broad Foundation. M. Tang was supported by National Natural Science Foundation of China (No. 30972504) and National Important Project on Scientific Research of China (No. 2011CB933404). This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 51 TC 30 Z9 32 U1 0 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 1 PY 2013 VL 210 IS 7 BP 1447 EP 1462 DI 10.1084/jem.20122494 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 170NY UT WOS:000320860700011 PM 23797094 ER PT J AU Zanker, D Waithman, J Yewdell, JW Chen, WS AF Zanker, Damien Waithman, Jason Yewdell, Jonathan W. Chen, Weisan TI Mixed Proteasomes Function To Increase Viral Peptide Diversity and Broaden Antiviral CD8(+) T Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLUENZA-A VIRUS; ANTIGEN PRESENTATION; IMMUNODOMINANCE HIERARCHY; IN-VIVO; IMMUNOGENICITY; EPITOPES; REPERTOIRE; RESIDUES; MEMORY AB The three proteasome subunits with proteolytic activity are encoded by standard or immunoproteasome genes. Many proteasomes expressed by normal cells and cells exposed to cytokines are "mixed", that is, contain both standard and immunoproteasome subunits. Using a panel of 38 defined influenza A virus-derived epitopes recognized by C57BL/6 mouse CD8(+) T cells, we used mice with targeted disruption of beta 1i, beta 2i, or beta 5i/beta 2i genes to examine the contribution of mixed proteasomes to the immunodominance hierarchy of antiviral CD8(+) T cells. We show that each immunoproteasome subunit has large effects on the primary and recall immunodominance hierarchies due to modulating both the available T cell repertoire and generation of individual epitopes as determined both biochemically and kinetically in Ag presentation assays. These findings indicate that mixed proteasomes function to enhance the diversity of peptides and support a broad CD8(+) T cell response. The Journal of Immunology, 2013, 191: 52-59. C1 [Zanker, Damien; Chen, Weisan] La Trobe Univ, Sch Mol Sci, Bundoora, Vic 3086, Australia. [Waithman, Jason] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Perth, WA 6872, Australia. [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Chen, WS (reprint author), La Trobe Univ, Sch Mol Sci, Bundoora, Vic 3086, Australia. EM weisan.chen@latrobe.edu.au OI Zanker, Damien/0000-0003-1163-9902 FU National Health and Medical Research Council [433608, 542508, 567122, 487926, 603100, 603104] FX This work was supported in part by National Health and Medical Research Council Project Grants 433608 and 542508 (to W.C.) and by National Health and Medical Research Council Program Grant 567122. D.Z. was supported by National Health and Medical Research Council Biomedical Postgraduate Scholarship 487926. J.W. is a National Health and Medical Research Council Biomedical Training Fellow (Grant 603100), and W.C. is a National Health and Medical Research Council Senior Research Fellow (Grant 603104). NR 33 TC 19 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 JUL 1 PY 2013 VL 191 IS 1 BP 52 EP 59 DI 10.4049/jimmunol.1300802 PG 8 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000009 PM 23709680 ER PT J AU Sandgren, KJ Smed-Sorensen, A Forsell, MN Soldemo, M Adams, WC Liang, F Perbeck, L Koup, RA Wyatt, RT Hedestam, GBK Lore, K AF Sandgren, Kerrie J. Smed-Sorensen, Anna Forsell, Mattias N. Soldemo, Martina Adams, William C. Liang, Frank Perbeck, Leif Koup, Richard A. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson Lore, Karin TI Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPIDERMAL LANGERHANS CELLS; T-CELLS; ANTIBODY-RESPONSES; CROSS-PRESENTATION; IN-VIVO; DC-SIGN; TRANS-INFECTION; MEDIATED UPTAKE; TYPE-1 GP120 AB Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient Ag uptake and presentation by dendritic cells (DCs) is important for strong CD4(+) Th cell responses and the development of effective humoral immune responses. In this study, we examined the capacity of distinct primary human DC subsets to internalize and present recombinant Env to CD4(+) T cells. Consistent with their specific receptor expression, skin DCs bound and internalized Env via C-type lectin receptors, whereas blood DC subsets, including CD1c(+) myeloid DCs, CD123(+) plasmacytoid DCs (PDCs), and CD141(+) DCs exhibited a restricted repertoire of C-type lectin receptors and relied on CD4 for uptake of Env. Despite a generally poor capacity for Ag uptake compared with myeloid DCs, the high expression of CD4 on PDCs allowed them to bind and internalize Env very efficiently. CD4-mediated uptake delivered Env to EEA1(+) endosomes that progressed to Lamp1(+) and MHC class II+ lysosomes where internalized Env was degraded rapidly. Finally, all three blood DC subsets were able to internalize an Env-CMV pp65 fusion protein via CD4 and stimulate pp65-specific CD4(+) T cells. Thus, in the in vitro systems described in this paper, CD4-mediated uptake of Env is a functional pathway leading to Ag presentation, and this may therefore be a mechanism used by blood DCs, including PDCs, for generating immune responses to Env-based vaccines. The Journal of Immunology, 2013, 191: 60-69. C1 [Sandgren, Kerrie J.; Adams, William C.; Liang, Frank; Lore, Karin] Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, S-14186 Huddinge, Sweden. [Smed-Sorensen, Anna; Soldemo, Martina; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-14186 Huddinge, Sweden. [Forsell, Mattias N.] Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden. [Perbeck, Leif] Karolinska Univ Hosp Solna, Dept Surg, S-17176 Stockholm, Sweden. [Koup, Richard A.; Lore, Karin] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Wyatt, Richard T.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Lore, K (reprint author), Karolinska Inst, Karolinska Univ Hosp Huddinge, Ctr Infect Med, F59, S-14186 Huddinge, Sweden. EM karin.lore@ki.se FU Swedish International Development Agency; Swedish Research Council; Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Society of Medicine; Swedish Society of Medical Research; Fernstrom Foundation; Foundation for AIDS Research (amfAR) in basic biomedical research FX This work was supported by grants from the Swedish International Development Agency (to A.S.-S., G.B.K.H., and K.L.), the Swedish Research Council (to K.L.), and the Swedish Governmental Agency for Innovation Systems (Vinnova) (to K.L.). K.J.S. and F.L. are recipients of scholarships from the Swedish Society of Medicine, the Swedish Society of Medical Research, and the Fernstrom Foundation. M.N.F. is supported by a Mathilde Krim fellowship from The Foundation for AIDS Research (amfAR) in basic biomedical research. NR 69 TC 11 Z9 11 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2013 VL 191 IS 1 BP 60 EP 69 DI 10.4049/jimmunol.1202489 PG 10 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000010 PM 23729440 ER PT J AU Shi, GP Vistica, BP Nugent, LF Tan, CY Wawrousek, EF Klinman, DM Gery, I AF Shi, Guangpu Vistica, Barbara P. Nugent, Lindsey F. Tan, Cuiyan Wawrousek, Eric F. Klinman, Dennis M. Gery, Igal TI Differential Involvement of Th1 and Th17 in Pathogenic Autoimmune Processes Triggered by Different TLR Ligands SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; REGULATORY T-CELLS; RHEUMATOID-ARTHRITIS SYNOVIUM; ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; IMMUNE-RESPONSES; CYTOKINE PRODUCTION; B-CELLS; DISEASE; ACTIVATION AB The interaction between TLRs and their cognate ligands triggers both the innate and adaptive immune systems, and thus can play a pivotal role in the defense against pathogen invasion. This work investigates the differentiation of naive CD4 cells into Th1 or Th17 phenotypes in mice treated with different TLR ligands. We use a model system in which naive transgenic cells specific to hen egg lysozyme are adoptively transferred into recipients that express hen egg lysozyme in the lens of the eye. The transferred naive T cells induce ocular inflammation only in recipients treated with TLR ligands. Treatment with LPS preferentially stimulated IL-17 production, whereas CpG oligodeoxynucleotide and polyinosinic: polycytidylic acid primarily stimulated Th1 cells. Peptidoglycan stimulated the two Th subpopulations equally. The preferential induction of Th1 or Th17 by the four ligands was detected in the spleen (where a major portion of the adoptively transferred cells homed) and in the eyes, where activated Th cells initiate inflammation. Analysis of the cytokines present in recipient mice suggests that Th1 induction is elicited by IL-12 and/or IFN-alpha, whereas Th17 generation is preferentially mediated by IL-6. Importantly, we show in this article that treatment with LPS selectively promoted in the recipient mice the generation of IL-6-producing activated B cells. An inverse correlation was found between the level of regulatory T cells and severity of inflammation induced by the donor cells. Taken together, our data show that specific TLR ligands differentially activate the immune system as evidenced by the generation of distinct Th phenotypes from naive CD4 cells. C1 [Shi, Guangpu; Vistica, Barbara P.; Nugent, Lindsey F.; Tan, Cuiyan; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wawrousek, Eric F.] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 42 TC 15 Z9 16 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 JUL 1 PY 2013 VL 191 IS 1 BP 415 EP 423 DI 10.4049/jimmunol.1201732 PG 9 WC Immunology SC Immunology GA 169FQ UT WOS:000320765000047 PM 23720812 ER PT J AU Ramos, VFML Karp, BI Lungu, C Alter, K Hallett, M AF Ramos, V. F. M. L. Karp, B., I Lungu, C. Alter, K. Hallett, M. TI Response to incobotulinumtoxinA after resistance to onabotulinumtoxinA and rimabotulinumtoxinB SO JOURNAL OF NEURAL TRANSMISSION LA English DT Meeting Abstract CT 2nd International Congress on Treatment of Dystonia together with the 1st International Congress on Rehabilitation of Dystonia CY MAY 08-11, 2013 CL Hannover, GERMANY C1 [Ramos, V. F. M. L.; Karp, B., I; Lungu, C.; Hallett, M.] NIH, Bethesda, MD 20892 USA. [Alter, K.] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Alter, K.] Mt Washington Pediat Hosp, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD JUL PY 2013 VL 120 IS 7 BP 1153 EP 1153 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169RV UT WOS:000320798800061 ER PT J AU Ramos, VFML Karp, BI Hallett, M AF Ramos, V. F. M. L. Karp, B., I Hallett, M. TI Tricks to treatments: sensory tricks in dystonia SO JOURNAL OF NEURAL TRANSMISSION LA English DT Meeting Abstract CT 2nd International Congress on Treatment of Dystonia together with the 1st International Congress on Rehabilitation of Dystonia CY MAY 08-11, 2013 CL Hannover, GERMANY C1 [Ramos, V. F. M. L.; Karp, B., I; Hallett, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD JUL PY 2013 VL 120 IS 7 BP 1153 EP 1153 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169RV UT WOS:000320798800060 ER PT J AU Penzes, P Buonanno, A Passafaro, M Sala, C Sweet, RA AF Penzes, Peter Buonanno, Andres Passafaro, Maria Sala, Carlo Sweet, Robert A. TI Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE Alzheimer's disease; autism; dendritic spine; dopamine; ErbB4; GABAergic interneuron ID LINKED MENTAL-RETARDATION; AUTISM SPECTRUM DISORDER; CENTRAL-NERVOUS-SYSTEM; PARVALBUMIN-POSITIVE INTERNEURONS; HIPPOCAMPAL GAMMA OSCILLATIONS; DENDRITIC SPINE MORPHOGENESIS; GLUTAMIC-ACID DECARBOXYLASE; 22Q13.3 DELETION SYNDROME; INCREASED FAMILIAL RISK; EARLY-ONSET PSYCHOSIS AB Psychiatric and neurodegenerative disorders, including intellectual disability, autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease, pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance - modulated largely by dopamine - critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here, we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan. C1 [Penzes, Peter] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Penzes, Peter] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Buonanno, Andres] Eunice Shriver Kennedy NICHD, Mol Neurobiol Sect, NIH, Program Dev Neurobiol, Bethesda, MD USA. [Passafaro, Maria; Sala, Carlo] Univ Milan, CNR Inst Neurosci, Milan, Italy. [Passafaro, Maria; Sala, Carlo] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy. [Passafaro, Maria] CNR, Inst Neurosci, Dulbecco Telethon Inst, I-20133 Milan, Italy. [Sala, Carlo] Neurol Inst, Milan, Italy. [Sala, Carlo] Fdn Carlo Besta, Milan, Italy. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. RP Penzes, P (reprint author), Northwestern Univ, Dept Physiol, Feinberg Sch Med, 303 E,Chicago Ave, Chicago, IL 60611 USA. EM p-penzes@northwestern.edu RI Penzes, Peter/L-3987-2016; Sala, Carlo/A-2493-2009 OI Penzes, Peter/0000-0001-5449-1640; Sala, Carlo/0000-0003-0662-9523 FU NIH [MH071316, MH097216, MH071533, AG027224]; Eunice Shriver Kennedy National Institute of Child Health and Human Development Intramural Research Program; Veterans Health Administration [BX000452]; Comitato Telethon Fondazione Onlus [GGP09196, GGP11095, GGP12097, GGP11116B]; Fondazione CARI-PLO project [2009.264]; Italian Institute of Technology, Seed Grant, Ministry of Health in the frame of ERA-NET NEURON and PNR-CNR Aging Program FX This study was supported by NIH grants MH071316 and MH097216 to P. P., Eunice Shriver Kennedy National Institute of Child Health and Human Development Intramural Research Program to A. B., Veterans Health Administration Grant BX000452 and NIH Grants MH071533 and AG027224 to R. A. S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs, the National Institutes of Health, or the United States government. We thank Ruoqi Gao for assistance with editing the manuscript. This study was financially supported by Comitato Telethon Fondazione Onlus, grant n. GGP09196 and GGP11095 (to CS), n. GGP12097 and GGP11116B (to MP) Fondazione CARI-PLO project number 2009.264, Italian Institute of Technology, Seed Grant, Ministry of Health in the frame of ERA-NET NEURON and PNR-CNR Aging Program 2012-2014 (to CS). The authors declare no conflicts of interest. NR 217 TC 40 Z9 41 U1 5 U2 28 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 JUL PY 2013 VL 126 IS 2 BP 165 EP 182 DI 10.1111/jnc.12261 PG 18 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 175DY UT WOS:000321211700004 PM 23574039 ER PT J AU Whiting, DM Tomycz, ND Bailes, J de Jonge, L Lecoultre, V Wilent, B Alcindor, D Prostko, ER Cheng, BC Angle, C Cantella, D Whiting, BB Mizes, JS Finnis, KW Ravussin, E Oh, MY AF Whiting, Donald M. Tomycz, Nestor D. Bailes, Julian de Jonge, Lilian Lecoultre, Virgile Wilent, Bryan Alcindor, Dunbar Prostko, E. Richard Cheng, Boyle C. Angle, Cynthia Cantella, Diane Whiting, Benjamin B. Mizes, J. Scott Finnis, Kirk W. Ravussin, Eric Oh, Michael Y. TI Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism Clinical article SO JOURNAL OF NEUROSURGERY LA English DT Article DE obesity; weight loss; deep brain stimulation; energy metabolism; functional neurosurgery; respiratory chamber ID VENTROMEDIAL HYPOTHALAMUS; RATS; LESIONS; PREVALENCE; OVERWEIGHT; HUMANS; GAIN AB Object. Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans. Methods. Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, underwent bilateral implantation of LHA DBS electrodes as part of an institutional review board and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism. Results. No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30-39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber. Conclusions. Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first "proof of principle" for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy. C1 [Whiting, Donald M.; Tomycz, Nestor D.; Alcindor, Dunbar; Prostko, E. Richard; Cheng, Boyle C.; Angle, Cynthia; Cantella, Diane; Whiting, Benjamin B.; Oh, Michael Y.] Allegheny Gen Hosp, Dept Neurosurg, Pittsburgh, PA 15212 USA. [Lecoultre, Virgile; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Wilent, Bryan] Sentient Med Syst, Clin Neurophysiol, Philadelphia, PA USA. [Mizes, J. Scott] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. [Bailes, Julian] Univ Chicago, Pritzker Sch Med, NorthShore Univ Hlth Syst, Evanston, IL USA. [de Jonge, Lilian] NIH, Bethesda, MD 20892 USA. [Finnis, Kirk W.] Medtron Neuromodulat, Minneapolis, MN USA. RP Tomycz, ND (reprint author), Allegheny Gen Hosp, 420 East North Ave,Suite 302, Pittsburgh, PA 15212 USA. EM ndtomycz@gmail.com FU Medtronic Co.; West Virginia University FX Medtronic Co. provided DBS hardware and financial support for this study. Medtronic Co. was not involved in preparation or submission of the manuscript. West Virginia University supplied grant support for this study. Dr. Tomycz participated on the Surgeon Advisory Board for St. Jude. Dr. Finnis is an employee of Medtronic. Dr. Oh is a consultant for St. Jude. NR 21 TC 33 Z9 34 U1 1 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2013 VL 119 IS 1 BP 56 EP 63 DI 10.3171/2013.2.JNS12903 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 168WT UT WOS:000320739300015 PM 23560573 ER PT J AU Johnson, KA Minoshima, S Bohnen, NI Donohoe, KJ Foster, NL Herscovitch, P Karlawish, JH Rowe, CC Hedrick, S Pappas, V Carrillo, MC Hartley, DM AF Johnson, Keith A. Minoshima, Satoshi Bohnen, Nicolaas I. Donohoe, Kevin J. Foster, Norman L. Herscovitch, Peter Karlawish, Jason H. Rowe, Christopher C. Hedrick, Saima Pappas, Virginia Carrillo, Maria C. Hartley, Dean M. TI Update on Appropriate Use Criteria for Amyloid PET Imaging: Dementia Experts, Mild Cognitive Impairment, and Education SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE amyloid PET; dementia; Alzheimer disease ID ALZHEIMERS ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; RECOMMENDATIONS; DISEASE AB Amyloid PET imaging is a novel diagnostic test that can detect in living humans one of the two defining pathologic lesions of Alzheimer disease, amyloid-beta deposition in the brain. The Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging previously published appropriate use criteria for amyloid PET as an important tool for increasing the certainty of a diagnosis of Alzheimer disease in specific patient populations. Here, the task force further clarifies and expands 3 topics discussed in the original paper: first, defining dementia experts and their use of proper documentation to demonstrate the medical necessity of an amyloid PET scan; second, identifying a specific subset of individuals with mild cognitive impairment for whom an amyloid PET scan is appropriate; and finally, developing educational programs to increase awareness of the amyloid PET appropriate use criteria and providing instructions on how this test should be used in the clinical decision-making process. C1 [Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Minoshima, Satoshi] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Bohnen, Nicolaas I.] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Donohoe, Kevin J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Foster, Norman L.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Karlawish, Jason H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Melbourne, Vic, Australia. [Rowe, Christopher C.] Austin Hlth, Ctr PET, Melbourne, Vic, Australia. [Hedrick, Saima; Pappas, Virginia] Soc Nucl Med & Mol Imaging, Reston, VA USA. [Carrillo, Maria C.; Hartley, Dean M.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60601 USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Div Med & Sci Relat, 225 N Michigan Ave, Chicago, IL 60601 USA. EM maria.carrillo@alz.org FU NIA NIH HHS [P30 AG010124] NR 4 TC 19 Z9 19 U1 0 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL 1 PY 2013 VL 54 IS 7 BP 1011 EP 1013 DI 10.2967/jnumed.113.127068 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 173WR UT WOS:000321113500005 PM 23753186 ER PT J AU Gill, JM Saligan, L Lee, H Rotolo, S Szanton, S AF Gill, Jessica M. Saligan, Leorey Lee, Hyunhwa Rotolo, Susan Szanton, Sarah TI Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls (vol 74, pg 301, 2013) SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Correction C1 [Gill, Jessica M.; Saligan, Leorey; Lee, Hyunhwa] NINR, NIH, Bethesda, MD 20892 USA. [Gill, Jessica M.] George Mason Univ, Sch Nursing, Fairfax, VA 22030 USA. [Szanton, Sarah] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 USA. RP Gill, JM (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM jgill1376@yahoo.com NR 1 TC 0 Z9 0 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD JUL PY 2013 VL 75 IS 1 BP 92 EP 92 DI 10.1016/j.jpsychores.2013.03.012 PG 1 WC Psychiatry SC Psychiatry GA 170CF UT WOS:000320826500017 ER PT J AU Madden, JT Toth, SJ Dettmar, CM Newman, JA Oglesbee, RA Hedderich, HG Everly, RM Becker, M Ronau, JA Buchanan, SK Cherezov, V Morrow, ME Xu, SL Ferguson, D Makarov, O Das, C Fischetti, R Simpson, GJ AF Madden, Jeremy T. Toth, Scott J. Dettmar, Christopher M. Newman, Justin A. Oglesbee, Robert A. Hedderich, Hartmut G. Everly, R. Michael Becker, Michael Ronau, Judith A. Buchanan, Susan K. Cherezov, Vadim Morrow, Marie E. Xu, Shenglan Ferguson, Dale Makarov, Oleg Das, Chittaranjan Fischetti, Robert Simpson, Garth J. TI Integrated nonlinear optical imaging microscope for on-axis crystal detection and centering at a synchrotron beamline SO JOURNAL OF SYNCHROTRON RADIATION LA English DT Article DE XRD; NLO; SHG; SONICC; centering; protein; TPE-UVF; microscopy; LCP; two-photon ID X-RAY-DIFFRACTION; THROUGHPUT MACROMOLECULAR CRYSTALLOGRAPHY; PROTEIN CRYSTALS; LIPIDIC MESOPHASES; MEMBRANE-PROTEINS; RADIATION-DAMAGE; FLUORESCENCE; CRYSTALLIZATION; PHOTODAMAGE; SCATTERING AB Nonlinear optical (NLO) instrumentation has been integrated with synchrotron X-ray diffraction (XRD) for combined single-platform analysis, initially targeting applications for automated crystal centering. Second-harmonic-generation microscopy and two-photon-excited ultraviolet fluorescence microscopy were evaluated for crystal detection and assessed by X-ray raster scanning. Two optical designs were constructed and characterized; one positioned downstream of the sample and one integrated into the upstream optical path of the diffractometer. Both instruments enabled protein crystal identification with integration times between 80 and 150 ms per pixel, representing a similar to 10(3)-10(4)-fold reduction in the per-pixel exposure time relative to X-ray raster scanning. Quantitative centering and analysis of phenylalanine hydroxylase from Chromobacterium violaceum cPAH, Trichinella spiralis deubiquitinating enzyme TsUCH37, human kappa-opioid receptor complex kOR-T4L produced in lipidic cubic phase (LCP), intimin prepared in LCP, and alpha-cellulose samples were performed by collecting multiple NLO images. The crystalline samples were characterized by single-crystal diffraction patterns, while alpha-cellulose was characterized by fiber diffraction. Good agreement was observed between the sample positions identified by NLO and XRD raster measurements for all samples studied. C1 [Madden, Jeremy T.; Toth, Scott J.; Dettmar, Christopher M.; Newman, Justin A.; Oglesbee, Robert A.; Hedderich, Hartmut G.; Everly, R. Michael; Ronau, Judith A.; Morrow, Marie E.; Das, Chittaranjan; Simpson, Garth J.] Purdue Univ, Dept Chem, W Lafayette, IN 47906 USA. [Becker, Michael; Xu, Shenglan; Ferguson, Dale; Makarov, Oleg; Fischetti, Robert] Argonne Natl Lab, Adv Photon Source, GM CA APS, Argonne, IL 60439 USA. [Buchanan, Susan K.] NIDDK, NIH, Bethesda, MD 20814 USA. [Cherezov, Vadim] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Simpson, GJ (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47906 USA. EM gsimpson@purdue.edu RI Cherezov, Vadim/L-9812-2013 OI Cherezov, Vadim/0000-0002-5265-3914 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0000997]; NIH-NIGMS [R01GM-103401]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; NIH [P50 GM073197]; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX The authors acknowledge Huixian Wu, Victoria J. Hall, Emma L. DeWalt, Valerie Pye, Martin Caffrey, Nicholas Noinaj and James W. Fairman for aiding in sample preparation. Instrumentation development was supported in part by the Center for Direct Catalytic Conversion of Biomass to Biofuels (C3Bio), an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, Award No. DE-SC0000997, and by the NIH-NIGMS through the R01GM-103401. GM/CA@APS has been funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. Support is also acknowledged from the NIH Common Fund in Structural Biology, grant P50 GM073197. SKB is supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 46 TC 15 Z9 15 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0909-0495 J9 J SYNCHROTRON RADIAT JI J. Synchrot. Radiat. PD JUL PY 2013 VL 20 BP 531 EP 540 DI 10.1107/S0909049513007942 PN 4 PG 10 WC Instruments & Instrumentation; Optics; Physics, Applied SC Instruments & Instrumentation; Optics; Physics GA 163UZ UT WOS:000320363700003 PM 23765294 ER PT J AU McDermott, A Jesus, AA Liu, Y Kim, P Jacks, J Sanchez, GAM Chen, YQ Kannan, A Schnebelen, A Emanuel, PD Shalin, S Hiatt, K Goldbach-Mansky, R Gao, L AF McDermott, Amelia Jesus, Adriana Almeida Liu, Yin Kim, Peter Jacks, Jennifer Sanchez, Gina A. Montealegre Chen, Yongqing Kannan, Aarthi Schnebelen, Alicia Emanuel, Peter D. Shalin, Sara Hiatt, Kim Goldbach-Mansky, Raphaela Gao, Ling TI A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID SUBUNIT; LIPODYSTROPHY C1 [McDermott, Amelia] Univ Arkansas Med Sci, Coll Med, Little Rock, AR 72205 USA. [Kannan, Aarthi; Gao, Ling] Univ Arkansas Med Sci, Dept Dermatol, Little Rock, AR 72205 USA. [Schnebelen, Alicia; Shalin, Sara] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. [Emanuel, Peter D.] Univ Arkansas Med Sci, Div Hematol Oncol, Little Rock, AR 72205 USA. [Jesus, Adriana Almeida; Liu, Yin; Kim, Peter; Sanchez, Gina A. Montealegre; Chen, Yongqing; Goldbach-Mansky, Raphaela] NIAMSD, Bethesda, MD 20892 USA. [Jacks, Jennifer] Jacks Dermatol, Pine Bluff, AR USA. [Hiatt, Kim] Dermatol PLLC PA, Little Rock, AR USA. RP Gao, L (reprint author), Univ Arkansas Med Sci, Dept Dermatol, 4301 W Markham,Slot 576, Little Rock, AR 72205 USA. EM LGAO@uams.edu OI Hiatt, Kim/0000-0003-3214-4917; Emanuel, Peter/0000-0002-9764-2434 FU Intramural NIH HHS [ZIA AR041138-08, ZIA AR041138-09, ZIA AR041138-10] NR 5 TC 6 Z9 6 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2013 VL 69 IS 1 BP E29 EP E32 DI 10.1016/j.jaad.2013.01.015 PG 5 WC Dermatology SC Dermatology GA 165UG UT WOS:000320510100011 PM 23768303 ER PT J AU Osinusi, A Naggie, S AF Osinusi, Anuoluwapo Naggie, Susanna TI Boceprevir for HCV in patients with HIV: where next? SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID CHRONIC HEPATITIS-C; ALPHA-2A PLUS RIBAVIRIN; GENOTYPE 1 INFECTION; VIRUS C1 [Osinusi, Anuoluwapo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Naggie, Susanna] Duke Univ, Med Ctr, Div Infect Dis, Durham, NC 27710 USA. RP Osinusi, A (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM susanna.naggie@duke.edu NR 15 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2013 VL 13 IS 7 BP 563 EP 564 DI 10.1016/S1473-3099(13)70162-2 PG 2 WC Infectious Diseases SC Infectious Diseases GA 172UN UT WOS:000321030500004 PM 23768748 ER PT J AU Redd, AD Quinn, TC Tobian, AAR AF Redd, Andrew D. Quinn, Thomas C. Tobian, Aaron A. R. TI Frequency and implications of HIV superinfection SO LANCET INFECTIOUS DISEASES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTION-DRUG USERS; TYPE-1 SUPERINFECTION; PRIMARY INFECTION; VIRAL LOAD; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; MALE CIRCUMCISION; AMSTERDAM COHORT; SEXUAL-BEHAVIOR AB HIV superinfection occurs when an individual with HIV is infected with a new distinct HIV viral strain. Superinfection has been reported throughout the world, and studies have recorded incidence rates of 0-7-7% per year. Use of next-generation sequencing has improved detection of superinfection, which can be transmitted by injecting drug use and sexual intercourse. Superinfection might have incidence rates comparable to those of initial HIV infection. Clinicians should encourage safe sexual and injecting drug use practices for HIV-infected patients because superinfection has detrimental effects on clinical outcomes and could pose a concern for large-scale antiretroviral treatment plans. The occurrence of superinfection has implications for vaccine research, since it seems initial HIV infection is not fully protective against a subsequent infection. Additional collaborative research could benefit care of patients and inform future vaccine design. C1 [Redd, Andrew D.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 North Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU NIH [1K23AI093152-01A1]; Doris Duke Charitable Foundation Clinician Scientist Development Award [22006.02]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX AART is supported by the NIH (1K23AI093152-01A1) and Doris Duke Charitable Foundation Clinician Scientist Development Award (#22006.02). ADR and TCQ are supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. These funding sources had no involvement in the writing of the manuscript or the decision to submit it for publication. NR 73 TC 34 Z9 37 U1 0 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2013 VL 13 IS 7 BP 622 EP 628 DI 10.1016/S1473-3099(13)70066-5 PG 7 WC Infectious Diseases SC Infectious Diseases GA 172UN UT WOS:000321030500022 PM 23726798 ER PT J AU Scalzo, F Alger, JR Hu, X Saver, JL Dani, KA Muir, KW Demchuk, AM Coutts, SB Luby, M Warach, S Liebeskind, DS AF Scalzo, Fabien Alger, Jeffry R. Hu, Xiao Saver, Jeffrey L. Dani, Krishna A. Muir, Keith W. Demchuk, Andrew M. Coutts, Shelagh B. Luby, Marie Warach, Steven Liebeskind, David S. CA STIR VISTA Imaging Investigators TI Multi-center prediction of hemorrhagic transformation in acute ischemic stroke using permeability imaging features SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Brain ischemia; Hemorrhagic transformation; Prediction; Acute stroke diagnostic; Stroke; Permeability ID BRAIN-BARRIER-PERMEABILITY; TISSUE FATE; THROMBOLYSIS; MODEL; MRI AB Permeability images derived from magnetic resonance (MR) perfusion images are sensitive to blood brain barrier derangement of the brain tissue and have been shown to correlate with subsequent development of hemorrhagic transformation (HT) in acute ischemic stroke. This paper presents a multi-center retrospective study that evaluates the predictive power in terms of HT of six permeability MRI measures including contrast slope (CS), final contrast (FC), maximum peak bolus concentration (MPB), peak bolus area (PB), relative recirculation (rR), and percentage recovery (%R). Dynamic T2*-weighted perfusion MR images were collected from 263 acute ischemic stroke patients from four medical centers. An essential aspect of this study is to exploit a classifier-based framework to automatically identify predictive patterns in the overall intensity distribution of the permeability maps. The model is based on normalized intensity histograms that are used as input features to the predictive model. Linear and nonlinear predictive models are evaluated using a cross-validation to measure generalization power on new patients and a comparative analysis is provided for the different types of parameters. Results demonstrate that perfusion imaging in acute ischemic stroke can predict HT with an average accuracy of more than 85% using a predictive model based on a nonlinear regression model. Results also indicate that the permeability feature based on the percentage of recovery performs significantly better than the other features. This novel model may be used to refine treatment decisions in acute stroke. (c) 2013 Elsevier Inc. All rights reserved. C1 [Scalzo, Fabien; Alger, Jeffry R.; Saver, Jeffrey L.; Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Hu, Xiao] Univ Calif Los Angeles, Neurosurg Neural Syst & Dynam Lab NSDL, Los Angeles, CA USA. [Dani, Krishna A.; Muir, Keith W.] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QQ, Lanark, Scotland. [Demchuk, Andrew M.; Coutts, Shelagh B.] Univ Calgary, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB, Canada. [Demchuk, Andrew M.; Coutts, Shelagh B.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Luby, Marie; Warach, Steven] NIH, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Scalzo, F (reprint author), Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. EM fabien.scalzo@gmail.com RI Muir, Keith/A-7670-2011; OI Muir, Keith/0000-0001-9535-022X; Saver, Jeffrey/0000-0001-9141-2251 FU National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health [K23-NS054084, P50-NS044378, R01-NS066008]; Canadian Institutes for Health Research (CIHR) [MOP-118096]; Heart and Stroke Foundation (HSF) of Alberta; NWT; Nunavut FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), grants from the National Institutes of Health K23-NS054084, P50-NS044378, R01-NS066008, and the Canadian Institutes for Health Research (CIHR MOP-118096) and Heart and Stroke Foundation (HSF) of Alberta, NWT and Nunavut. STIR and VISTA Imaging steering committee: Steven Warach (co-chair), Gregory Albers, Stephen Davis, Geoffrey Donnan, Marc Fisher, Tony Furlan, James Grotta, Werner Hacke, Dong-Wha Kang, Chelsea Kidwell, Walter Koroshetz, Kennedy R. Lees, Michael Lev, David Liebeskind, A. Gregory Sorensen, Vincent Thijs, Gotz Thomalla, Joanna Wardlaw, Max Wintermark (co-chair). NR 31 TC 12 Z9 13 U1 0 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2013 VL 31 IS 6 BP 961 EP 969 DI 10.1016/j.mri.2013.03.013 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ZF UT WOS:000320818600020 PM 23587928 ER PT J AU Lopez, G Sidransky, E AF Lopez, Grisel Sidransky, Ellen TI Predicting parkinsonism: New opportunities from Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Editorial Material DE Parkinson disease; Gaucher disease; Presymptomatic; Optical coherence tomography; Glucocerebrosidase; Biomarker C1 [Lopez, Grisel; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 14 TC 1 Z9 1 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2013 VL 109 IS 3 BP 235 EP 236 DI 10.1016/j.ymgme.2013.04.012 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 170DB UT WOS:000320829000001 PM 23665160 ER PT J AU Kano, S Colantuoni, C Han, F Zhou, Z Yuan, Q Wilson, A Takayanagi, Y Lee, Y Rapoport, J Eaton, W Cascella, N Ji, H Goldman, D Sawa, A AF Kano, S. Colantuoni, C. Han, F. Zhou, Z. Yuan, Q. Wilson, A. Takayanagi, Y. Lee, Y. Rapoport, J. Eaton, W. Cascella, N. Ji, H. Goldman, D. Sawa, A. TI Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Letter ID CHIP-SEQ DATA C1 [Kano, S.; Colantuoni, C.; Wilson, A.; Cascella, N.; Sawa, A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Colantuoni, C.; Han, F.; Ji, H.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Takayanagi, Y.; Eaton, W.] Johns Hopkins Univ, Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Lee, Y.; Rapoport, J.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM asawa1@jhmi.edu RI Goldman, David/F-9772-2010; Kano, Shin-ichi/F-4144-2015 OI Goldman, David/0000-0002-1724-5405; Kano, Shin-ichi/0000-0002-5171-3436 FU Intramural NIH HHS [Z01 AA000301-09]; NIMH NIH HHS [K99 MH093458] NR 10 TC 34 Z9 34 U1 0 U2 2 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 JUL PY 2013 VL 18 IS 7 BP 740 EP 742 DI 10.1038/mp.2012.120 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700001 PM 22925834 ER PT J AU Kano, S Colantuoni, C Han, F Zhou, Z Yuan, Q Wilson, A Takayanagi, Y Lee, Y Rapoport, J Eaton, W Cascella, N Ji, H Goldman, D Sawa, A AF Kano, S. Colantuoni, C. Han, F. Zhou, Z. Yuan, Q. Wilson, A. Takayanagi, Y. Lee, Y. Rapoport, J. Eaton, W. Cascella, N. Ji, H. Goldman, D. Sawa, A. TI PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children SO MOLECULAR PSYCHIATRY LA English DT Letter ID POSTTRAUMATIC-STRESS-DISORDER; ANXIETY C1 [Kano, S.; Colantuoni, C.; Wilson, A.; Cascella, N.; Sawa, A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Colantuoni, C.; Han, F.] Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Takayanagi, Y.; Eaton, W.] Johns Hopkins Univ, Dept Mental Hlth, Sch Publ Hlth, Baltimore, MD USA. [Lee, Y.; Rapoport, J.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM asawa1@jhmi.edu OI Ressler, Kerry/0000-0002-5158-1103 NR 10 TC 0 Z9 0 U1 1 U2 3 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 JUL PY 2013 VL 18 IS 7 BP 742 EP 743 DI 10.1038/mp.2012.98 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700002 ER PT J AU Stewart, SE Yu, D Scharf, JM Neale, BM Fagerness, JA Mathews, CA Arnold, PD Evans, PD Gamazon, ER Osiecki, L McGrath, L Haddad, S Crane, J Hezel, D Illman, C Mayerfeld, C Konkashbaev, A Liu, C Pluzhnikov, A Tikhomirov, A Edlund, CK Rauch, SL Moessner, R Falkai, P Maier, W Ruhrmann, S Grabe, HJ Lennertz, L Wagner, M Bellodi, L Cavallini, MC Richter, MA Cook, EH Kennedy, JL Rosenberg, D Stein, DJ Hemmings, SMJ Lochner, C Azzam, A Chavira, DA Fournier, E Garrido, H Sheppard, B Umana, P Murphy, DL Wendland, JR Veenstra-VanderWeele, J Denys, D Blom, R Deforce, D Van Nieuwerburgh, F Westenberg, HGM Walitza, S Egberts, K Renner, T Miguel, EC Cappi, C Hounie, AG do Rosario, MC Sampaio, AS Vallada, H Nicolini, H Lanzagorta, N Camarena, B Delorme, R Leboyer, M Pato, CN Pato, MT Voyiaziakis, E Heutink, P Cath, DC Posthuma, D Smit, JH Samuels, J Bienvenu, OJ Cullen, B Fyer, AJ Grados, MA Greenberg, BD McCracken, JT Riddle, MA Wang, Y Coric, V Leckman, JF Bloch, M Pittenger, C Eapen, V Black, DW Ophoff, RA Strengman, E Cusi, D Turiel, M Frau, F Macciardi, F Gibbs, JR Cookson, MR Singleton, A Hardy, J Crenshaw, AT Parkin, MA Mirel, DB Conti, DV Purcell, S Nestadt, G Hanna, GL Jenike, MA Knowles, JA Cox, N Pauls, DL AF Stewart, S. E. Yu, D. Scharf, J. M. Neale, B. M. Fagerness, J. A. Mathews, C. A. Arnold, P. D. Evans, P. D. Gamazon, E. R. Osiecki, L. McGrath, L. Haddad, S. Crane, J. Hezel, D. Illman, C. Mayerfeld, C. Konkashbaev, A. Liu, C. Pluzhnikov, A. Tikhomirov, A. Edlund, C. K. Rauch, S. L. Moessner, R. Falkai, P. Maier, W. Ruhrmann, S. Grabe, H-J Lennertz, L. Wagner, M. Bellodi, L. Cavallini, M. C. Richter, M. A. Cook, E. H., Jr. Kennedy, J. L. Rosenberg, D. Stein, D. J. Hemmings, S. M. J. Lochner, C. Azzam, A. Chavira, D. A. Fournier, E. Garrido, H. Sheppard, B. Umana, P. Murphy, D. L. Wendland, J. R. Veenstra-VanderWeele, J. Denys, D. Blom, R. Deforce, D. Van Nieuwerburgh, F. Westenberg, H. G. M. Walitza, S. Egberts, K. Renner, T. Miguel, E. C. Cappi, C. Hounie, A. G. do Rosario, M. Conceicao Sampaio, A. S. Vallada, H. Nicolini, H. Lanzagorta, N. Camarena, B. Delorme, R. Leboyer, M. Pato, C. N. Pato, M. T. Voyiaziakis, E. Heutink, P. Cath, D. C. Posthuma, D. Smit, J. H. Samuels, J. Bienvenu, O. J. Cullen, B. Fyer, A. J. Grados, M. A. Greenberg, B. D. McCracken, J. T. Riddle, M. A. Wang, Y. Coric, V. Leckman, J. F. Bloch, M. Pittenger, C. Eapen, V. Black, D. W. Ophoff, R. A. Strengman, E. Cusi, D. Turiel, M. Frau, F. Macciardi, F. Gibbs, J. R. Cookson, M. R. Singleton, A. Hardy, J. Crenshaw, A. T. Parkin, M. A. Mirel, D. B. Conti, D. V. Purcell, S. Nestadt, G. Hanna, G. L. Jenike, M. A. Knowles, J. A. Cox, N. Pauls, D. L. CA North Amer Brain Expression Consor UK Brain Expression Database TI Genome-wide association study of obsessive-compulsive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE DLGAP; genetic; genomic; GWAS; neurodevelopmental disorder; obsessive-compulsive disorder ID OCD COLLABORATIVE GENETICS; FAMILY-BASED ASSOCIATION; QUANTITATIVE TRAIT LOCI; TRANSPORTER GENE; LINKAGE; SLC1A1; SNPS; TWIN; REPLICATION; EXPRESSION AB Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P = 2.49 x 10(-6) and P = 3.44 x 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value = 3.84 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P < 0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P = 0.001) was observed within the top-ranked SNPs (P < 0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. C1 [Stewart, S. E.; Yu, D.; Scharf, J. M.; Neale, B. M.; Fagerness, J. A.; Osiecki, L.; McGrath, L.; Haddad, S.; Crane, J.; Hezel, D.; Illman, C.; Mayerfeld, C.; Purcell, S.; Jenike, M. A.; Pauls, D. L.] Harvard Univ, Sch Med, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Stewart, S. E.; Yu, D.; Scharf, J. M.; Fagerness, J. A.; Osiecki, L.; McGrath, L.; Haddad, S.; Crane, J.; Hezel, D.; Illman, C.; Mayerfeld, C.; Purcell, S.; Jenike, M. A.; Pauls, D. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Stewart, S. E.] Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada. [Scharf, J. M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Scharf, J. M.; Purcell, S.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Neale, B. M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Scharf, J. M.; Neale, B. M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Mathews, C. A.; Azzam, A.; Sheppard, B.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Arnold, P. D.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Arnold, P. D.; Richter, M. A.; Kennedy, J. L.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Evans, P. D.; Gamazon, E. R.; Konkashbaev, A.; Pluzhnikov, A.; Tikhomirov, A.; Cox, N.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Liu, C.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Edlund, C. K.; Conti, D. V.] Univ So Calif, Zilkha Neurogenet Inst, Keck Sch Med, Dept Preventat Med,Div Biostat, Los Angeles, CA USA. [Edlund, C. K.; Conti, D. V.] Univ So Calif, Keck Sch Med, Epigenome Ctr, Los Angeles, CA 90033 USA. [Rauch, S. L.] Partners Psychiat, Boston, MA USA. [Rauch, S. L.] McLean Hosp, Boston, MA USA. [Moessner, R.; Maier, W.; Lennertz, L.; Wagner, M.] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Falkai, P.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Ruhrmann, S.] Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Grabe, H-J] Univ Med Greifswald, Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Bellodi, L.] Psychiat Univ Vita Salute San Raffaele, Milan, Italy. [Cavallini, M. C.] Fdn Ctr San Raffaele Monte Tabor, Milan, Italy. [Richter, M. A.] Sunnybrook Hlth Sci Ctr, Dept Psychiat, Toronto, ON M4N 3M5, Canada. [Cook, E. H., Jr.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Kennedy, J. L.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Rosenberg, D.] Wayne State Univ, Detroit, MI USA. [Rosenberg, D.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Stein, D. J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Hemmings, S. M. J.; Lochner, C.] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Chavira, D. A.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Fournier, E.; Garrido, H.; Umana, P.] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Murphy, D. L.; Wendland, J. R.] NIMH, Lab Clin Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Wendland, J. R.] F Hoffmann Roche Ltd, CNS Clin Biomarker Grp, Pharma Res & Early Dev, Basel, Switzerland. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pharmacol, Nashville, TN 37235 USA. [Veenstra-VanderWeele, J.] Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA. [Denys, D.; Blom, R.; Westenberg, H. G. M.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Denys, D.; Blom, R.; Westenberg, H. G. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [Deforce, D.; Van Nieuwerburgh, F.] Univ Ghent, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium. [Walitza, S.] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Egberts, K.; Renner, T.] Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, Germany. [Miguel, E. C.; Cappi, C.; Hounie, A. G.; do Rosario, M. Conceicao; Sampaio, A. S.; Vallada, H.] Univ Sao Paulo, Fac Med, Dept Psychiat, Sao Paulo, Brazil. [Sampaio, A. S.] Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil. [Nicolini, H.] Univ Mexico City, Ctr Genom Sci, Mexico City, DF, Mexico. [Nicolini, H.; Lanzagorta, N.] Carracci Med Grp, Mexico City, DF, Mexico. [Camarena, B.] Inst Nacl Psiquiatria Ramon de la Fuente Muniz, Depto Genet Psiquiatr, Mexico City, DF, Mexico. [Delorme, R.; Leboyer, M.] Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, INSERM,U955, F-75019 Paris, France. [Delorme, R.; Leboyer, M.] Inst Mondor Rech Biomed, Creteil, France. [Delorme, R.; Leboyer, M.] French Natl Sci Fdn, Fdn Fondamental, Creteil, France. [Pato, C. N.; Pato, M. T.; Voyiaziakis, E.; Knowles, J. A.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Heutink, P.; Posthuma, D.] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Clin Genet, Sect Med Gen, Amsterdam, Netherlands. [Cath, D. C.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Utrecht, Netherlands. [Cath, D. C.] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands. [Cath, D. C.; Smit, J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, Utrecht, Netherlands. [Samuels, J.; Bienvenu, O. J.; Cullen, B.; Grados, M. A.; Riddle, M. A.; Wang, Y.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Fyer, A. J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Greenberg, B. D.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [McCracken, J. T.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Coric, V.; Leckman, J. F.; Bloch, M.; Pittenger, C.] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Coric, V.; Bloch, M.; Pittenger, C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Eapen, V.] Univ New S Wales, Acad Unit Child Psychiat, South West Sydney AUCS, Sydney, NSW, Australia. [Black, D. W.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. [Ophoff, R. A.; Strengman, E.] UCLA Ctr Neurobehav Genet, Los Angeles, CA USA. [Ophoff, R. A.; Strengman, E.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Cusi, D.; Frau, F.] Univ Milan, Grad Sch Nephrol, Dept Med Surg & Dent, Milan, Italy. [Cusi, D.] San Paolo Hosp, Div Nephrol, Milan, Italy. [Turiel, M.] Univ Milan, Dept Hlth Technol, Milan, Italy. [Frau, F.] Filarete Fdn, Milan, Italy. [Macciardi, F.] Univ Calif Irvine, Sch Med, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Gibbs, J. R.; Cookson, M. R.; Singleton, A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Hardy, J.] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Crenshaw, A. T.; Parkin, M. A.; Mirel, D. B.; Purcell, S.] Broad Inst Harvard MIT, Cambridge, MA USA. RP Stewart, SE (reprint author), Univ British Columbia, Dept Psychiat, OCD Clin, BCMHARI,CFRI, A3-118,938 West 28th Ave, Vancouver, BC V5Z 4H4, Canada. EM sevelynstewart@gmail.com; dpauls@pngu.mgh.harvard.edu RI Macciardi, Fabio/N-3768-2014; Wagner, Michael/E-2325-2011; Stein, Dan/A-1752-2008; Trabzuni, Daniah/C-4034-2012; Vallada, Homero/D-1333-2014; Traynor, Bryan/G-5690-2010; Renner, Tobias/I-2120-2013; Hardy, John/C-2451-2009; Deforce, Dieter/J-4725-2013; SAMPAIO, ALINE/M-1229-2013; Singleton, Andrew/C-3010-2009; Weale, Michael/F-2587-2010; Stewart, Evelyn/K-6961-2014; Van Nieuwerburgh, Filip/H-9697-2015; Veenstra-VanderWeele, Jeremy/K-1935-2015; OI Macciardi, Fabio/0000-0003-0537-4266; Wagner, Michael/0000-0003-2589-6440; Stein, Dan/0000-0001-7218-7810; Trabzuni, Daniah/0000-0003-4826-9570; Nicolini, Humberto/0000-0003-2494-0067; Hanna, Gregory/0000-0002-0742-6990; Samuels, Jack/0000-0002-6715-7905; Azzam, Amin/0000-0002-7024-7450; Walitza, Susanne/0000-0002-8161-8683; Vallada, Homero/0000-0001-5123-8295; Deforce, Dieter/0000-0002-0635-661X; SAMPAIO, ALINE/0000-0001-5568-6167; Weale, Michael/0000-0003-4593-1186; Van Nieuwerburgh, Filip/0000-0001-8815-5485; Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076; Hemmings, Sian/0000-0001-8461-1017; Zonderman, Alan B/0000-0002-6523-4778; Stewart, S. Evelyn/0000-0002-0994-6383; Lanzagorta, Nuria/0000-0001-6769-6813; Gamazon, Eric/0000-0003-4204-8734 FU Judah Foundation; NIH [MH079489, MH073250]; American Recovery and Re-investment Act (ARRA) awards [NS40024-07S1, NS16648-29S1]; American Academy of Child and Adolescent Psychiatry (AACAP); Anxiety Disorders Association of America (ADAA); University of British Columbia; Michael Smith Foundation Clinical Research Scholar Award; Tourette Syndrome Association; American Academy of Neurology Foundation; National Center for Research Resources [RR020278]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' [HHSN268200782096C]; UK Medical Research Council; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000932-02] FX The authors would like to express their utmost gratitude to the OCD-affected families who participated in this research. In addition, they would like to thank the International OCD Foundation (IOCDF) for their role in establishing the IOCDF Genetics Collaborative, as well as other individuals who played roles in assisting this study, including Rhonda Ellwyn, Katherine Beattie, Colm O'Dushlaine, Doug Ruderfer, Priya Moorjani and V. Guttenthaler. This work was supported primarily by a grant from the Judah Foundation (a private, non-industry related foundation established by a family affected by OCD), NIH grants MH079489 and MH073250 to DLP, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, by an American Academy of Child and Adolescent Psychiatry (AACAP) Early Investigator Research Grant, an Anxiety Disorders Association of America (ADAA) Junior Investigator Research Grant, the University of British Columbia and a Michael Smith Foundation Clinical Research Scholar Award to SES, and grants from the Tourette Syndrome Association (DLP and JMS), the American Academy of Neurology Foundation (JMS) and NIH grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by grant U54 RR020278 from the National Center for Research Resources. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for related genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi/study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. Frontal lobe eQTL data was provided by the North American Brain Expression Consortium and the UK Human Brain Expression Database. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. The North American Brain Expression Consortium comprises: Sampath Arepalli, Mark R Cookson, Allissa Dillman, Luigi Ferrucci, J Raphael Gibbs, Dena G Hernandez, Robert Johnson, Dan L Longo, Michael A Nalls, Richard O0Brien, Andrew Singleton, Bryan Traynor, Juan Troncoso, Marcel van der Brug, H Ronald Zielke and Alan Zonderman.; The UK Human Brain Expression Database membership comprises: John A Hardy, Mina Ryten, Colin Smith, Daniah Trabzuni, Robert Walker and Mike Weale. None of the funding sources supporting this work had any influence or played any role in: (a) the design or conduct of the study; (b) management, analysis or interpretation of the data; or c) preparation, review or approval of the manuscript. NR 71 TC 76 Z9 79 U1 4 U2 54 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 JUL PY 2013 VL 18 IS 7 BP 788 EP 798 DI 10.1038/mp.2012.85 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700012 PM 22889921 ER PT J AU Gunduz-Cinar, O MacPherson, KP Cinar, R Gamble-George, J Sugden, K Williams, B Godlewski, G Ramikie, TS Gorka, AX Alapafuja, SO Nikas, SP Makriyannis, A Poulton, R Patel, S Hariri, AR Caspi, A Moffitt, TE Kunos, G Holmes, A AF Gunduz-Cinar, O. MacPherson, K. P. Cinar, R. Gamble-George, J. Sugden, K. Williams, B. Godlewski, G. Ramikie, T. S. Gorka, A. X. Alapafuja, S. O. Nikas, S. P. Makriyannis, A. Poulton, R. Patel, S. Hariri, A. R. Caspi, A. Moffitt, T. E. Kunos, G. Holmes, A. TI Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity SO MOLECULAR PSYCHIATRY LA English DT Article DE amygdala; anxiety; cannabinoid; fear; gene; stress ID ACID AMIDE HYDROLASE; PROBLEM DRUG-USE; ENDOCANNABINOID SYSTEM; INDIVIDUAL-DIFFERENCES; BASOLATERAL AMYGDALA; CONDITIONED FEAR; CB1 RECEPTORS; SHORT-TERM; MONOACYLGLYCEROL LIPASE; PREFRONTAL CORTEX AB Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans. C1 [Gunduz-Cinar, O.; MacPherson, K. P.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, Sect Behav Sci & Genet, NIH, Bethesda, MD USA. [Gunduz-Cinar, O.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Cinar, R.; Godlewski, G.; Kunos, G.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Gamble-George, J.; Ramikie, T. S.; Patel, S.] Vanderbilt Univ, Med Ctr, Dept Psychiat & Mol Physiol & Biophys, Nashville, TN USA. [Sugden, K.; Williams, B.; Gorka, A. X.; Hariri, A. R.; Caspi, A.; Moffitt, T. E.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Sugden, K.; Williams, B.; Caspi, A.; Moffitt, T. E.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Sugden, K.; Williams, B.; Hariri, A. R.; Caspi, A.; Moffitt, T. E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. [Sugden, K.; Williams, B.; Caspi, A.; Moffitt, T. E.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, London WC2R 2LS, England. [Alapafuja, S. O.; Nikas, S. P.; Makriyannis, A.] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Poulton, R.] Univ Otago, Dunedin Sch Med, Dunedin, New Zealand. RP Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, Sect Behav Sci & Genet, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM Andrew.Holmes@nih.gov RI Patel, Sachin/E-5608-2012; caspi, avshalom/D-5294-2011; Moffitt, Terrie/D-5295-2011; Gunduz Cinar, Ozge/E-5756-2010 OI CINAR, RESAT/0000-0002-8597-7253; Moffitt, Terrie/0000-0002-8589-6760; Gamble-George, Joyonna/0000-0002-5492-9216; Gunduz Cinar, Ozge/0000-0002-3826-8905 FU NIAAA Intramural Research Program; Department of Defense in the Center for Neuroscience and Regenerative Medicine; NIA [AG032282]; MRC [G0100527]; NIDA [DA031579]; NIMH [MH077874, MH072837, MH090412]; Royal Society FX This work was supported by the NIAAA Intramural Research Program (OGC, KPM, RC, GK, AH), Department of Defense in the Center for Neuroscience and Regenerative Medicine (OGC, AH), NIA (AG032282 to TEM), MRC (G0100527 to TEM), NIDA (DA031579 to ARH) and NIMH (MH077874 to AC; MH072837 to ARH, MH090412 to SP). AC is a Royal Society Wolfson Merit Award holder. We thank Daniel Fisher and Caitlin Schaapveld for assistance with behavioral experiments. NR 58 TC 75 Z9 75 U1 1 U2 17 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 JUL PY 2013 VL 18 IS 7 BP 813 EP 823 DI 10.1038/mp.2012.72 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 168NL UT WOS:000320712700015 PM 22688188 ER PT J AU Kerkar, SP Leonardi, AJ van Panhuys, N Zhang, L Yu, ZY Crompton, JG Pan, JH Palmer, DC Morgan, RA Rosenberg, SA Restifo, NP AF Kerkar, Sid P. Leonardi, Anthony J. van Panhuys, Nicolas Zhang, Ling Yu, Zhiya Crompton, Joseph G. Pan, Jenny H. Palmer, Douglas C. Morgan, Richard A. Rosenberg, Steven A. Restifo, Nicholas P. TI Collapse of the Tumor Stroma is Triggered by IL-12 Induction of Fas SO MOLECULAR THERAPY LA English DT Article ID T-CELL THERAPY; IMMUNE ESCAPE; ANTITUMOR IMMUNITY; SUPPRESSOR-CELLS; GENE-EXPRESSION; DENDRITIC CELLS; INTERLEUKIN-12; CANCER; MICROENVIRONMENT; IMMUNOTHERAPY AB Engineering CD8(+) T cells to deliver interleukin 12 -(IL-12) to the tumor site can lead to striking improvements in the ability of adoptively transferred T cells to induce the regression of established murine cancers. We have recently shown that IL-12 triggers an acute inflammatory environment that reverses dysfunctional antigen presentation by myeloid-derived cells within tumors and leads to an increase in the infiltration of adoptively transferred antigen-specific CD8(+) T cells. Here, we find that local delivery of IL-12 increased the expression of Fas within tumor-infiltrating macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSC), and that these changes were abrogated in mice deficient in IL-12-receptor signaling. Importantly, upregulation of Fas in host mice played a critical role in the proliferation and antitumor activity of adoptively transferred IL-12-modified CD8(+) T cells. We also observed higher percentages of myeloid-derived cell populations within tumors in Fas-deficient mice, indicating that tumor stromal destruction was dependent on the Fas death receptor. Taken together, these results describe the likely requirement for costimulatory reverse signaling through Fasl on T cells that successfully infiltrate tumors, a mechanism triggered by the induction of Fas expression on myeloid-derived cells by IL-12 and the subsequent collapse of the tumor stroma. C1 [Leonardi, Anthony J.; Zhang, Ling; Yu, Zhiya; Crompton, Joseph G.; Pan, Jenny H.; Palmer, Douglas C.; Morgan, Richard A.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kerkar, Sid P.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD USA. [van Panhuys, Nicolas] NIAID, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Kerkar, SP (reprint author), NCI, NIH, Room 3-5762,10 Ctr Dr, Bethesda, MD 20892 USA. EM kerkars@mail.nih.gov; restifon@nih.gov RI Palmer, Douglas/B-9454-2008; van Panhuys, Nicholas/E-1812-2011; OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580; van Panhuys, Nicholas/0000-0003-2199-852X FU Intramural Research Program of the 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. The authors declare no conflict of interest. NR 43 TC 33 Z9 33 U1 1 U2 10 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 JUL PY 2013 VL 21 IS 7 BP 1369 EP 1377 DI 10.1038/mt.2013.58 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 173WL UT WOS:000321112500011 PM 23568260 ER PT J AU Mendell, JR Lloyd-Puryear, M AF Mendell, Jerry R. Lloyd-Puryear, Michele TI Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy SO MUSCLE & NERVE LA English DT Article DE Committee on Heritable Disorders for Newborns and Children; Department of Health and Human Services; Duchenne muscular dystrophy; Newborn Screening; Recommended Uniform Screening Panel; Secretary's Advisory ID CORTICOSTEROID TREATMENT; FOLLOW-UP; RESTORATION; PREDNISONE; PRO051; TRIAL; GENE AB This report summarizes the progress made in newborn screening for Duchenne muscular dystrophy (DMD). This subject was discussed fully at a symposium held on September 11-12, 2012, in Bethesda, Maryland, by a group of experts from multiple disciplines. The meeting was triggered by the simultaneous combination of improvements in methods for newborn screening for DMD and greater potential for treatment. On the screening side, a two-tier system of newborn screening was introduced that enabled creatine kinase levels and DMD gene analysis to be done on the same dried blood spots obtained at birth. Treatment improvements included promising results from exon skipping as well as multiple studies showing long-term benefits of glucocorticoids and data indicating that early intervention of both forms of therapy was the most beneficial. Conclusions from this symposium with supportive data could have a significant impact on propelling efforts for approval of newborn screening for DMD. Muscle Nerve, 2013 C1 [Mendell, Jerry R.] Ohio State Univ, Nationwide Childrens Hosp, Paul D Wellstone Muscular Dystrophy Cooperat Res, Columbus, OH 43205 USA. [Mendell, Jerry R.] Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. [Lloyd-Puryear, Michele] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Mendell, JR (reprint author), Ohio State Univ, Nationwide Childrens Hosp, Paul D Wellstone Muscular Dystrophy Cooperat Res, 700 Childrens Dr, Columbus, OH 43205 USA. EM jerry.mendell@nationwidechildrens.org FU Muscular Dystrophy Association; Centers for Disease Control and Prevention [5U50DD000030, 1R18DD000344]; Research Institute at Nationwide Children's Hospital, Columbus, OH FX The following individuals significantly contributed to the success of this Symposium through discussions on individual topics or participation in Panels: Sanjay Bidichandani, Jeffrey Bosco, Amy Brower, Michele Caggana, Ram Chandrasekar, Pat Furlong, Scott Grosse, Madhuri Hedge, R. Rodney Howell, Alex Kemper, Anne Kennedy, Bruce Korf, Fred Lorey, Craig McDonald, Francesco Muntoni, John Porter, Piero Rinaldo, Robert Saul, Robert Weiss. The symposium was supported by the Muscular Dystrophy Association. The Symposium was dependent on the organization of Sanjay Bidichandani, MBBS, Ph.D., Vice President of Research and Paul Muhlrad, Ph.D., Director of Basic Research at the Muscular Dystrophy Association. The Muscular Dystrophy Association supported the Symposium on Newborn Screening. The two-tier system of screening used in the State of Ohio newborn screening was supported by cooperative agreements from the Centers for Disease Control and Prevention (5U50DD000030 and 1R18DD000344) and the Research Institute at Nationwide Children's Hospital, Columbus, OH; Paul D. Wellstone Cooperative Muscular Dystrophy Center, Nationwide Children's Hospital (1U54HD066409-01;JRM); and Ohio Department of Health (J.R.M.). NR 19 TC 33 Z9 33 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2013 VL 48 IS 1 BP 21 EP 26 DI 10.1002/mus.23810 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 169NT UT WOS:000320787700003 PM 23716304 ER PT J AU Belkaid, Y Naik, S AF Belkaid, Yasmine Naik, Shruti TI Compartmentalized and systemic control of tissue immunity by commensals SO NATURE IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; INTESTINAL MICROBIOTA; SKIN MICROBIOME; GUT MICROBIOTA; TOXOPLASMA-GONDII; INNATE IMMUNITY; GERM-FREE; BACTERIA; DISEASE; INFLAMMATION AB The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct commensal niches. Mammals have formed an evolutionary partnership with the microbiota that is critical for metabolism, tissue development and host defense. Despite our growing understanding of the impact of this host-microbe alliance on immunity in the gastrointestinal tract, the extent to which individual microenvironments are controlled by resident microbiota remains unclear. In this Perspective, we discuss how resident commensals outside the gastrointestinal tract can control unique physiological niches and the potential implications of the dialog between these commensals and the host for the establishment of immune homeostasis, protective responses and tissue pathology. C1 [Belkaid, Yasmine; Naik, Shruti] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. We thank members of the Belkaid laboratory for helpful discussions, particularly S. Spencer and J. Grainger for critical reading of the manuscript. NR 102 TC 70 Z9 70 U1 4 U2 64 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 JUL PY 2013 VL 14 IS 7 BP 646 EP 653 DI 10.1038/ni.2604 PG 8 WC Immunology SC Immunology GA 165UB UT WOS:000320509100002 PM 23778791 ER PT J AU Van Rhijn, I Kasmar, A de Jong, A Gras, S Bhati, M Doorenspleet, ME de Vries, N Godfrey, DI Altman, JD de Jager, W Rossjohn, J Moody, DB AF Van Rhijn, Ildiko Kasmar, Anne de Jong, Annemieke Gras, Stephanie Bhati, Mugdha Doorenspleet, Marieke E. de Vries, Niek Godfrey, Dale I. Altman, John D. de Jager, Wilco Rossjohn, Jamie Moody, D. Branch TI A conserved human T cell population targets mycobacterial antigens presented by CD1b SO NATURE IMMUNOLOGY LA English DT Article ID TUBERCULOSIS INFECTION; LIPID ANTIGENS; ALPHA-CHAIN; MAIT CELLS; RECEPTOR; RECOGNITION; RESPONSES; EXPRESSION; LYMPHOCYTES; MEMORY AB Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR alpha-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an alpha-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCR alpha sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen. C1 [Van Rhijn, Ildiko; Kasmar, Anne; de Jong, Annemieke; Moody, D. Branch] Harvard Univ, Sch Med, Dept Rheumatol & Immunol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Van Rhijn, Ildiko] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Utrecht, Netherlands. [Gras, Stephanie; Bhati, Mugdha; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Doorenspleet, Marieke E.; de Vries, Niek] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1012 WX Amsterdam, Netherlands. [Godfrey, Dale I.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. [Altman, John D.] NIH Tetramer Core Facil, Emory Vaccine Ctr, Atlanta, GA USA. [de Jager, Wilco] Univ Utrecht, Med Ctr, Dept Pediat Immunol, Utrecht, Netherlands. [Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. RP Moody, DB (reprint author), Harvard Univ, Sch Med, Dept Rheumatol & Immunol, Brigham & Womens Hosp, Boston, MA 02115 USA. EM i.vanrhijn@uu.nl; bmoody@rics.bwh.harvard.edu RI de Vries, Niek/J-9348-2013; OI de Vries, Niek/0000-0002-6257-8604; de Jong, Annemieke/0000-0001-6707-6585; Rossjohn, Jamie/0000-0002-2020-7522 FU US National Institute of Allergy and Infectious Diseases [AI04393, AR048632, K08 AI089858]; Burroughs Wellcome Fund; Nederlands Wetenschappelijk Onderzoek (Meervoud) [836.08.001]; National Health and Medical Research Council; Australian Research Council FX We thank the Tetramer Core Facility of the US National Institutes of Health for CD1b protein; M. Turner, C. Seshadri and the Shattuck Hospital for clinical collaboration; L. Tan for technical help; and the beamline staff at the Australian synchrotron for assistance with data collection. Supported by the US National Institute of Allergy and Infectious Diseases (AI04393, AR048632 to D. B. M., and K08 AI089858 to A. K.) the Burroughs Wellcome Fund, Nederlands Wetenschappelijk Onderzoek (Meervoud 836.08.001 to I. V. R.), the National Health and Medical Research Council (D. I. G. and J.R.) and the Australian Research Council (S.G.). NR 48 TC 65 Z9 65 U1 1 U2 19 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 JUL PY 2013 VL 14 IS 7 BP 706 EP + DI 10.1038/ni.2630 PG 10 WC Immunology SC Immunology GA 165UB UT WOS:000320509100012 PM 23727893 ER PT J AU Bunting, SF Nussenzweig, A AF Bunting, Samuel F. Nussenzweig, Andre TI End-joining, translocations and cancer SO NATURE REVIEWS CANCER LA English DT Review ID DOUBLE-STRAND BREAKS; CLASS-SWITCH RECOMBINATION; DNA-DAMAGE-RESPONSE; RECURRENT CHROMOSOMAL TRANSLOCATIONS; FRAGILE SITE INSTABILITY; CYTIDINE DEAMINASE AID; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; NONHOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE AB Fusion genes that are caused by chromosome translocations have been recognized for several decades as drivers of deregulated cell growth in certain types of cancer. In recent years, oncogenic fusion genes have been found in many haematological and solid tumours, demonstrating that translocations are a common cause of malignancy. Sequencing approaches have now confirmed that numerous, non-clonal translocations are a typical feature of cancer cells. These chromosome rearrangements are often highly complex and contain DNA sequence from multiple genomic sites. The factors and pathways that promote translocations are becoming clearer, with non-homologous end-joining implicated as a key source of genomic rearrangements. C1 [Bunting, Samuel F.] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Nussenzweig, Andre] NIH, Lab Genome Integr, Bethesda, MD 20892 USA. RP Bunting, SF (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Room 337, Piscataway, NJ 08854 USA. EM bunting@cabm.rutgers.edu; andre_nussenzweig@nih.gov FU NCI R00 award [RCA 160574A]; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research; Department of Defense [BC 102335] FX S.F.B. is a recipient of NCI R00 award RCA 160574A. A.N. was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant (BC 102335). NR 130 TC 110 Z9 111 U1 4 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUL PY 2013 VL 13 IS 7 BP 443 EP 454 DI 10.1038/nrc3537 PG 12 WC Oncology SC Oncology GA 169HH UT WOS:000320770200007 PM 23760025 ER PT J AU Pancera, M Shahzad-ul-Hussan, S Doria-Rose, NA McLellan, JS Bailer, RT Dai, KF Loesgen, S Louder, MK Staupe, RP Yang, YP Zhang, BS Parks, R Eudailey, J Lloyd, KE Blinn, J Alam, SM Haynes, BF Amin, MN Wang, LX Burton, DR Koff, WC Nabel, GJ Mascola, JR Bewley, CA Kwong, PD AF Pancera, Marie Shahzad-ul-Hussan, Syed Doria-Rose, Nicole A. McLellan, Jason S. Bailer, Robert T. Dai, Kaifan Loesgen, Sandra Louder, Mark K. Staupe, Ryan P. Yang, Yongping Zhang, Baoshan Parks, Robert Eudailey, Joshua Lloyd, Krissey E. Blinn, Julie Alam, S. Munir Haynes, Barton F. Amin, Mohammed N. Wang, Lai-Xi Burton, Dennis R. Koff, Wayne C. Nabel, Gary J. Mascola, John R. Bewley, Carole A. Kwong, Peter D. TI Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16 SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; HIV-1 ENVELOPE GLYCOPROTEINS; HAMSTER OVARY CELLS; GLYCOSYLATION SITES; CRYSTAL-STRUCTURE; 2G12 RECOGNIZES; GP120; POTENT; COMPLEX AB HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization. C1 [Pancera, Marie; Doria-Rose, Nicole A.; McLellan, Jason S.; Bailer, Robert T.; Dai, Kaifan; Louder, Mark K.; Staupe, Ryan P.; Yang, Yongping; Zhang, Baoshan; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Shahzad-ul-Hussan, Syed; Loesgen, Sandra; Bewley, Carole A.] NIDDK, Lab Bioorgan Chem, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Parks, Robert; Eudailey, Joshua; Lloyd, Krissey E.; Blinn, Julie; Alam, S. Munir; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Amin, Mohammed N.; Wang, Lai-Xi] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Amin, Mohammed N.; Wang, Lai-Xi] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, Ragon Inst, MIT, Cambridge, MA USA. [Burton, Dennis R.] Harvard Univ, Cambridge, MA 02138 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY USA. RP Bewley, CA (reprint author), NIDDK, Lab Bioorgan Chem, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov; pdkwong@nih.gov FU US National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; Center for HIV AIDS Vaccine Immunology from the US National Institutes of Health [AI 5U19 AI 067854-06]; US National Institutes of Health [1R21 AI101035]; US National Institutes of Health (NIH/NCRR) [P41 RR018502-01]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank J. Stuckey for assistance with figures and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center for discussions or comments on the manuscript; A. Kumar for sharing the ELISA binding protocol with biotinylated lectins; P. Azadi and S. Archer-Hartmann, University of Georgia, for performing glycan analyses and glycopeptide mapping; J. Baalwa (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), D. Ellenberger (International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA), D. Gabuzda (Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA), F. Gao (Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA), B. Hahn (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), K. Hong (State Key Laboratory for Infectious Disease Control and Prevention, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China), J. Kim (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), F. McCutchan (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), D. Montefiori (Department of Surgery, Duke University, Durham, North Carolina, USA), L. Morris, (Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa), J. Overbaugh (Program for Appropriate Technology in Health, Seattle, Washington, USA), E. Sanders-Buell (US Military HIV Research Program, Henry M. Jackson Foundation, Bethesda, Maryland, USA), G. Shaw (Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA), R. Swanstrom (University of North Carilina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), M. Thomson (University of Birmingham, Birmingham, UK), S. Tovanabutra (Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand), C. Williamson (Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and National Health Laboratory Services, Cape Town, South Africa) and L. Zhang (Department of Public Health, Center for Disease Control and Prevention in Jiangxi Province, Nanchang, China) contributing the HIV-1 Envelope plasmids used in our neutralization panel. Support for this work was provided by the US National Institutes of Health Intramural Research Programs (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases), by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium and by the Center for HIV AIDS Vaccine Immunology Grant AI 5U19 AI 067854-06 from the US National Institutes of Health (J. E., K. E. L., J. B., S. M. A. and B. F. H.), by US National Institutes of Health grant 1R21 AI101035 (M. N. A. and L-X. W.) and by the US National Institutes of Health (NIH/NCRR)-funded grant P41 RR018502-01 to the Complex Carbohydrate Research Center. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science under contract number W-31-109-Eng-38. NR 62 TC 116 Z9 117 U1 1 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2013 VL 20 IS 7 BP 804 EP + DI 10.1038/nsmb.2600 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 175SM UT WOS:000321253300008 PM 23708607 ER PT J AU Yadav, H Jain, S AF Yadav, Hariom Jain, Shalini TI Herbo-probiotic therapy in cardioprotection: A new way of nature to nurture SO NUTRITION LA English DT Letter C1 [Yadav, Hariom; Jain, Shalini] NIH, Natl Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. RP Yadav, H (reprint author), NIH, Natl Diabet & Digest & Kidney Dis, Bldg 10, Bethesda, MD 20892 USA. EM yadavhariom@gmail.com OI Yadav, Hariom/0000-0003-4504-1597 NR 10 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD JUL-AUG PY 2013 VL 29 IS 7-8 BP 1070 EP 1071 DI 10.1016/j.nut.2012.11.001 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 172UF UT WOS:000321029700025 PM 23352466 ER PT J AU Shih, LC LaFaver, K Lim, C Papavassiliou, E Tarsy, D AF Shih, Ludy C. LaFaver, Kathrin Lim, Chen Papavassiliou, Efstathios Tarsy, Daniel TI Loss of benefit in VIM thalamic deep brain stimulation (DBS) for essential tremor (ET): How prevalent is it? SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Essential tremor; Deep brain stimulation; Long-term outcome ID LONG-TERM EFFICACY; MOVEMENT-DISORDERS; FOLLOW-UP; TOLERANCE; NUCLEUS AB Ventralis intermedius (Vim) thalamic deep brain stimulation for medication-refractory essential tremor (ET) has been shown to significantly improve severity of limb tremor in several large case series with significant reduction in objective motor scores. A variable proportion of patients experience decline in benefit over time, however, most studies have not been designed to describe the phenomenon of waning benefit in terms that are helpful for patient counseling. In this retrospective single center study, we define waning benefit as a phenomenon that occurs after patients begin to require reprogramming visits to optimize DBS benefit on tremor. We employed a survival analysis with time to escape (TTE) as a quantitative measure of time elapsed between implantation and the need for subsequent reprogramming. In our cohort of ET patients operated on with Vim DBS from 1994 to 2009, among 45 subjects who met inclusion criteria, 73% reported waning benefit at some point during a mean follow-up period of 56 months (range 12-152 months). The mean TTE from implantation date was 18 months (range 3-75 months). We conclude that loss of benefit over time from Vim DBS for ET is more prevalent than previously published estimates have indicated and should be discussed during patient counseling regarding durability of expected benefit. In addition, this data suggests that a disease-based explanation rather than technical factors are more likely to explain the decline in benefit. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Shih, Ludy C.; Tarsy, Daniel] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol, Boston, MA 02215 USA. [LaFaver, Kathrin] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Lim, Chen] New York Med Coll, Valhalla, NY 10595 USA. [Papavassiliou, Efstathios] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Neurosurg,Dept Surg, Boston, MA 02215 USA. RP Shih, LC (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, Kirstein 228,330 Brookline Ave, Boston, MA 02215 USA. EM lshih@bidmc.harvard.edu FU Clinical Investigator Training Program: Beth Israel Deaconess Medical Center; Harvard/MIT Health Science and Technology; Pfizer, Inc.; Merck Co. FX L.C. Shih was supported in part by the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center and Harvard/MIT Health Science and Technology, in collaboration with Pfizer, Inc. and Merck & Co. The authors have no relevant financial disclosures to make regarding relevant companies involved in this work over the past three years. NR 22 TC 17 Z9 17 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2013 VL 19 IS 7 BP 676 EP 679 DI 10.1016/j.parkreldis.2013.03.006 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 169AW UT WOS:000320750300006 PM 23582712 ER PT J AU Samal, B Ait-Ali, D Bunn, S Mustafa, T Eiden, LE AF Samal, Babru Ait-Ali, Djida Bunn, Stephen Mustafa, Tomris Eiden, Lee E. TI Discrete signal transduction pathway utilization by a neuropeptide (PACAP) and a cytokine (TNF-alpha) first messenger in chromaffin cells, inferred from coupled transcriptome-promoter analysis of regulated gene cohorts SO PEPTIDES LA English DT Article DE Affymetrix; Agilent; Chromaffin cell; Cyclic AMP; ERK; Gene induction; Microarray; NF-kB; PACAP; PAC1; Signal transduction; TNF-alpha; Transcriptional regulation; TNFR2 ID CYCLASE-ACTIVATING POLYPEPTIDE; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; CONTROL MAQC PROJECT; IN-VIVO; CATECHOLAMINE SECRETION; RECEPTOR ACTIVATION; PC12 CELLS; EXPRESSION; NEUROENDOCRINE AB Cultured bovine adrenal chromaffin cells (BCCs) are employed to study first messenger-specific signaling by cytokines and neurotransmitters occurring in the adrenal medulla following immune-related stress responses. Here, we show that the cytokine TNF-alpha, and the neuropeptide transmitter PACAP, acting through the TNFR2 and PAC1 receptors, activate distinct signaling pathways, with correspondingly distinct transcriptomic signatures in chromaffin cells. We have carried out a comprehensive integrated transcriptome analysis of TNF-alpha and PACAP gene regulation in BCCs using two microarray platforms to maximize transcript identification. Microarray data were validated using qRT-PCR. More than 90% of the transcripts up-regulated either by TNF-alpha or PACAP were specific to a single first messenger. The final list of transcripts induced by each first messenger was subjected to multiple algorithms to identify promoter/ enhancer response elements for trans-acting factors whose activation could account for gene expression by either TNF-alpha or PACAP. Distinct groups of transcription factors potentially controlling the expression of TNF-alpha or PACAP-responsive genes were found: most of the genes up-regulated by TNF-alpha contained transcription factor binding sites for members of the Rel transcription factor family, suggesting TNF-alpha-TNFR2 signaling occurs mainly through the NF-KB signaling pathway. Surprisingly, EGR1 was predicted to be the primary transcription factor controlling PACAP-modulated genes, suggesting PACAP signaling to the nucleus occurs predominantly through ERK, rather than CREB activation. Comparison of TNFR2-dependent versus TNFR1-dependent gene induction, and EGR1-mediated transcriptional activation, may provide a pharmacological avenue to the unique pathways activated by the first messengers TNF-alpha and PACAP in neuronal and endocrine cells. Published by Elsevier Inc. C1 [Samal, Babru; Ait-Ali, Djida; Mustafa, Tomris; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Bunn, Stephen] Univ Otego, Sch Med Sci, Dept Anat, Ctr Neuroendocrinol, Dunedin, New Zealand. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU NIMH [ZO1-MH002386] FX The authors thank Chang-Mei Hsu for expert assistance in chromaffin cell preparation, treatment, harvesting, and RNA preparation. This work was supported by the NIMH intramural research program (ZO1-MH002386). NR 48 TC 2 Z9 2 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUL PY 2013 VL 45 BP 48 EP 60 DI 10.1016/j.peptides.2013.03.020 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 170KW UT WOS:000320850300008 PM 23608709 ER PT J AU Davenport, AP Alexander, SPH Sharman, JL Pawson, AJ Benson, HE Monaghan, AE Liew, WC Mpamhanga, CP Bonner, TI Neubig, RR Pin, JP Spedding, M Harmar, AJ AF Davenport, Anthony P. Alexander, Stephen P. H. Sharman, Joanna L. Pawson, Adam J. Benson, Helen E. Monaghan, Amy E. Liew, Wen Chiy Mpamhanga, Chidochangu P. Bonner, Tom I. Neubig, Richard R. Pin, Jean Philippe Spedding, Michael Harmar, Anthony J. TI International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands SO PHARMACOLOGICAL REVIEWS LA English DT Review ID LYSOPHOSPHATIDIC ACID RECEPTOR; L-ALPHA-LYSOPHOSPHATIDYLINOSITOL; RAT ADRENOMEDULLIN RECEPTOR; NEUROPEPTIDE-Y RECEPTOR; BREAST-CANCER CELLS; ORPHAN RECEPTOR; CANNABINOID RECEPTOR; FATTY-ACIDS; CONSTITUTIVE ACTIVITY; INSULIN-SECRETION AB In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA(1) (GPR81) with lactate, HCA(2) (GPR109A) with 3-hydroxybutyric acid, HCA(3) (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA(4) (GPR23), LPA(5) (GPR92), LPA(6) (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org). C1 [Davenport, Anthony P.] Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England. [Alexander, Stephen P. H.] Univ Nottingham, Sch Med, Sch Biomed Sci, Nottingham, England. [Sharman, Joanna L.; Pawson, Adam J.; Benson, Helen E.; Monaghan, Amy E.; Liew, Wen Chiy; Mpamhanga, Chidochangu P.; Harmar, Anthony J.] Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Bonner, Tom I.] NIMH, Sect Funct Neurosci, Bethesda, MD 20892 USA. [Neubig, Richard R.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Pin, Jean Philippe] Univ Montpellier, CNRS, Inst Funct Genom, Dept Mol Pharmacol,UMR5203, F-34059 Montpellier, France. [Spedding, Michael] Les Labs Servier, Suresnes, France. RP Davenport, AP (reprint author), Univ Cambridge, Ctr Clin Invest, Addenbrookes Hosp, Clin Pharmacol Unit, Level 6,Box 110, Cambridge CB2 0QQ, England. EM apd10@medschl.cam.ac.uk RI Alexander, Steve/B-8105-2009; Davenport, Anthony/A-5773-2008; Pawson, Adam/Q-5678-2016; OI Alexander, Steve/0000-0003-4417-497X; Davenport, Anthony/0000-0002-2096-3117; Pawson, Adam/0000-0003-2280-845X; Benson, Helen/0000-0002-7830-2477; Spedding, Michael/0000-0002-1248-8221; Sharman, Joanna/0000-0002-5275-6446 FU International Union of Basic and Clinical Pharmacology; British Pharmacological Society; Wellcome Trust [268427, 085686/2/08, 099156/Z/12/Z]; British Heart Foundation [PS/02/001, PG/09/050/27734]; Pulmonary Hypertension Association; National Institute for Health Research Cambridge Biomedical Research Centre; National Institutes of Health [National Institute of Mental Health] FX The authors thank the International Union of Basic and Clinical Pharmacology and British Pharmacological Society for support.; This work was supported in part by the Wellcome Trust [Grants 268427, 085686/2/08; Biomedical Resources Grant 099156/Z/12/Z] for support for IUPHAR-DB (to A. H., S. P. H. A., and A. P. D.); the British Heart Foundation [Grants PS/02/001 and PG/09/050/27734] (to A. P. D.); Pulmonary Hypertension Association; the National Institute for Health Research Cambridge Biomedical Research Centre; the Intramural Research Program of the National Institutes of Health [National Institute of Mental Health] (to T.B.). NR 238 TC 71 Z9 71 U1 3 U2 37 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUL PY 2013 VL 65 IS 3 BP 967 EP 986 DI 10.1124/pr.112.007179 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172FV UT WOS:000320986500004 PM 23686350 ER PT J AU Kleitman, N Rao, MS Owens, DF AF Kleitman, Naomi Rao, Mahendra S. Owens, David F. TI Pluripotent Stem Cells in Translation: A Food and Drug Administration-National Institutes of Health Collaboration SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Pluripotent stem cells; Stem cells; Clinical translation; Clinical trials AB Recently, the U.S. Food and Drug Administration (FDA), the U.S. National Institutes of Health, and the stem cell research community have collaborated on a series of workshops that address moving pluripotent stem cell therapies into the clinic. The first two workshops in the series focused on preclinical science, and a third, future workshop will focus on clinical trials. This summary addresses major points from both of the recent preclinically focused meetings. When entering into a therapeutics developmental program based on pluripotent cells, investigators must make decisions at the very early stages that will have major ramifications during later phases of development. Presentations and discussions from both invited participants and FDA staff described the need to characterize and document the quality, variability, and suitability of the cells and commercial reagents used at every translational stage. This requires consideration of future regulatory requirements, ranging from donor eligibility of the original source material to the late-stage manufacturing protocols. Federal, industrial, and academic participants agreed that planning backward is the best way to anticipate what evidence will be needed to justify human testing of novel therapeutics and to eliminate wasted efforts. C1 [Kleitman, Naomi; Owens, David F.] NINDS, NIH, Bethesda, MD 20892 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, MS (reprint author), 50 South Dr, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov OI Kleitman, Naomi/0000-0003-1089-0257 FU NIH FX We thank the participants of both workshops for providing invaluable insights into this emerging area, our FDA colleagues for comments on a draft of this report, and Drs. Story Landis (NINDS/NIH) and Celia Witten (CBER/FDA) for providing overall leadership. We also thank members of the planning committees from both the FDA and the NIH for making these workshops a reality. FDA: Drs. Rachael F. Anatol, Patrick Au, Kimberly A. Benton, Theresa T. Chen, Donald W. Fink, Thomas P. Finn, Ying Huang, Deborah A. Hursh, Wei Liang, Malcolm C. Moos, Stephanie L. Simek, and Steven O. Winitsky. NIH: Drs. Kristin Abraham (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), Rosemarie Hunziker (National Institute of Biomedical Imaging and Bioengineering [NIBIB]), Christine Kelley (NIBIB), Naomi Kleitman (NINDS), Susan Marino (NINDS), David Owens (NINDS), Mahendra Rao (National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS]), Pamela Robey (National Institute of Dental and Craniofacial Research), Sheryl Sato (NIDDK), Sonia Skarlatos (National Heart, Lung, and Blood Institute [NHLBI]), and John W. Thomas (NHLBI). We would like to also acknowledge the contributions made by Dr. Laura Cole (National Institute on Deafness and Other Communication Disorders [NIDCD]), Buck Wong (NIDCD), Dr. Scott Lipnick (Office of the Director), and Megan Laycock (NIAMS). Funding for both workshops was provided by the NIH. NR 7 TC 4 Z9 4 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JUL PY 2013 VL 2 IS 7 BP 483 EP 487 DI 10.5966/sctm.2013-0042 PG 5 WC Cell & Tissue Engineering SC Cell Biology GA 175MU UT WOS:000321235600010 PM 23757505 ER PT J AU Orihuela, R Kojima, C Tokar, EJ Person, RJ Xu, YY Qu, W Waalkes, MP AF Orihuela, Ruben Kojima, Chikara Tokar, Erik J. Person, Rachel J. Xu, Yuanyuan Qu, Wei Waalkes, Michael P. TI Oxidative DNA damage after acute exposure to arsenite and monomethylarsonous acid in biomethylation-deficient human cells SO TOXICOLOGY MECHANISMS AND METHODS LA English DT Article DE Arsenic; immuno-spin trapping; reactive oxygen species ID PYRUVATE-DEHYDROGENASE; METHYLATED ARSENICALS; ENDOTHELIAL-CELLS; HUMAN HEPATOCYTES; REACTIVE OXYGEN; FREE-RADICALS; HUMAN-DISEASE; AS-III; GLUTATHIONE; STRESS AB The carcinogen inorganic arsenic (iAs) undergoes biomethylation (BMT) in some cells. The methylated metabolite, monomethylarsonous (MMA(3+)), may cause oxidative DNA damage (ODD). With chronic iAs exposure, BMT-competent cells show ODD while BMT-deficient do not. To further define these events, we studied ODD produced by acute iAs or MMA(3+) in the BMT-deficient human prostate cell line, RWPE-1. ODD, measured by the immuno-spin trapping method, was assessed after exposure to iAs or MMA(3+) alone, with the arsenic BMT inhibitor selenite or after glutathione (GSH) depletion. The expression of oxidative stress-related genes (HO-1, SOD-1, SOD-2, Nrf2 and Keap-1) was also assessed. Exposure to iAs at 24 h (0-20 mu M), stimulated ODD only at levels above the LC50 of a 48 h exposure (17 mu M). If iAs induced ODD, it also activated oxidative stress-related genes. Selenium did not alter iAs-induced ODD. MMA(3+) at 24 h (0-0.5 mu M) caused ODD at levels below the LC50 of a 48 h exposure (1.5 mu M), which were greatly increased by GSH depletion but not selenite. MMA(3+) induced ODD at levels not activating oxidant stress response genes. Overall, iAs induced ODD in BMT-deficient cells only at toxic levels. MMA(3+) caused ODD at non-toxic levels, independently of cellular BMT capacity and in a fashion not requiring further BMT. C1 [Orihuela, Ruben; Kojima, Chikara; Tokar, Erik J.; Person, Rachel J.; Xu, Yuanyuan; Qu, Wei; Waalkes, Michael P.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Inorgan Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Inorgan Toxicol Grp, POB 12233,Mail Drop E1-07,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov OI ORIHUELA, RUBEN/0000-0001-6718-6194 NR 44 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1537-6516 J9 TOXICOL MECH METHOD JI Toxicol. Mech. Methods PD JUL PY 2013 VL 23 IS 6 BP 389 EP 395 DI 10.3109/15376516.2012.762570 PG 7 WC Toxicology SC Toxicology GA 173GE UT WOS:000321065600002 PM 23301828 ER PT J AU Perkins, NJ Schisterman, EF Vexler, A AF Perkins, Neil J. Schisterman, Enrique F. Vexler, Albert TI Multivariate Normally Distributed Biomarkers Subject to Limits of Detection and Receiver Operating Characteristic Curve Inference SO ACADEMIC RADIOLOGY LA English DT Article DE Area under the curve; left censoring; limit of detection; maximum likelihood; ROC ID ROC ANALYSIS; SAMPLES AB Rationale and Objectives: Biomarkers are of ever-increasing importance to clinical practice and epidemiologic research. Multiple biomarkers are often measured per patient. Measurement of true biomarker levels is limited by laboratory precision, specifically measuring relatively low, or high, biomarker levels resulting in undetectable levels below, or above, a limit of detection (LOD). Ignoring these missing observations or replacing them with a constant are methods commonly used although they have been shown to lead to biased estimates of several parameters of interest, including the area under the receiver operating characteristic (ROC) curve and regression coefficients. Materials and Methods: We developed asymptotically consistent, efficient estimators, via maximum likelihood techniques, for the mean vector and covariance matrix of multivariate normally distributed biomarkers affected by LOD. We also developed an approximation for the Fisher information and covariance matrix for our maximum likelihood estimations (MLEs). We apply these results to an ROC curve setting, generating an MLE for the area under the curve for the best linear combination of multiple biomarkers and accompanying confidence-interval. Results: Point and confidence interval estimates are scrutinized by simulation study, with bias and root mean square error and coverage probability, respectively, displaying behavior consistent with MLEs. An example using three polychlorinated biphenyls to classify women with and without endometriosis illustrates how the underlying distribution of multiple biomarkers with LOD can be assessed and display increased discriminatory ability over naive methods. Conclusions: Properly addressing LODs can lead to optimal biomarker combinations with increased discriminatory ability that may have been ignored because of measurement obstacles. C1 [Perkins, Neil J.; Schisterman, Enrique F.; Vexler, Albert] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Dept Biostat, Buffalo, NY 14260 USA. RP Perkins, NJ (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 perkinsn@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 838 EP 846 DI 10.1016/j.acra.2013.04.001 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600007 PM 23747152 ER PT J AU Tang, LL Kang, L Liu, CL Schisterman, EF Liu, AY AF Tang, Liansheng Larry Kang, Le Liu, Chunling Schisterman, Enrique F. Liu, Aiyi TI An Additive Selection of Markers to Improve Diagnostic Accuracy Based on a Discriminatory Measure SO ACADEMIC RADIOLOGY LA English DT Article DE Receiver operating characteristic (ROC); area under the ROC curves (AUC); discriminatory score; Box-Cox transformation ID OPERATING CHARACTERISTIC CURVES; MAXIMUM-LIKELIHOOD-ESTIMATION; CHARACTERISTIC ROC CURVES; STATISTICAL VALIDATION; MODEL; AREAS AB Rationale and Objectives: The estimation of the area under the receiver operating characteristic (ROC) curve (AUC) often relies on the assumption that the truly positive population tends to have higher marker results than the truly negative population. The authors propose a discriminatory measure to relax such an assumption and apply the measure to identify the appropriate set of markers for combination. Materials and Methods: The proposed measure is based on the maximum of the AUC and 1-AUC. The existing methods are applied to estimate the measure. The subset of markers is selected using a combination method that maximizes a function of the proposed discriminatory score with the number of markers as a penalty in the function. Results: The properties of the estimators for the proposed measure were studied through large-scale simulation studies. The application was illustrated through a real example to identify the set of markers to combine. Conclusion: Simulation results showed excellent small-sample performance of the estimators for the proposed measure. The application in the example yielded a reasonable subset of markers for combination. C1 [Tang, Liansheng Larry] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Kang, Le] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Schisterman, Enrique F.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Bethesda, MD USA. EM liua@mail.nih.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [ZIA HD008875-01] NR 33 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 854 EP 862 DI 10.1016/j.acra.2013.02.009 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600009 PM 23611438 ER PT J AU Liu, DP Zhou, XH AF Liu, Danping Zhou, Xiao-Hua TI ROC Analysis in Biomarker Combination with Covariate Adjustment SO ACADEMIC RADIOLOGY LA English DT Article DE Biomarker combination; covariate adjustment; AUC; covariate standardization ID OPERATING CHARACTERISTIC CURVE; REGRESSION; ACCURACY; MARKERS; AREA AB Rational and Objectives: Receiver operating characteristic (ROC) analysis is often used to find the optimal combination of biomarkers. When the subject level covariates affect the magnitude and/or accuracy of the biomarkers, the combination rule should take into account of the covariate adjustment. The authors propose two new biomarker combination methods that make use of the covariate information. Materials and Methods: The first method is to maximize the area under the covariate-adjusted ROC curve (AAUC). To overborne the limitations of the AAUC measure, the authors further proposed the area under covariate-standardized ROC curve (SAUC), which is an extension of the covariate-specific ROC curve. With a series of simulation studies, the proposed optimal AAUC and SAUC methods are compared with the optimal AUC method that ignores the covariates. The biomarker combination methods are illustrated by an example from Alzheimer's disease research. Results: The simulation results indicate that the optimal AAUC combination performs well in the current study population. The optimal SAUC method is flexible to choose any reference populations, and allows the results to be generalized to different populations. Conclusions: The proposed optimal AAUC and SAUC approaches successfully address the covariate adjustment problem in estimating the optimal marker combination. The optimal SAUC method is preferred-for practical use, because the biomarker combination rule can be easily evaluated for different population of interest. C1 [Liu, Danping] NICHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98101 USA. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Liu, DP (reprint author), NICHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM danping.liu@nih.gov FU National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NIH/NIA [U01AG016976] FX D.L.'s research is supported by the Intramural Research Program of the National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This work was supported in part by NIH/NIA grant U01AG016976. NR 16 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 874 EP 882 DI 10.1016/j.acra.2013.03.009 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600011 PM 23747153 ER PT J AU Rudzinski, ER Teot, LA Anderson, JR Moore, J Bridge, JA Barr, FG Gastier-Foster, JM Skapek, SX Hawkins, DS Parham, DM AF Rudzinski, Erin R. Teot, Lisa A. Anderson, James R. Moore, Julie Bridge, Julia A. Barr, Frederic G. Gastier-Foster, Julie M. Skapek, Stephen X. Hawkins, Douglas S. Parham, David M. TI Dense Pattern of Embryonal Rhabdomyosarcoma, a Lesion Easily Confused With Alveolar Rhabdomyosarcoma A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Alveolar rhabdomyosarcoma; Embryonal rhabdomyosarcoma; Histologic classification; Rhabdomyosarcoma; Myogenin ID INTERGROUP-RHABDOMYOSARCOMA; FUSION STATUS; STUDY-III; CLASSIFICATION; DIAGNOSIS; MYOGENIN; VARIANT AB Objectives: To examine whether the frequency of fusion-negative alveolar rhabdomyosarcoma (ARMSn) increased coincident with changes in the definition of alveolar histology. Methods: We re-reviewed alveolar rhabdomyosarcoma (ARMS) in the Children's Oncology Group study D9803, comparing histopathology with fusion status. Results: Our review of 255 original ARMS cases (compared with a control group of 38 embryonal rhabdomyosarcomas [ERMS] cases) revealed that many had an ARMS-like densely cellular pattern with cytologic features and myogenin expression more typical of ERMS. Following re-review, 84 (33%) cases of original ARMS were rediagnosed as ERMS. All reclassified ERMS, including dense ERMS, were fusion negative, whereas 82% of confirmed ARMS cases were fusion positive. Total ARMS diagnoses returned to historic rates of 25% to 30% of all rhabdomyosarcomas, and ARMSn decreased from 37% to 18% of ARMS cases. The outcome of reclassified ERMS was similar to confirmed ERMS. Conclusions: To address the role of fusion status in risk stratification, pathologists should include both a histologic diagnosis and an evaluation of fusion status for all new ARMS diagnoses. C1 [Rudzinski, Erin R.; Hawkins, Douglas S.] Seattle Childrens Hosp, Seattle, WA 98015 USA. [Teot, Lisa A.] Boston Childrens Hosp, Boston, MA USA. [Anderson, James R.; Bridge, Julia A.] Univ Nebraska Med Ctr, Omaha, NE USA. [Moore, Julie] Nationwide Childrens Hosp, Columbus, OH USA. [Barr, Frederic G.] NCI, Bethesda, MD USA. [Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Hawkins, Douglas S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hawkins, Douglas S.] Univ Washington, Seattle, WA 98195 USA. [Parham, David M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Rudzinski, ER (reprint author), Seattle Childrens Hosp, Dept Labs, M-S OC-8-720,4800 Sandpoint Way NE, Seattle, WA 98015 USA. EM erin.rudzinski@seattlechildrens.org FU St Baldrick's Foundation, Monrovia, CA [179772]; National Institutes of Health, Bethesda, MD [NIH-RC2-CA148216, NIH-R01-CA104896, NIH-U10-CA098412, NIH-U10-CA98543]; Joanna McAfee Childhood Cancer Foundation, Warner Robins, GA [U-10-CA98543-07] FX Research support was provided by research grant 179772 from St Baldrick's Foundation, Monrovia, CA (E.R.R); NIH-RC2-CA148216 (S.X.S., J.M.; J.A.B., F.G.B., and J.M.G.-F), NIH-R01-CA104896 (F.G.B., J.M.G.-F), NIH-U10-CA098412 (J.R.A.), and NIH-U10-CA98543 (COG Chair's grant) from the National Institutes of Health, Bethesda, MD; and grants (F.G.B) and U-10-CA98543-07 (J.A.B.) from the Joanna McAfee Childhood Cancer Foundation, Warner Robins, GA. NR 24 TC 20 Z9 20 U1 0 U2 4 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 2013 VL 140 IS 1 BP 82 EP 90 DI 10.1309/AJCPA1WN7ARPCMKQ PG 9 WC Pathology SC Pathology GA 167LS UT WOS:000320634100009 PM 23765537 ER PT J AU Chen, YT Zheng, TZ Lan, Q Kim, C Qin, Q Foss, F Chen, XZ Holford, T Leaderer, B Boyle, P Wang, CF Dai, M Liu, ZJ Ma, SG Chanock, SJ Rothman, N Zhang, YW AF Chen, Yingtai Zheng, Tongzhang Lan, Qing Kim, Christopher Qin, Qin Foss, Francine Chen, Xuezhong Holford, Theodore Leaderer, Brian Boyle, Peter Wang, Chengfeng Dai, Min Liu, Zhenjiang Ma, Shuangge Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Polymorphisms in DNA repair pathway genes, body mass index, and risk of non-Hodgkin lymphoma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID RAT SKELETAL-MUSCLE; CANCER-RISK; PHYSICAL-ACTIVITY; OXIDATIVE STRESS; POOLED ANALYSIS; LUNG-CANCER; OBESITY; EXERCISE; WOMEN; MEN AB We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI 25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P=0.004) for T-cell lymphoma and ERCC2 (rs13181; P=0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk. Am. J. Hematol. 88:606-611, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Chen, Yingtai; Wang, Chengfeng; Dai, Min] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. [Chen, Yingtai; Zheng, Tongzhang; Kim, Christopher; Holford, Theodore; Leaderer, Brian; Ma, Shuangge; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Lan, Qing; Kim, Christopher; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Qin, Qin] Univ So Maine, Wise Lab Environm & Genet Toxicol, Portland, ME 04103 USA. [Foss, Francine] Yale Univ, Sch Med, New Haven, CT USA. [Chen, Xuezhong] Gansu Prov Canc Hosp, Lanzhou, Peoples R China. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Liu, Zhenjiang] Gansu Prov Coll Chinese Med, Lanzhou, Peoples R China. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU NIH [CA62006, CA165923, 1D43TW008323, 1D43TW007864, HD70324]; Intramural Research Program of the National Cancer Institute FX This research was supported by the NIH grants CA62006, CA165923, 1D43TW008323, 1D43TW007864, and HD70324, and the Intramural Research Program of the National Cancer Institute. NR 50 TC 6 Z9 7 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 2013 VL 88 IS 7 BP 606 EP 611 DI 10.1002/ajh.23463 PG 6 WC Hematology SC Hematology GA 167VB UT WOS:000320662200013 PM 23619945 ER PT J AU Chou, CF Cotch, MF Vitale, S Zhang, XZ Klein, R Friedman, DS Klein, BEK Saaddine, JB AF Chou, Chiu-Fang Cotch, Mary Frances Vitale, Susan Zhang, Xinzhi Klein, Ronald Friedman, David S. Klein, Barbara E. K. Saaddine, Jinan B. TI Age-Related Eye Diseases and Visual Impairment Among U.S. Adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ANGELES LATINO EYE; BLUE MOUNTAINS EYE; QUALITY-OF-LIFE; UNDERCORRECTED REFRACTIVE ERRORS; UNITED-STATES; MACULAR DEGENERATION; SOCIOECONOMIC-FACTORS; VISION IMPAIRMENT; OLDER POPULATION; RISK INDICATORS AB Background: Visual impairment is a common health-related disability in the U.S. The association between clinical measurements of age-related eye diseases and visual impairment in data from a national survey has not been reported. Purpose: To examine common eye conditions and other correlates associated with visual impairment in the U.S. Methods: Data from the 2005-2008 National Health and Nutrition Examination Survey of 5222 Americans aged >= 40 years were analyzed in 2012 for visual impairment (presenting distance visual acuity worse than 20/40 in the better-seeing eye), and visual impairment not due to refractive error (distance visual acuity worse than 20/40 after refraction). Diabetic retinopathy (DR) and age-related macular degeneration (AMD) were assessed from retinal fundus images; glaucoma was assessed from two successive frequency-doubling tests and a cup-to-disc ratio measurement. Results: Prevalence of visual impairment and of visual impairment not due to refractive error was 7.5% (95% CI=6.9%, 8.1%) and 2.0% (1.7%, 2.3%), respectively. The prevalence of visual impairment not due to refractive error was significantly higher among people with AMD (2.2%) compared to those without AMD (0.8%), or with DR (3.5%) compared to those without DR (1.2%). Independent predictive factors of visual impairment not due to refractive error were AMD (OR=4.52, 95% CI=2.50, 8.17); increasing age (OR=1.09 per year, 95% CI=1.06, 1.13); and less than a high school education (OR=2.99, 95% CI=1.18, 7.55). Conclusions: Visual impairment is a public health problem in the U.S. Visual impairment in two thirds of adults could be eliminated with refractive correction. Screening of the older population may identify adults at increased risk of visual impairment due to eye diseases. C1 [Chou, Chiu-Fang; Zhang, Xinzhi; Saaddine, Jinan B.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA 30341 USA. [Cotch, Mary Frances; Vitale, Susan] NIH, NEI, Div Epidemiol & Clin Applicat, Bethesda, MD USA. [Friedman, David S.] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Chou, CF (reprint author), CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, 4770 Buford Hwy,NE K-10, Atlanta, GA 30341 USA. EM CChou@cdc.gov OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Center for Health Statistics (NCHS), CDC; Division of Diabetes Translation, CDC [05FED47304]; National Eye Institute, NIH [ZIAEY000402] FX This study was supported by the National Center for Health Statistics (NCHS), CDC. Funding for the National Health and Nutrition Examination Survey (NHANES) retinal and frequency-doubling technology component was provided by the Intra Agency Agreement 05FED47304 from the Division of Diabetes Translation, CDC. Funding for the vision component was provided by the National Eye Institute, NIH, Intramural Research Program award ZIAEY000402. NR 39 TC 17 Z9 17 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2013 VL 45 IS 1 BP 29 EP 35 DI 10.1016/j.amepre.2013.02.018 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 170CO UT WOS:000320827500004 PM 23790986 ER PT J AU Schnabel, RB Yin, XY Larson, MG Yamamoto, JF Fontes, JD Kathiresan, S Rong, J Levy, D Keaney, JF Wang, TJ Murabito, JM Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Yin, Xiaoyan Larson, Martin G. Yamamoto, Jennifer F. Fontes, Joao D. Kathiresan, Sekar Rong, Jian Levy, Daniel Keaney, John F., Jr. Wang, Thomas J. Murabito, Joanne M. Vasan, Ramachandran S. Benjamin, Emelia J. TI Multiple Inflammatory Biomarkers in Relation to Cardiovascular Events and Mortality in the Community SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular disease; cohort; epidemiology; inflammation; mortality ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; CORONARY-HEART-DISEASE; INTERCELLULAR-ADHESION MOLECULE-1; TYPE-2 DIABETIC-PATIENTS; RHEUMATOID-ARTHRITIS; BODY-COMPOSITION; RISK-FACTORS; OLDEST-OLD; MARKERS AB Objective Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. Approach and Results We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 +/- 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. Conclusions Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD. C1 [Schnabel, Renate B.; Yin, Xiaoyan; Larson, Martin G.; Yamamoto, Jennifer F.; Fontes, Joao D.; Rong, Jian; Levy, Daniel; Murabito, Joanne M.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Yamamoto, Jennifer F.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fontes, Joao D.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Kathiresan, Sekar] MIT, Broad Inst Harvard, Cambridge, MA 02139 USA. RP Schnabel, RB (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Bldg E 70 O70,Martinistr 52, D-20246 Hamburg, Germany. EM schnabelr@gmx.de RI Schnabel, Renate/F-6527-2014; OI Murabito, Joanne/0000-0002-0192-7516; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [N01-/HC-/25195, 6R01-/NS17950]; NIH [HL064753, HL076784, AG028321, 1 RO1HL71039, K24 HL04334]; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-/1, SCHN 1149/3-/1]; Doris Duke Charitable Foundation Clinical Scientist Development Award [1K23HL083102] FX This work was supported by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute contract N01-/HC-/25195, 6R01-/NS17950, and NIH grants HL064753, HL076784, AG028321 (E.J. Benjamin), and 1 RO1HL71039 (R.S. Vasan); NIH Research career award K24 HL04334 (R.S. Vasan); Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-/1 and Emmy Noether Program SCHN 1149/3-/1 (R.B. Schnabel); 1K23HL083102, Doris Duke Charitable Foundation Clinical Scientist Development Award (S. Kathiresan). NR 49 TC 26 Z9 27 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2013 VL 33 IS 7 BP 1728 EP 1733 DI 10.1161/ATVBAHA.112.301174 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 167YP UT WOS:000320671800040 PM 23640499 ER PT J AU Foran, JM Pavletic, SZ Logan, BR Agovi-Johnson, MA Perez, WS Bolwell, BJ Bornhauser, M Bredeson, CN Cairo, MS Camitta, BM Copelan, EA Dehn, J Gale, RP George, B Gupta, V Hale, GA Lazarus, HM Litzow, MR Maharaj, D Marks, DI Martino, R Maziarz, RT Rowe, JM Rowlings, PA Savani, BN Savoie, ML Szer, J Waller, EK Wiernik, PH Weisdorf, DJ AF Foran, James M. Pavletic, Steven Z. Logan, Brent R. Agovi-Johnson, Manza A. Perez, Waleska S. Bolwell, Brian J. Bornhaeuser, Martin Bredeson, Christopher N. Cairo, Mitchell S. Camitta, Bruce M. Copelan, Edward A. Dehn, Jason Gale, Robert P. George, Biju Gupta, Vikas Hale, Gregory A. Lazarus, Hillard M. Litzow, Mark R. Maharaj, Dipnarine Marks, David I. Martino, Rodrigo Maziarz, Richard T. Rowe, Jacob M. Rowlings, Philip A. Savani, Bipin N. Savoie, Mary Lynn Szer, Jeffrey Waller, Edmund K. Wiernik, Peter H. Weisdorf, Daniel J. TI Unrelated Donor Allogeneic Transplantation after Failure of Autologous Transplantation for Acute Myelogenous Leukemia: A Study from the Center for International Blood and Marrow Transplantation Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Acute myelogenous leukemia; Unrelated donor; Transplantation; Allogeneic; Autologous ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; CONDITIONING REGIMEN; ADULT PATIENTS; 1ST REMISSION; HEMATOLOGIC MALIGNANCIES; RELAPSE; SURVIVAL; CHEMOTHERAPY; THERAPY AB The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P < .001), with Karnofsky Performance Status score >= 90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0:38; P < .001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score >90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed. (C) 2013 American Society for Blood and Marrow Transplantation. C1 [Foran, James M.] Mayo Clin Florida, Jacksonville, FL USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Logan, Brent R.; Perez, Waleska S.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Agovi-Johnson, Manza A.] Univ S Carolina, Norman J Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Bolwell, Brian J.; Copelan, Edward A.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bornhaeuser, Martin] Univ Klinikum Carl Gustav Carus, Dresden, Germany. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Cairo, Mitchell S.] New York Med Coll, Valhalla, NY 10595 USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Dehn, Jason] Natl Marrow Donor Program, Minneapolis, MN USA. [Gale, Robert P.] Univ London Imperial Coll Sci Technol & Med, London, England. [George, Biju] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Gupta, Vikas] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Maharaj, Dipnarine] Bethesda Hlth City, Boynton Beach, FL USA. [Marks, David I.] Bristol Childrens Hosp, Bristol, Avon, England. [Martino, Rodrigo] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Rowlings, Philip A.] Calvary Mater Newcastle, Waratah, NSW, Australia. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Brentwood, TN USA. [Savoie, Mary Lynn] Tom Baker Canc Clin, Calgary, AB, Canada. [Szer, Jeffrey] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Waller, Edmund K.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Wiernik, Peter H.] St Lukes Roosevelt & Beth Israel Med Ctr, Continuum Canc Ctr New York, New York, NY USA. [Weisdorf, Daniel J.] Univ Minnesota, Minneapolis, MN 55455 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Med Ctr, 420 Delaware St SE,MMC 480, Minneapolis, MN 55455 USA. EM weisd001@umn.edu OI Szer, Jeff/0000-0001-6783-2301 FU Public Health Service Grant/Cooperative Agreement, National Cancer Institute [U24-CA76518]; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; National Cancer Institute [5U01HL069294]; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos; Amgen; Angioblast FX The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U01HL069294 from the National Cancer Institute and the National Heart, Lung and Blood Institute; Contract HHSH234200637015C with the Health Resources and Services Administration; Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos, Amgen, Angioblast, anonymous donation to the Medical College of Wisconsin, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Buchanan Family Foundation, CaridianBCT, Celgene, CellGenix, Children's Leukemia Research Association, Fresenius-Biotech North America, Gamida Cell Teva Joint Venture, Genentech, Genzyme, GlaxoSmithKline, HistoGenetics, Kiadis Pharma, Leukemia and Lymphoma Society, Medical College of Wisconsin, Merck & Co, Millennium: Takeda Oncology, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, Optum Healthcare Solutions, Osiris Therapeutics, Otsuka America Pharmaceutical, RemedyMD, Sanofi, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, StemCyte, Stemsoft Software, Swedish Orphan Biovitrum, Tarix Pharmaceuticals, Teva Neuroscience, Therakos, and Wellpoint. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 34 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2013 VL 19 IS 7 BP 1102 EP 1108 DI 10.1016/j.bbmt.2013.04.022 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 173QH UT WOS:000321093500017 PM 23632091 ER PT J AU Wee, J Mortimer, PS Lindhurst, M Biesecker, L Holden, CA AF Wee, J. Mortimer, P. S. Lindhurst, M. Biesecker, L. Holden, C. A. TI Expanding the spectrum of Proteus syndrome: bilateral cerebriform plantar collagenomas and varicose veins secondary to a mosaic AKT1 mutation SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract CT 93rd Annual Meeting of the British-Association-of-Dermatologists CY JUL 09-11, 2013 CL Liverpool, ENGLAND SP British Assoc Dermatologists C1 [Wee, J.; Mortimer, P. S.] St George Hosp, London, England. [Lindhurst, M.; Biesecker, L.] NHGRI, Bethesda, MD 20892 USA. [Holden, C. A.] St Heliers Hosp, Surrey, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JUL PY 2013 VL 169 SU 1 SI SI BP 13 EP 14 PG 2 WC Dermatology SC Dermatology GA 178JI UT WOS:000321443500027 ER PT J AU Eichmann, K Krause, RM AF Eichmann, Klaus Krause, Richard M. TI Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE History of infectious diseases; History of bacteriology; Bile solubility; Quellung reaction; Bacteriotropin ID SOLUBLE SPECIFIC SUBSTANCE; LOBAR PNEUMONIA; SERUM TREATMENT; ANTIPNEUMOCOCCIC SERUM; LECTURE AB During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today's knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld's contributions in this development, which have remained largely unknown. C1 [Eichmann, Klaus] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany. [Krause, Richard M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Eichmann, K (reprint author), Max Planck Inst Immunobiol & Epigenet, Stubeweg 51, D-79108 Freiburg, Germany. EM eichmann@immunbio.mpg.de; Richard_Krause@nih.gov NR 65 TC 1 Z9 2 U1 1 U2 20 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2013 VL 70 IS 13 BP 2225 EP 2236 DI 10.1007/s00018-013-1351-z PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163JR UT WOS:000320332600002 PM 23689587 ER PT J AU Linehan, WM Rouault, TA AF Linehan, W. Marston Rouault, Tracey A. TI Molecular Pathways: Fumarate Hydratase-Deficient Kidney Cancer-Targeting the Warburg Effect in Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; HEREDITARY LEIOMYOMATOSIS; UTERINE LEIOMYOMAS; MET PROTOONCOGENE; HLRCC SYNDROME; MUTATIONS; TUMORS; HIF; FH; INHIBITION AB Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1 alpha and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. (C)2013 AACR. C1 [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr MSC 1107,CRC Room 1W-5940, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 54 TC 35 Z9 35 U1 0 U2 24 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2013 VL 19 IS 13 BP 3345 EP 3352 DI 10.1158/1078-0432.CCR-13-0304 PG 8 WC Oncology SC Oncology GA 173RF UT WOS:000321095900004 PM 23633457 ER PT J AU Shibata, SI Chung, V Synold, TW Longmate, JA Suttle, AB Ottesen, LH Lenz, HJ Kummar, S Harvey, RD Hamilton, AL O'Neil, BH Lenz, HJ Kummar, S Harvey, RD Hamilton, AL O'Neil, BH Sarantopoulos, J LoRusso, P Rudek, MA Dowlati, A Mulkerin, DL Belani, CP Gandhi, L Lau, SC Ivy, SP Newman, EM AF Shibata, Stephen I. Chung, Vincent Synold, Timothy W. Longmate, Jeffrey A. Suttle, A. Benjamin Ottesen, Lone H. Lenz, Heinz-Josef Kummar, Shivaani Harvey, R. Donald Hamilton, Anne L. O'Neil, Bert H. Lenz, Heinz-Josef Kummar, Shivaani Harvey, R. Donald Hamilton, Anne L. O'Neil, Bert H. Sarantopoulos, John LoRusso, Patricia Rudek, Michelle A. Dowlati, Afshin Mulkerin, Daniel L. Belani, Chandra P. Gandhi, Leena Lau, S. Cecilia Ivy, S. Percy Newman, Edward M. TI Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study SO CLINICAL CANCER RESEARCH LA English DT Article ID ORAL PAZOPANIB; INHIBITOR; TRIAL AB Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median C-max and area under the curve [AUC((0-24))] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. Clin Cancer Res; 19(13); 3631-9. (C)2013 AACR. C1 [Shibata, Stephen I.; Chung, Vincent; Synold, Timothy W.; Longmate, Jeffrey A.; Lau, S. Cecilia; Newman, Edward M.] City Hope Natl Med Ctr, Duarte, CA USA. [Lenz, Heinz-Josef] Univ So Calif, Los Angeles, CA USA. [Kummar, Shivaani] Natl Canc Inst, Bethesda, MD 20892 USA. [Ivy, S. Percy] Natl Canc Inst, Bethesda, MD USA. [Ivy, S. Percy] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Rudek, Michelle A.] Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Harvey, R. Donald] Emory Univ, Sch Med, Atlanta, GA USA. [O'Neil, Bert H.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Sarantopoulos, John] Inst Drug Dev CTRC, San Antonio, TX USA. [LoRusso, Patricia] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Mulkerin, Daniel L.] Univ Wisconsin, Madison, WI USA. [Belani, Chandra P.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Gandhi, Leena] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamilton, Anne L.] Royal Prince Alfred Hosp, Sydney, NSW, Australia. RP Newman, EM (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, North,Room 2000A,1500 East Duarte Rd, Duarte, CA 91010 USA. EM enewman@coh.org OI Belani, Chandra/0000-0001-5049-5329; Gandhi, Leena/0000-0002-2398-9179 FU NIH [U01-CA062505, P30-CA033572, U01-CA062487, U01-CA099168, U01-CA70095, P30-CA006973, U01-CA069853, P30-CA054174, U01-CA062490, U01-CA062502, U01-C 062491] FX The study was supported by NIH grants: U01-CA062505 and P30-CA033572 (Beckman Research Institute of City of Hope, Duarte, CA); U01-CA062487 (Karmanos Cancer Institute, Detroit, MI); U01-CA099168 (University of Pittsburgh, Pittsburgh, PA); U01-CA70095 and P30-CA006973 (Johns Hopkins University, Baltimore, MD); U01-CA069853 and P30-CA054174 (Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX); U01-CA062490 (Dana-Farber Cancer Institute, Boston, MA); U01-CA062502 (Case Western Reserve, Cleveland, OH); and U01-C 062491 (University of Wisconsin Paul P Carbone Comprehensive Cancer Center, Madison, WI). NR 10 TC 15 Z9 15 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2013 VL 19 IS 13 BP 3631 EP 3639 DI 10.1158/1078-0432.CCR-12-3214 PG 9 WC Oncology SC Oncology GA 173RF UT WOS:000321095900030 PM 23653147 ER PT J AU Brauer, MJ Zhuang, GL Schmidt, M Yao, J Wu, XM Kaminker, JS Jurinka, SS Kolumam, G Chung, AS Jubb, A Modrusan, Z Ozawa, T James, CD Phillips, H Haley, B Tam, RNW Clermont, AC Cheng, JH Yang, SX Swain, SM Chen, D Scherer, SJ Koeppen, H Yeh, RF Yue, P Stephan, JP Hegde, P Ferrara, N Singh, M AF Zhuang, Guanglei Schmidt, Maike Yao, Jenny Wu, Xiumin Kaminker, Joshua S. Jurinka, Stefanie S. Kolumam, Ganesh Chung, Alicia S. Jubb, Adrian Modrusan, Zora Ozawa, Tomoko James, C. David Phillips, Heidi Haley, Benjamin Tam, Rachel N. W. Clermont, Anne C. Cheng, Jason H. Yang, Sherry X. Swain, Sandra M. Chen, Daniel Scherer, Stefan J. Koeppen, Hartmut Yeh, Ru-Fang Yue, Peng Stephan, Jean-Philippe Hegde, Priti Ferrara, Napoleone Singh, Mallika Bais, Carlos TI Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC COLORECTAL-CANCER; RENAL-CELL CARCINOMA; TUMOR-GROWTH; ANTIANGIOGENIC THERAPY; INDUCED ANGIOGENESIS; BREAST-CANCER; BEVACIZUMAB; RESISTANCE; INHIBITION; CHEMOTHERAPY AB Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. Conclusions: In this work, we identified surrogate markers(VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. Clin Cancer Res; 19(13); 3681-92. (C)2013 AACR. C1 [Zhuang, Guanglei; Schmidt, Maike; Yao, Jenny; Wu, Xiumin; Kaminker, Joshua S.; Jurinka, Stefanie S.; Kolumam, Ganesh; Chung, Alicia S.; Jubb, Adrian; Modrusan, Zora; Phillips, Heidi; Haley, Benjamin; Tam, Rachel N. W.; Clermont, Anne C.; Cheng, Jason H.; Chen, Daniel; Scherer, Stefan J.; Koeppen, Hartmut; Yeh, Ru-Fang; Yue, Peng; Stephan, Jean-Philippe; Hegde, Priti; Ferrara, Napoleone; Bais, Carlos] Genentech Inc, San Francisco, CA 94131 USA. [Ozawa, Tomoko; James, C. David] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Ozawa, Tomoko; James, C. David] Univ Calif San Francisco, Brain Tumor Res Ctr, San Francisco, CA USA. [Singh, Mallika] Novartis Inst Biomed Res, Emeryville, CA USA. [Yang, Sherry X.] NCI, NIH, Div Canc Treatment & Diag, Nat Clin Target Validat Lab, Bethesda, MD USA. [Swain, Sandra M.] Medstar Washington Hosp, Washington Canc Inst, Washington, DC USA. RP Singh, M (reprint author), Genentech Inc, 1 DNA Way, San Francisco, CA 94131 USA. EM mallika.singh@novartis.com RI Zhuang, Guanglei/K-6097-2013; OI Swain, Sandra/0000-0002-1320-3830 NR 50 TC 18 Z9 18 U1 3 U2 19 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2013 VL 19 IS 13 BP 3681 EP 3692 DI 10.1158/1078-0432.CCR-12-3635 PG 12 WC Oncology SC Oncology GA 173RF UT WOS:000321095900035 PM 23685835 ER PT J AU Gilbert, J Lee, JW Argiris, A Haigentz, M Feldman, LE Jang, M Arun, P Van Waes, C Forastiere, AA AF Gilbert, Jill Lee, Ju Whei Argiris, Athanassios Haigentz, Missak, Jr. Feldman, Lawrence Eric Jang, Minyoung Arun, Pattatheyil Van Waes, Carter Forastiere, Arlene A. TI Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): A trial of the Eastern Cooperative Oncology Group SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE head and neck cancer; chemotherapy; bortezomib; irinotecan; phase II ID FACTOR-KAPPA-B; TUMOR-CELLS; CANCER; THERAPY; DOCETAXEL; CISPLATIN; ACTIVATOR; PATHWAY; EGFR AB Background Constitutive activation of nuclear factor B (NF-B) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-B, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-B. Patients and Methods We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone. Results The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib. Conclusions The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer. Head Neck, 2013 C1 [Gilbert, Jill] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [Lee, Ju Whei] Dana Farber Canc Inst, Boston, MA 02115 USA. [Argiris, Athanassios] Univ Pittsburgh, Pittsburgh, PA USA. [Haigentz, Missak, Jr.] Montefiore Hosp & Med Ctr, Bronx, NY USA. [Feldman, Lawrence Eric] Univ Illinois Chicago MBCCOP, Chicago, IL USA. [Jang, Minyoung; Arun, Pattatheyil; Van Waes, Carter] NIDCD, Head & Neck Surgey Branch, NIH, Bethesda, MD USA. [Forastiere, Arlene A.] Johns Hopkins Univ, Baltimore, MD USA. RP Gilbert, J (reprint author), Vanderbilt Univ, Med Ctr, 2220 Pierce Ave,777 PRB, Nashville, TN 37232 USA. EM jill.gilbert@vanderbilt.edu FU Public Health Service from the National Cancer Institute, National Institutes of Health [CA23318, CA66636, CA21115, CA39229, CA49957, CA14958, CA16116]; Department of Health and Human Services; Milllennium Pharmaceuticals FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA39229, CA49957, CA14958, CA16116 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.; Milllennium Pharmaceuticals provided bortezomib for prior preclinical studies6 to C. V. W. and bortezomib and funding to NCI for a prior clinical trial and correlative studies.16 NR 18 TC 10 Z9 12 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUL PY 2013 VL 35 IS 7 BP 942 EP 948 DI 10.1002/hed.23046 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 168RI UT WOS:000320723000013 PM 22791234 ER PT J AU Mumford, SL Dasharathy, SS Pollack, AZ Perkins, NJ Mattison, DR Cole, SR Wactawski-Wende, J Schisterman, EF AF Mumford, Sunni L. Dasharathy, Sonya S. Pollack, Anna Z. Perkins, Neil J. Mattison, Donald R. Cole, Stephen R. Wactawski-Wende, Jean Schisterman, Enrique F. TI Serum uric acid in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study SO HUMAN REPRODUCTION LA English DT Article DE anovulation; estradiol; menstrual cycle; premenopausal women; uric acid ID POLYCYSTIC-OVARY-SYNDROME; MARGINAL STRUCTURAL MODELS; ESTRADIOL-17-BETA E2; PREMENOPAUSAL WOMEN; CARDIOVASCULAR RISK; INSULIN-RESISTANCE; OXIDATIVE STRESS; SEX-DIFFERENCES; METABOLISM; THERAPY AB Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E-2) and reproductive hormone concentrations in regularly menstruating women? Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E-2 and progesterone, and positively associated with FSH. E-2 may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated. The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n 9) or 2 (n 250) menstrual cycle(s). Participants were healthy women aged 1844 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations. Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E-2 was associated with a decrease in uric acid of 1.1 ( 0.011; 95 confidence interval (CI): 0.019, 0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by 0.8 ( 0.008; 95 CI: 0.012, 0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6 increase in uric acid ( 0.016; 95 CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95 CI: 1.25, 4.56). The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles. These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E-2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract HHSN275200403394C). No competing interests declared. C1 [Mumford, Sunni L.; Dasharathy, Sonya S.; Pollack, Anna Z.; Perkins, Neil J.; Mattison, Donald R.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. [Cole, Stephen R.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Mattison, Donald R.] Risk Sci Int, Ottawa, ON K1N7G2, Canada. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). NR 42 TC 12 Z9 12 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2013 VL 28 IS 7 BP 1853 EP 1862 DI 10.1093/humrep/det085 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 170MK UT WOS:000320855600015 PM 23562957 ER PT J AU Chen, CZ Southall, N Xiao, JB Marugan, JJ Ferrer, M Hu, X Jones, RE Feng, S Agoulnik, IU Zheng, W Agoulnik, AI AF Chen, Catherine Z. Southall, Noel Xiao, Jingbo Marugan, Juan J. Ferrer, Marc Hu, Xin Jones, Raisa E. Feng, Shu Agoulnik, Irina U. Zheng, Wei Agoulnik, Alexander I. TI Identification of Small-Molecule Agonists of Human Relaxin Family Receptor 1 (RXFP1) by Using a Homogenous Cell-Based cAMP Assay SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE relaxin; GPCR; RXFP1; qHTS; agonist; small molecule ID PROTEIN-COUPLED RECEPTOR-7; LEUCINE-RICH REPEAT; PEPTIDE RECEPTORS; SPLICE VARIANTS; LGR7; MEMBRANE AB The relaxin hormone is involved in a variety of biological functions, including female reproduction and parturition, as well as regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) relaxin family receptor 1 (RXFP1) is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. Although agonists of the receptor could have a wide range of pharmacologic utility, until now there have been no reported small-molecule agonists for relaxin receptors. Here, we report the development of a quantitative high-throughput platform for an RXFP1 agonist screen based on homogenous cell-based HTRF cyclic AMP (cAMP) assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365 677 compounds. Neither compound showed activity in a counterscreen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small-molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists. C1 [Chen, Catherine Z.; Southall, Noel; Xiao, Jingbo; Marugan, Juan J.; Ferrer, Marc; Hu, Xin; Jones, Raisa E.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Feng, Shu] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Agoulnik, Irina U.] Florida Int Univ, Dept Cellular Biol & Pharmacol, Miami, FL 33199 USA. [Agoulnik, Alexander I.] Florida Int Univ, Dept Human & Mol Genet, Miami, FL 33199 USA. RP Zheng, W (reprint author), NIH, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; aagoulni@fiu.edu RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Agoulnik, Irina/0000-0003-4889-0324; Agoulnik, Alexander/0000-0001-6587-6845 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681, R03 MH085705]; Intramural Research Program of the National Human Genome Research Institute; National Center for Advancing Translational Sciences, National Institutes of Health FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research U54MH084681 and R03 MH085705 (to A. I. A.) and the Intramural Research Program of the National Human Genome Research Institute and National Center for Advancing Translational Sciences, National Institutes of Health. NR 19 TC 9 Z9 9 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2013 VL 18 IS 6 BP 670 EP 677 DI 10.1177/1087057112469406 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 170XI UT WOS:000320888100004 PM 23212924 ER PT J AU McCallum, MM Nandhikonda, P Temmer, JJ Eyermann, C Simeonov, A Jadhav, A Yasgar, A Maloney, D Arnold, A AF McCallum, Megan M. Nandhikonda, Premchendar Temmer, Jonathan J. Eyermann, Charles Simeonov, Anton Jadhav, Ajit Yasgar, Adam Maloney, David Arnold, Alexander (Leggy) TI High-Throughput Identification of Promiscuous Inhibitors from Screening Libraries with the Use of a Thiol-Containing Fluorescent Probe SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE promiscuous inhibitors; glutathione; fluorescence; high-throughput screening; thiol-reactive or electrophilic compound ID COMPOUND LIBRARIES; FALSE POSITIVES; ASSAY; DISCOVERY; REACTIVITY; RECEPTOR; FILTERS; HTS AB Testing small molecules for their ability to modify cysteine residues of proteins in the early stages of drug discovery is expected to accelerate our ability to develop more selective drugs with lesser side effects. In addition, this approach also enables the rapid evaluation of the mode of binding of new drug candidates with respect to thiol reactivity and metabolism by glutathione. Herein, we describe the development of a fluorescence-based high-throughput assay that allows the identification of thiol-reactive compounds. A thiol-containing fluorescent probe, MSTI, was synthesized and used to evaluate small molecules from the Library of Pharmacologically Active Compounds (LOPAC) collection of bioactive molecules. LOPAC compounds that are known to react with sulfur nucleophiles were identified with this assay, for example, irreversible protease inhibitors, nitric oxide-releasing compounds, and proton-pump inhibitors. The results confirm that both electrophilic and redox reactive compounds can be quickly identified in a high-throughput manner, enabling the assessment of screening libraries with respect to thiol-reactive compounds. C1 [McCallum, Megan M.; Nandhikonda, Premchendar; Temmer, Jonathan J.; Arnold, Alexander (Leggy)] Univ Wisconsin, Milwaukee, WI 53211 USA. [Eyermann, Charles; Simeonov, Anton; Jadhav, Ajit; Yasgar, Adam; Maloney, David] NIH, Bethesda, MD 20892 USA. RP Arnold, A (reprint author), Univ Wisconsin, Dept Chem & Biochem, 3210 N Cramer St, Milwaukee, WI 53211 USA. EM Arnold2@uwm.edu RI Nandhikonda, Premchendar/K-1473-2014 FU University of Wisconsin Milwaukee; UWM Research Growth Initiative (RGI), National Institute of Drug Abuse [R03DA031090]; UWM Research Foundation; Lynde and Harry Bradley Foundation; Richard and Ethel Herzfeld Foundation; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported in part by the University of Wisconsin Milwaukee, the UWM Research Growth Initiative (RGI), National Institute of Drug Abuse (R03DA031090), the UWM Research Foundation, the Lynde and Harry Bradley Foundation, the Richard and Ethel Herzfeld Foundation, and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (U54MH084681). NR 27 TC 7 Z9 7 U1 2 U2 24 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2013 VL 18 IS 6 BP 705 EP 713 DI 10.1177/1087057113476090 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 170XI UT WOS:000320888100008 PM 23446699 ER PT J AU Fox, NA Barker, TV White, LK Suway, JG Pine, DS AF Fox, Nathan A. Barker, Tyson V. White, Lauren K. Suway, Jenna G. Pine, Daniel S. TI Commentary: To intervene or not? Appreciating or treating individual differences in childhood temperament - remarks on Rapee (2013) SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Editorial Material ID SOCIAL ANXIETY DISORDER; BEHAVIORAL-INHIBITION; CHILDREN; RISK C1 [Fox, Nathan A.; Barker, Tyson V.; White, Lauren K.; Suway, Jenna G.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Fox, NA (reprint author), Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. EM fox@umd.edu FU NICHD NIH HHS [T32 HD007542]; NIMH NIH HHS [U01 MH093349] NR 10 TC 1 Z9 1 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JUL PY 2013 VL 54 IS 7 BP 789 EP 790 DI 10.1111/jcpp.12101 PG 2 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 169KF UT WOS:000320778200010 PM 23746203 ER PT J AU Ryschkewitsch, CF Jensen, PN Major, EO AF Ryschkewitsch, Caroline F. Jensen, Peter N. Major, Eugene O. TI Multiplex qPCR assay for ultra sensitive detection of JCV DNA with simultaneous identification of genotypes that discriminates non-virulent from virulent variants SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE qPCR; JC Virus; Variants; PML diagnostics ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; REAL-TIME PCR; NUCLEOTIDE-SEQUENCES; BONE-MARROW; VIRUS-DNA; POLYOMAVIRUS; PATHOGENESIS; INDIVIDUALS; REGIONS; URINE AB Background: JC virus (JCV) is the etiologic agent for progressive multifocal leukoencephalopathy (PML), a demyelinating disease occurring in the brain of patients with underlying immune compromised states. All viable JCV genomes contain a conserved region in the T protein coding nucleotide sequence that when detected by PCR in CSF is a confirmatory diagnostic marker for PML along with clinical and neuroradio-logical evidence. The non-coding regulatory region (NCRR) is hypervariable, as evidenced by nucleotide sequence of the non-virulent variant, which is predominantly excreted in urine, versus that of virulent variants found in brain and CSF of PML patients. All variants can be found in blood. Objective: A single assay that quantifies and identifies JCV DNA in clinical samples and discriminates between variants has significant value to physicians and patients at risk for PML. Study design: Separate primer pairs were tested together to quantitatively detect conserved viral DNA nucleotide sequence in patient samples, while simultaneously detecting the NCRR specific for the non-virulent variant. Results: In testing using control plasmids and patients' CSF, blood, and urine, PML patients predictably demonstrated the non-virulent, archetype NCRR in urine, but virulent NCRR variants in CSF and blood. Conclusion: The JCV qPCR multiplex assay targets two regions in JCV genomes to simultaneously identify and measure viral DNA, as well as distinguish between variants associated with PML and those that are not. The multiplex results could signal risk for PML if patients are viremic with JCV variants closely associated with PML pathogenesis. Published by Elsevier B. V. C1 [Ryschkewitsch, Caroline F.; Jensen, Peter N.; Major, Eugene O.] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Major, EO (reprint author), Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Lab Mol Med & Neurosci, 10 Ctr Dr,Bldg 10,Room 3B14, Bethesda, MD 20892 USA. EM ryschkec@ninds.nih.gov; JensenP@ninds.nih.gov; majorg@ninds.nih.gov FU Division of Intramural Research, National Institute of Neurological Disorders and Stroke FX Funding is provided through the Division of Intramural Research, National Institute of Neurological Disorders and Stroke. NR 19 TC 25 Z9 25 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD JUL PY 2013 VL 57 IS 3 BP 243 EP 248 DI 10.1016/j.jcv.2013.03.009 PG 6 WC Virology SC Virology GA 166XL UT WOS:000320593300011 PM 23619054 ER PT J AU Metayer, C Colt, JS Buffler, PA Reed, HD Selvin, S Crouse, V Ward, MH AF Metayer, Catherine Colt, Joanne S. Buffler, Patricia A. Reed, Helen D. Selvin, Steve Crouse, Vonda Ward, Mary H. TI Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE childhood leukemia; herbicides; pesticides; dust ID NON-HODGKINS-LYMPHOMA; AGRICULTURAL HEALTH; PESTICIDE EXPOSURE; CANCER INCIDENCE; FARM-WORKERS; CHILDREN; CALIFORNIA; GERMANY; COHORT; POLLUTANTS AB We examine the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Models included the herbicide of interest, age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49 (95% CI: 0.82-2.72), 1.49 (95% CI: 0.83-2.67), and 1.57 (95% CI: 0.90-2.73), respectively (P-value for linear trend = 0.05). The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL. C1 [Metayer, Catherine; Buffler, Patricia A.; Selvin, Steve] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. [Colt, Joanne S.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Reed, Helen D.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Crouse, Vonda] Childrens Hosp Cent Calif, Dept Pediat Oncol, Madera, CA USA. RP Metayer, C (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM cmetayer@berkeley.edu FU National Institute of Environmental Health Sciences [R01 ES09137, P42-ES04705]; National Cancer Institute [7590-S-04, 7590-S-01, N02-CP-11015]; National Institutes of Health FX This research could not have been conducted without the important support from our clinical collaborators and participating hospitals, which include: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Dr. Mignon Loh and Dr. Katherine Matthay), Children's Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children's Hospital (Dr. Gary Dahl), Children's Hospital Oakland (Dr. James Feusner), Kaiser Permanente Sacramento (Dr. Vincent Kiley), Kaiser Permanente Santa Clara (Dr. Carolyn Russo and Dr. Alan Wong), Kaiser Permanente San Francisco (Dr. Kenneth Leung), and Kaiser Permanente Oakland (Dr. Stacy Month), and the families of the study participants. We also wish to acknowledge the effort and dedication of all our collaborators at the Northern California Childhood Leukemia Study who helped make this study possible, and the staff at the Battelle Memorial Institute, Columbus, OH who performed laboratory analyses. This work was financially supported by National Institute of Environmental Health Sciences, Grants R01 ES09137 and P42-ES04705; the Intramural Research Program of the National Cancer Institute (subcontracts 7590-S-04, 7590-S-01); the National Cancer Institute (contract N02-CP-11015), and from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Cancer Institute. NR 61 TC 16 Z9 17 U1 6 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD JUL-AUG PY 2013 VL 23 IS 4 BP 363 EP 370 DI 10.1038/jes.2012.115 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 166VG UT WOS:000320586200005 PM 23321862 ER PT J AU Schmitt, KC Rothman, RB Reith, MEA AF Schmitt, Kyle C. Rothman, Richard B. Reith, Maarten E. A. TI Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEUROTRANSMITTER-SODIUM SYMPORTER; PROTEIN-PROTEIN INTERACTIONS; BIOGENIC-AMINE TRANSPORTERS; BINDING-SITES; MONOAMINE TRANSPORTERS; BACTERIAL HOMOLOG; CRYSTAL-STRUCTURE; COCAINE; LEUT; IDENTIFICATION AB The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic, and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. Because both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands possess an addictive liability equivalent to that of cocaine. However, certain recently developed ligands, such as atypical benztropine-like DAT inhibitors with reduced or even a complete lack of cocaine-like rewarding effects, suggest that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classic preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific pleiotropic functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein that can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychological effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders. C1 [Schmitt, Kyle C.] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA. [Reith, Maarten E. A.] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Reith, Maarten E. A.] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. [Rothman, Richard B.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Schmitt, KC (reprint author), NYU, Sch Med, Dept Neurosurg, Publ Hlth Labs, 455 1st Ave,8th Floor, New York, NY 10016 USA. EM kyle.schmitt@nyumc.org FU National Institutes of Health National Institute on Drug Abuse [R01 DA019676]; National Institutes of Health National Institute of Mental Health [R01 MH083840]; National Institutes of Health [National Institute on Drug Abuse] FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01 DA019676]; the National Institutes of Health National Institute of Mental Health [Grant R01 MH083840]; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]. NR 67 TC 29 Z9 30 U1 3 U2 11 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 JUL PY 2013 VL 346 IS 1 BP 2 EP 10 DI 10.1124/jpet.111.191056 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 164XQ UT WOS:000320446100001 PM 23568856 ER PT J AU Niciu, MJ Grunschel, BDG Corlett, PR Pittenger, C Bloch, MH AF Niciu, Mark J. Grunschel, Beth D. G. Corlett, Philip R. Pittenger, Christopher Bloch, Michael H. TI Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Ketamine; OCD; depression; SAE; suicidality ID RECEPTOR ANTAGONIST RESPONSE AB Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that is Food and Drug Administration-approved in the United States for anesthesia due to its sedative effects with low risk of severe respiratory depression. Subanesthetic dose intravenous ketamine has rapidly acting antidepressant effects in treatment-resistant unipolar and bipolar depression. We recently reported an open-label trial of ketamine in 10 subjects with treatment-refractory obsessive-compulsive disorder, seven of whom had active comorbid depression. Although ketamine had no sustained anti-obsessive effect, four of the seven subjects with comorbid depression experienced an acute antidepressant effect. However, we unexpectedly observed delayed-onset dysphoria, worsening anxiety and suicidal thinking in two of the three subjects with obsessive-compulsive disorder and extensive psychiatric comorbidity but minimal depressive symptoms at the start of infusion. The implications of these adverse neuropsychiatric effects in two patients with similar psychiatric comorbidity are discussed. We conclude that there remains insufficient data on therapeutic ketamine in the presence of comorbid psychiatric disorders to promote its off-label use in a non-research milieu. C1 [Niciu, Mark J.; Grunschel, Beth D. G.; Corlett, Philip R.; Pittenger, Christopher; Bloch, Michael H.] Yale Univ, Dept Psychiat, CMHC, CNRU, New Haven, CT 06520 USA. [Niciu, Mark J.] NIMH, NIH, Bethesda, MD 20814 USA. [Pittenger, Christopher; Bloch, Michael H.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. RP Niciu, MJ (reprint author), NIMH, NIH, Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 7-5545, Bethesda, MD 20814 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014 OI Niciu, Mark/0000-0002-5612-3021 FU National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) [T32MH19961]; Robert L. McNeil Jr. Fellowship in Translational Research; VA-Connecticut Alcohol Research Center; Yale University Department of Psychiatry; CTSA from the National Center for Research Resources (NCRR) [UL1RR024139]; National Center for Advancing Translational Science (NCATS), NIH; NIH Roadmap for Medical Research; NIH/NIMH from the NCRR [UL1RR024139, K08MH081190]; NIH/NIMH [K23MH091240-01]; American Psychiatric Institute for Research and Education (APIRE)/Eli Lilly and Co. Psychiatric Research Fellowship; American Academy of Child and Adolescent Psychiatry/Eli Lilly and Co. Pilot Research Award; Trichotillomania Learning Center; National Alliance for Research on Schizophrenia and Depression (NARSAD) from the NCRR [UL1RR024139] FX Salary support was provided to each author by the following sources: MJN: National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) T32MH19961, the Robert L. McNeil Jr. Fellowship in Translational Research and the VA-Connecticut Alcohol Research Center. BDGG: Yale University Department of Psychiatry. PRC: CTSA Grant Number UL1RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the NIH, and NIH Roadmap for Medical Research. CP: NIH/NIMH K08MH081190, UL1RR024139 from the NCRR and the NIH Roadmap for Medical Research. MHB: NIH/NIMH support of the Yale Child Study Center Research Training Program, K23MH091240-01, the American Psychiatric Institute for Research and Education (APIRE)/Eli Lilly and Co. Psychiatric Research Fellowship, the American Academy of Child and Adolescent Psychiatry/Eli Lilly and Co. Pilot Research Award, the Trichotillomania Learning Center, The National Alliance for Research on Schizophrenia and Depression (NARSAD), UL1RR024139 from the NCRR and the NIH Roadmap for Medical Research. The State of Connecticut also provided resource support to all authors via the Abraham Ribicoff Research Facilities/CNRU at CMHC, where this research was conducted. NR 21 TC 15 Z9 15 U1 3 U2 14 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JUL PY 2013 VL 27 IS 7 BP 651 EP 654 DI 10.1177/0269881113486718 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 168JZ UT WOS:000320703100010 PM 23676198 ER PT J AU Akhtar, A Kamal, AK AF Akhtar, Anjum Kamal, Ayeesha Kamran TI CLEAR: The Intraventricular Haemorrhage Thrombolysis Trial SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 0 TC 1 Z9 1 U1 0 U2 2 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD JUL PY 2013 VL 63 IS 7 BP 928 EP 928 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 165LQ UT WOS:000320485800028 PM 23901725 ER PT J AU Lubaki, NM Ilinykh, P Pietzsch, C Tigabu, B Freiberg, AN Koup, RA Bukreyev, A AF Lubaki, Ndongala M. Ilinykh, Philipp Pietzsch, Colette Tigabu, Bersabeh Freiberg, Alexander N. Koup, Richard A. Bukreyev, Alexander TI The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; DOUBLE-STRANDED-RNA; INFLUENZA-A VIRUS; VP35 PROTEIN; HEMORRHAGIC-FEVER; MARBURG VIRUSES; IN-VITRO; NONHUMAN-PRIMATES; INTERFERON ANTAGONISM; VIRION GLYCOPROTEINS AB Ebola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the "immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs. C1 [Lubaki, Ndongala M.; Ilinykh, Philipp; Pietzsch, Colette; Tigabu, Bersabeh; Freiberg, Alexander N.; Bukreyev, Alexander] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Bukreyev, Alexander] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Lubaki, Ndongala M.; Ilinykh, Philipp; Pietzsch, Colette; Tigabu, Bersabeh; Freiberg, Alexander N.; Bukreyev, Alexander] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. EM alexander.bukreyev@utmb.edu RI Ilinykh, Philipp/L-5404-2014 FU University of Texas Medical Branch; John Sealy Memorial Endowment Fund Pilot Grant "Mechanisms of 'immune paralysis' in Ebola infections"; McLaughlin Fellowship FX The study was supported by a departmental startup grant from the University of Texas Medical Branch (A.B.), the John Sealy Memorial Endowment Fund Pilot Grant "Mechanisms of 'immune paralysis' in Ebola infections" (A.B.), and the McLaughlin Fellowship (N.M.L.). NR 82 TC 24 Z9 25 U1 0 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 13 BP 7471 EP 7485 DI 10.1128/JVI.03316-12 PG 15 WC Virology SC Virology GA 160JT UT WOS:000320116500024 PM 23616668 ER PT J AU Rasheed, MAU Latner, DR Aubert, RD Gourley, T Spolski, R Davis, CW Langley, WA Ha, SJ Ye, LL Sarkar, S Kalia, V Konieczny, BT Leonard, WJ Ahmed, R AF Rasheed, Mohammed Ata Ur Latner, Donald R. Aubert, Rachael D. Gourley, Tania Spolski, Rosanne Davis, Carl W. Langley, William A. Ha, Sang-Jun Ye, Lilin Sarkar, Surojit Kalia, Vandana Konieczny, Bogumila T. Leonard, Warren J. Ahmed, Rafi TI Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells SO JOURNAL OF VIROLOGY LA English DT Article ID FOLLICULAR-HELPER-CELLS; CHRONIC VIRAL-INFECTION; GERMINAL CENTER RESPONSES; CXC CHEMOKINE RECEPTOR-5; CD4(+) T-CELLS; HUMAN B-CELLS; IMMUNOGLOBULIN PRODUCTION; ANTIBODY-PRODUCTION; HUMORAL IMMUNITY; BCL-6 EXPRESSION AB Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R(-/-)) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (T-FH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R(-/-) mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL-21R(-/-) mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R(-/-) mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R(-/-) CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses. C1 [Rasheed, Mohammed Ata Ur; Latner, Donald R.; Aubert, Rachael D.; Gourley, Tania; Davis, Carl W.; Langley, William A.; Ha, Sang-Jun; Ye, Lilin; Sarkar, Surojit; Kalia, Vandana; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Rasheed, Mohammed Ata Ur; Latner, Donald R.; Aubert, Rachael D.; Gourley, Tania; Davis, Carl W.; Langley, William A.; Ha, Sang-Jun; Ye, Lilin; Sarkar, Surojit; Kalia, Vandana; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, Bethesda, MD 20892 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu RI Rasheed, Mohammed/N-2749-2013; OI Ha, Sang-Jun/0000-0002-1192-6031 FU National Institutes of Health (NIH) [P01 AI097092-01A1, RO1 A1030048]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery grant [UM1AI100663]; Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH FX This work was supported by National Institutes of Health (NIH) grants P01 AI097092-01A1 (to R.A.) and RO1 A1030048 (to R.A.) and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery grant UM1AI100663 (to R.A.). This work was also supported in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (to W.J.L. and R.S.). NR 45 TC 42 Z9 42 U1 1 U2 9 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 JUL PY 2013 VL 87 IS 13 BP 7737 EP 7746 DI 10.1128/JVI.00063-13 PG 10 WC Virology SC Virology GA 160JT UT WOS:000320116500047 PM 23637417 ER PT J AU Savage, SA Pulsipher, MA Romano, A Berlyne, D AF Savage, Sharon A. Pulsipher, Michael A. Romano, Alessandra Berlyne, Deborah TI Aplastic Anemia & MDS International Foundation (AA&MDSIF): Bone marrow failure disease scientific symposium 2012 SO LEUKEMIA RESEARCH LA English DT Article DE Myelodysplastic syndromes; Aplastic anemia; Paroxysmal nocturnal hemoglobinuria; Bone marrow failure; Epigenetic therapy; Immunosuppressive therapy; Stem cell transplantation; Complement ID MYELODYSPLASTIC SYNDROMES AB Aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are rare disorders of bone marrow failure. Once considered distinct entities, these three diseases are now believed to have overlapping pathophysiologies. The Aplastic Anemia and MDS International Foundation, a nonprofit organization that supports patients and families living with bone marrow failure disorders, sponsored a scientific symposium in Bethesda, MD, in March 2012. This report summarizes the symposium presentations by 30 of the world's leading AA, MDS, and PNH researchers on recent findings, current areas of controversy, and recommendations for basic and clinical research to advance the field. (c) 2013 Published by Elsevier Ltd. C1 [Savage, Sharon A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Pulsipher, Michael A.] Univ Utah, Huntsman Canc Inst, Div Hematol & Hematol Malignancies, Salt Lake City, UT USA. [Romano, Alessandra] Univ Catania, Osped Ferrarotto, Div Clinicizzata Ematol, Catania, Italy. [Berlyne, Deborah] Aplast Anemia & Myelodysplast Syndrome Int Fdn, Rockville, MD USA. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, 6120 Execut Blvd,EPS 7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015; ROMANO, ALESSANDRA/I-9201-2012 OI Savage, Sharon/0000-0001-6006-0740; ROMANO, ALESSANDRA/0000-0002-6333-4433 FU National Institutes of Health, National Heart, Lung, and Blood Institute [1R13HL112578-01]; Office of Rare Disease Research; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX The authors thank all meeting participants for a highly productive meeting. Funding for this conference was made possible in part by 1R13HL112578-01 from the National Institutes of Health, National Heart, Lung, and Blood Institute and the Office of Rare Disease Research. This work was supported, in part, by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (S.A.S.). The views expressed in written conference materials or publications and by speakers or moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Author contributions. All authors participated in the AA&MDSIF meeting and in writing the manuscript. All authors approved of the final version. NR 8 TC 1 Z9 2 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2013 VL 37 IS 7 BP 848 EP 851 DI 10.1016/j.leukres.2013.04.013 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 166UF UT WOS:000320583100022 PM 23643149 ER PT J AU Fernandez-Duenas, V Gomez-Soler, M Morato, X Nunez, F Das, A Kumar, TS Jauma, S Jacobson, KA Ciruela, F AF Fernandez-Duenas, Victor Gomez-Soler, Maricel Morato, Xavier Nunez, Fabiana Das, Arijit Kumar, T. Santhosh Jauma, Serge Jacobson, Kenneth A. Ciruela, Francisco TI Dopamine D-2 receptor-mediated modulation of adenosine A(2A) receptor agonist binding within the A(2A)R/D2R oligomer framework SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE A(2A)R; D2R; Parkinson's disease; Receptor-receptor allosterism; Antiparkinsonian drugs ID PARKINSONS-DISEASE; HETEROMERS; SUBTYPES AB The molecular interaction between adenosine A(2A) and dopamine D-2 receptors (A(2A)Rs and D(2)Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A(2A)R challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D2R-mediated allosteric modulation of A(2A)R binding when an A(2A)R/D2R oligomer is established. Thus, we synthesized fluorescent A(2A)R agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A(2A)R binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A(2A)R agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A(2A)R agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D(2)Rs to modulate A(2A)R binding, thus serving to facilitate the preliminary selection of D2R-like candidate drugs in the management of Parkinson's disease. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Fernandez-Duenas, Victor; Gomez-Soler, Maricel; Morato, Xavier; Nunez, Fabiana; Ciruela, Francisco] Univ Barcelona, Fac Med, IDIBELL, Dept Patol & Terapeut Expt,Unitat Farmacol, Barcelona 08907, Spain. [Das, Arijit; Kumar, T. Santhosh; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jauma, Serge] Hosp Univ Bellvitge, Neurol Serv, Movement Disorders Unit, Barcelona 08907, Spain. RP Ciruela, F (reprint author), Fac Med Bellvitge, Dept Patol & Terapeut Expt, Unitat Farmacol, Pavello Govern,Av Feixa Llarga S-N, Barcelona 08907, Spain. EM fciruela@ub.edu RI Jacobson, Kenneth/A-1530-2009; Ciruela, Francisco/A-5096-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Ciruela, Francisco/0000-0003-0832-3739; Fernandez Duenas, Victor/0000-0001-7834-2965 FU "Ministerio de Economia y Competitividad" (MINECO) [SAF2011-24779, CSD2008-00005]; ICREA Academia from the Catalan Institution for Research and Advanced Studies (ICREA); NIDDK Intramural Research Program of the National Institutes of Health, Bethesda FX This work was supported by grants SAF2011-24779 and Consolider-Ingenio CSD2008-00005 from "Ministerio de Economia y Competitividad" (MINECO) and ICREA Academia-2010 from the Catalan Institution for Research and Advanced Studies (ICREA) to FC. Also, VF-D, MG-S, FN and FC belong to the "Neuropharmacology and Pain" accredited research group (Generalitat de Catalunya, 2009 SGR 232). Support to KAJ, AD, and TSK from the NIDDK Intramural Research Program of the National Institutes of Health, Bethesda, MD, USA is acknowledged. We thank Esther Castano, Eva Julia, and Benjamin Torrejon, from the Scientific and Technical Services (SCT)-Bellvitge Campus of the University of Barcelona for the technical assistance. NR 13 TC 5 Z9 5 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD JUL PY 2013 VL 63 IS 1 BP 42 EP 46 DI 10.1016/j.neuint.2013.04.006 PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 169BE UT WOS:000320751100005 PM 23619397 ER PT J AU Jarcho, JM Feier, NA Bert, A Labus, JA Lee, M Stains, J Ebrat, B Groman, SM Tillisch, K Brody, AL London, ED Mandelkern, MA Mayer, EA AF Jarcho, Johanna M. Feier, Natasha A. Bert, Alberto Labus, Jennifer A. Lee, Maunoo Stains, Jean Ebrat, Bahar Groman, Stephanie M. Tillisch, Kirsten Brody, Arthur L. London, Edythe D. Mandelkern, Mark A. Mayer, Emeran A. TI Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain SO PAIN LA English DT Article DE PET; NK-1 receptor; Irritable bowel syndrome; Inflammatory bowel disease; Somatic pain; Quality of life ID IRRITABLE-BOWEL-SYNDROME; POSITRON-EMISSION-TOMOGRAPHY; QUALITY-OF-LIFE; SUBSTANCE-P; NK1 RECEPTOR; SPINAL-CORD; HUMAN BRAIN; INFLAMMATORY PAIN; PLACEBO ANALGESIA; PERSISTENT PAIN AB Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [F-18] SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Jarcho, Johanna M.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Jarcho, Johanna M.; Feier, Natasha A.; Labus, Jennifer A.; Lee, Maunoo; Stains, Jean; Ebrat, Bahar; Tillisch, Kirsten; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, Los Angeles, CA 90095 USA. [Feier, Natasha A.] McGill Univ, Fac Dent, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada. [Bert, Alberto] SpA, Med Imaging Lab Im3D, Turin, Italy. [Groman, Stephanie M.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Brody, Arthur L.; London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Brody, Arthur L.; London, Edythe D.; Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, CHS 42-210 MC737818,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM emayer@ucla.edu OI Bert, Alberto/0000-0001-8391-7508; Jarcho, Johanna/0000-0001-9075-6968 FU National Institutes of Health [F31-DA021951, T32-MH017140, F31-DA028812, NIH AT00268]; Tobacco-Related Disease Research Program [19XT-0135]; Department of Veterans Affairs, Office of Research and Development (Merit Review Award) FX This work was supported in part by National Institutes of Health Grants F31-DA021951, T32-MH017140 (J.M.J.), F31-DA028812 (S.M.G.), NIH AT00268 (E.A.M.), and endowments from the Marjorie Greene Family Trust and National Institute on Drug Abuse (A.L.B. [R01 DA20872]), the Tobacco-Related Disease Research Program (A.L.B. [19XT-0135]), the Department of Veterans Affairs, Office of Research and Development (Merit Review Award [A.L.B.]), and the Thomas P. and Katherine K. Pike Chair in Addiction Studies (E.D.L.). NR 85 TC 12 Z9 12 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2013 VL 154 IS 7 BP 987 EP 996 DI 10.1016/j.pain.2013.02.026 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 166XD UT WOS:000320592200007 PM 23582152 ER PT J AU Huang, B Liu, M Huang, SG Wu, B Guo, H Su, XZ Lu, FL AF Huang, Bo Liu, Man Huang, Shiguang Wu, Bin Guo, Hong Su, Xin-zhuan Lu, Fangli TI Expression of Tim-1 and Tim-3 in Plasmodium berghei ANKA infection SO PARASITOLOGY RESEARCH LA English DT Article ID MURINE CEREBRAL MALARIA; IMMUNE-RESPONSE; MICE; CYTOKINES; SUSCEPTIBILITY; ENCEPHALITIS; PATHOGENESIS; FALCIPARUM; CHILDREN; ASTHMA AB Cerebral malaria (CM) is a serious and often fatal complication of Plasmodium falciparum infections; however, the precise mechanisms leading to CM is poorly understood. Mouse malaria models have provided insight into the key events in pathogenesis of CM. T-cell immune response is known to play an important role in malaria infection, and members of the T-cell immunoglobulin- and mucin-domain-containing molecule (Tim) family have roles in T-cell-mediated immune responses. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim family proteins in Plasmodium infection remains unclear. In the present study, the mRNA levels of Tim-1, Tim-3, and some key Th1 and Th2 cytokines in the spleen of Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) were determined using real-time polymerase chain reaction (qRT-PCR). Compared with uninfected controls, Tim-1 expression was significantly decreased in infected mice with CM at day 10 postinfection (p.i.) but significantly increased in infected mice with non-CM at day 22 p.i.; in contrast, Tim-3 expression was significantly increased in infected mice both with CM at day 10 p.i. and with non-CM at day 22 p.i. The expressions of IFN-gamma, TNF-alpha, IL-10, and IL-12 were significantly increased but IL-4 was significantly decreased in infected mice with CM at days 10 p.i., whereas the expressions of IFN-gamma, TNF-alpha, IL-4, IL-10, and TGF-beta were significantly increased but IL-12 was significantly decreased in infected mice with non-CM at days 22 p.i. Furthermore, the expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response in the spleen of PbANKA-infected mice, respectively. Our data suggest that PbANKA infection could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response in the early infective stage, whereas the infection could promote Th2 cell differentiation and induce Th2-biased immune response in the late infective stage. Our data indicate that both Tim-1 and Tim-3 may play a role in the process of PbANKA infection, which may represent a potential therapeutic target. C1 [Huang, Bo; Liu, Man; Wu, Bin; Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Bo; Liu, Man; Wu, Bin; Lu, Fangli] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Shiguang] Jinan Univ, Sch Med, Guangzhou 510632, Guangdong, Peoples R China. [Guo, Hong] Hainan Med Univ, Publ Lab, Haikou 571199, Hainan Province, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] Xiamen Univ, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian Province, Peoples R China. [Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Xiamen 361005, Fujian Province, Peoples R China. [Liu, Man] Medprin Regenerat Med Technol Co Ltd, Guangzhou 510663, Guangdong, Peoples R China. RP Lu, FL (reprint author), Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. EM thshg@126.com; fanglilu@yahoo.com OI Su, Xinzhuan/0000-0003-3246-3248 FU Fogarty International Center of the National Institutes of Health [R01TW008151]; Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Ministry of Education of China [B12003, B06016]; 111 Project; State Bureau of Foreign Experts FX Research reported in this publication was supported in part by the Fogarty International Center of the National Institutes of Health under Award Number R01TW008151, the Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the "111 Project" sponsored by the State Bureau of Foreign Experts and Ministry of Education of China (B12003 and B06016). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 4 Z9 7 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-0113 J9 PARASITOL RES JI Parasitol. Res. PD JUL PY 2013 VL 112 IS 7 BP 2713 EP 2719 DI 10.1007/s00436-013-3442-z PG 7 WC Parasitology SC Parasitology GA 165WO UT WOS:000320516500034 PM 23653017 ER PT J AU Jiang, JY Ahn, J Huang, WY Hayes, RB AF Jiang, Jieying Ahn, Jiyoung Huang, Wen-Yi Hayes, Richard B. TI Association of obesity with cardiovascular disease mortality in the PLCO trial SO PREVENTIVE MEDICINE LA English DT Article DE Cardiovascular disease; Body-mass index; Obesity ID BODY-MASS INDEX; CANCER SCREENING TRIAL; CORONARY-HEART-DISEASE; RISK-FACTORS; OVERWEIGHT; STROKE; WOMEN; PARTICIPANTS; PROSTATE; WEIGHT AB Objective. Obesity is a risk factor for cardiovascular disease (CVD) mortality, but the association between obesity and specific causes of CVD mortality is still under investigation. Method. We prospectively examined body-mass index (BMI) in relation to CVD-specific causes of death in approximately 86,000 US men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, followed for up to 13 years. BMI was calculated from self-reported weight and height at baseline. Hazard ratios (HRs) were calculated overall and stratified by sex, smoking status, and educational level. Result Overweight non-obese participants (BMI: 25.0-29.9) were not at excess risk for CVD mortality (HR and Cis are 1.02 [0.92-1.13]), compared to participants of normal BMI (18.5-24.9). Excess CVD mortality was observed for participants of BMI 30.0-34.9 (HR and Cis: 129[1.13-1.48]), BMI 35.0-39.9 (HR and CIs: 1.87[1.51-232]) and BMI 40.0 + (HR and Us: 221 [1.57-321]) (p < 0.001 for trend). BMI was unrelated to mortality due to stroke. The observed association of BMI with CVD was independent of gender, smoking status and educational level. Conclusion. Obesity is associated with increased mortality due to CVD. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jiang, Jieying; Ahn, Jiyoung; Hayes, Richard B.] NYU, Div Epidemiol, Dept Populat Hlth, Sch Med, New York, NY 10016 USA. [Huang, Wen-Yi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hayes, RB (reprint author), NYU, Div Epidemiol, Dept Populat Hlth, Sch Med, 650 1st Ave, New York, NY 10016 USA. EM Richard.B.Hayes@nyumc.org OI Hayes, Richard/0000-0002-0918-661X FU New York University School of Medicine; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health; Department of Health and Human Services (DHHS) FX This research was supported by New York University School of Medicine, by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services (DHHS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 13 Z9 13 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUL PY 2013 VL 57 IS 1 BP 60 EP 64 DI 10.1016/j.ypmed.2013.04.014 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 164SI UT WOS:000320429400012 PM 23632233 ER PT J AU Moreno, M Economidou, D Mar, AC Lopez-Granero, C Caprioli, D Theobald, DE Fernando, A Newman, AH Robbins, TW Dalley, JW AF Moreno, M. Economidou, D. Mar, A. C. Lopez-Granero, C. Caprioli, D. Theobald, D. E. Fernando, A. Newman, A. H. Robbins, T. W. Dalley, Jeffrey W. TI Divergent effects of D-2/3 receptor activation in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low impulsive rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Impulsivity; Locomotion; Quinpirole; Nafadotride; Dopamine; Nucleus accumbens ID REACTION-TIME-TASK; DOPAMINE D-3 RECEPTOR; ROMAN HIGH-AVOIDANCE; ATTENTIONAL PERFORMANCE; DRUG-ADDICTION; BRAIN; ANTAGONIST; LESIONS; STIMULATION; MODULATION AB Previously we demonstrated reduced D-2/3 receptor availability in the ventral striatum of hyper-impulsive rats on the five-choice serial reaction time task (5-CSRTT). However, the anatomical locus of D-2/3 receptor dysfunction in high impulsive (HI) rats is unknown. In the present study, we investigated whether D-2/3 receptor dysfunction in HI rats is localised to the core or shell sub-regions of the nucleus accumbens (NAcb). Rats were selected for low (low impulsive, LI) and high impulsivity on the 5-CSRTT and implanted with guide cannulae targeting the NAcb core and shell. The D-2/3 receptor agonist quinpirole was locally injected in the NAcb (0.1, 0.3 and 1 mu g per infusion) and its effects investigated on the performance of LI and HI rats on the 5-CSRTT as well as spontaneous locomotor activity in an open field. Intra-NAcb core quinpirole increased premature responding in HI rats but not in LI rats. In contrast, intra-NAcb shell quinpirole strongly increased locomotor activity in HI rats, unlike LI rats. This effect was blocked by intra-NAcb shell infusions of the D-2/3 receptor antagonist nafadotride (0.03 mu g). However, nafadotride was ineffective in blocking the effects of intra-NAcb core quinpirole on premature responding in HI rats. These findings indicate that impulsivity and hyperactivity are separately regulated by core and shell sub-regions of the NAcb and that HI rats show an enhanced response to D-2/3 receptor activation in these regions. These results suggest that the symptom clusters of hyperactivity and impulsivity in attention-deficit hyperactivity disorder may be neurally dissociable at the level of the NAcb. C1 [Moreno, M.; Lopez-Granero, C.] Univ Almeria, Dept Psychol, Almeria, Spain. [Economidou, D.; Mar, A. C.; Caprioli, D.; Theobald, D. E.; Fernando, A.; Robbins, T. W.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Economidou, D.; Mar, A. C.; Caprioli, D.; Theobald, D. E.; Fernando, A.; Robbins, T. W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England. [Newman, A. H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. RP Dalley, JW (reprint author), Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. EM jwd20@cam.ac.uk RI Lopez-Granero, Caridad/C-8316-2013; OI Lopez-Granero, Caridad/0000-0001-7781-3497; Moreno, Margarita/0000-0001-7336-6167 FU Medical Research Council [G0701500]; Ministerio de Ciencia e Innovacion of Spain [PSI2009-08626]; MRC; Wellcome Trust; NIDA-IRP, NIH FX This study was funded by grants from the Medical Research Council (G0701500) and the Ministerio de Ciencia e Innovacion of Spain (PSI2009-08626) and by a joint award from the MRC and Wellcome Trust in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. AHN was supported by the NIDA-IRP, NIH. NR 55 TC 16 Z9 17 U1 0 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2013 VL 228 IS 1 BP 19 EP 30 DI 10.1007/s00213-013-3010-3 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 163VM UT WOS:000320365100002 PM 23407782 ER PT J AU Sutherland, MT Carroll, AJ Salmeron, BJ Ross, TJ Stein, EA AF Sutherland, Matthew T. Carroll, Allison J. Salmeron, Betty Jo Ross, Thomas J. Stein, Elliot A. TI Insula's functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving SO PSYCHOPHARMACOLOGY LA English DT Article DE Alexithymia; Craving; Nicotine; Varenicline; Resting-state functional connectivity; Insula; Ventromedial prefrontal cortex; fMRI ID IOWA GAMBLING TASK; DECISION-MAKING; EMOTIONAL INTELLIGENCE; INDIVIDUAL-DIFFERENCES; INTEROCEPTIVE AWARENESS; MAINTAINING ABSTINENCE; SMOKING-CESSATION; BRAIN ACTIVATION; CINGULATE CORTEX; NEGATIVE FACTOR AB Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking. We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC). Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC. Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI-vmPFC circuit fully mediated this alexithymia-craving relation. That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI-vmPFC mediational effect was not observed following drug administration. These results suggest that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI-vmPFC functional coupling may be relevant factors for smoking cessation success. C1 [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Sutherland, Matthew T.; Carroll, Allison J.; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Deuxieme Maison, Miami, FL 33199 USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Psychol, Deuxieme Maison, RM 295,11299 SW 8th St, Miami, FL 33199 USA. EM masuther@fiu.edu RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS) FX This work was sponsored by the National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS). We thank Eliscia Smith, Angela Neal, Kimberly Slater, Loretta Spurgeon, Anita Signau and the NIDA-IRP nurses, pharmacy, and recruitment staff for assistance with data collection. NR 103 TC 18 Z9 18 U1 3 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2013 VL 228 IS 1 BP 143 EP 155 DI 10.1007/s00213-013-3018-8 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 163VM UT WOS:000320365100013 PM 23455594 ER PT J AU Kakiuchi-Kiyota, S Crabbs, TA Arnold, LL Pennington, KL Cook, JC Malarkey, DE Cohen, SM AF Kakiuchi-Kiyota, Satoko Crabbs, Torrie A. Arnold, Lora L. Pennington, Karen L. Cook, Jon C. Malarkey, David E. Cohen, Samuel M. TI Evaluation of Expression Profiles of Hematopoietic Stem Cell, Endothelial Cell, and Myeloid Cell Antigens in Spontaneous and Chemically Induced Hemangiosarcomas and Hemangiomas in Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE mouse; hemangiosarcomas; hemangiomas; hematopoietic stem cells; endothelial progenitor cells; immunohistochemistry ID PROGENITOR CELLS; HUMAN RELEVANCE; FACTOR-VIII; P53; ANGIOSARCOMAS; TROGLITAZONE; TUMORS; DIFFERENTIATION; PROLIFERATION; PRECURSORS AB It is unclear whether the process of spontaneous and chemically induced hemangiosarcoma and hemangioma formation in mice involves the transformation of differentiated endothelial cells (ECs) or recruitment of multipotential bone marrow-derived hematopoietic stem cells or endothelial progenitor cells (EPCs), which show some degree of endothelial differentiation. In the present study, immunohistochemical staining for hematopoietic stem cell markers (CD45 and CD34), EC markers (vascular endothelial growth factor receptor 2 [VEGFR2], CD31, and factor VIII-related antigen), and a myeloid lineage marker (CD14) was employed to better define the origin of hemangiosarcomas and hemangiomas in mice. Staining was negative for CD45, factor VIII-related antigen, and CD14 and positive for CD34, VEGFR2, and CD31, indicating that mouse hemangiosarcomas and hemangiomas are composed of cells derived from EPCs expressing CD34, VEGFR2, and CD31 but not factor VIII-related antigen. The lack of CD45 expression suggests that mouse vascular tumors may arise from EPCs that are at a stage later than hematopoietic stem cells. Since factor VIII-related antigen expression is known to occur later than CD31 expression in EPCs, our observations may indicate that these tumor cells are arrested at a stage prior to complete differentiation. In addition, myeloid lineage cells do not appear to contribute to hemangiosarcoma and hemangioma formation in mice. C1 [Kakiuchi-Kiyota, Satoko; Arnold, Lora L.; Pennington, Karen L.; Cohen, Samuel M.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Kakiuchi-Kiyota, Satoko; Cook, Jon C.] Pfizer Inc, Drug Safety Res & Dev, Groton, CT 06340 USA. [Crabbs, Torrie A.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Malarkey, David E.] NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Malarkey, David E.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Cohen, SM (reprint author), 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM scohen@unmc.edu FU Division of the National Toxicology Program of the NIH; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Dr. Norimitsu Shirai at Pfizer, Inc., for his pathological expertise and the individuals at EPL, Inc.: the Histology Lab for retrieving the paraffin blocks and cutting sections, the Photo Lab for taking photos of immunostaining, and Beth Mahler for editing images. We also gratefully acknowledge the technical expertise of Heather Jensen, Otis Lyght, Geoffrey Hurlburt, Yvette Rebolloso, David Olson, Quashana Brown, and Natasha Clayton in the Immunohistochemistry Lab of the Pathology Support Group of the Cellular and Molecular Pathology Branch of the National Toxicology Program, NIEHS for development of the methodology and performance of the immunohistochemistry. Heather Jensen was particularly helpful technically and in assisting in preparation of the manuscript. This research was supported (in part) by the Division of the National Toxicology Program of the NIH, National Institute of Environmental Health Sciences. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U.S. government. NR 41 TC 8 Z9 8 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2013 VL 41 IS 5 BP 709 EP 721 DI 10.1177/0192623312464309 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA 169FK UT WOS:000320764000002 PM 23125116 ER PT J AU Surh, I Brix, A French, JE Collins, BJ Sanders, JM Vallant, M Dunnick, JK AF Surh, Inok Brix, Amy French, John E. Collins, Bradley J. Sanders, J. Michael Vallant, Molly Dunnick, June K. TI Toxicology and Carcinogenesis Study of Senna in C3B6.129F1-Trp53 (tm1Brd) N12 Haploinsufficient Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE senna; Trp53; carcinogenesis; toxicity; laxative; large intestine ID TRANSGENIC MOUSE MODELS; ABERRANT CRYPT FOCI; ANTHRAQUINONE GLYCOSIDES; CELL-PROLIFERATION; P53-DEFICIENT MICE; COLORECTAL-CANCER; EATING-DISORDERS; LAXATIVE ABUSE; RAT COLON; IN-VITRO AB Senna is a pod or leaf of Senna alexandrina P. Mill and is used as a stimulant laxative. In the large intestine, bacterial enzymes reduce sennosides to rhein-9-anthrone, the active form for the laxative effect. To determine the potential toxic effects of senna, a 5-week dose range finding study in the C57BL/6N mouse and a 40-week toxicology and carcinogenesis study in the C3B6.129F1-Trp53(tm1Brd) N12 haploinsufficient (p53(+/-)) mouse were conducted. In the 5-week study, C57BL/6N mice were exposed to up to 10,000 ppm senna in feed. Increased incidences of epithelial hyperplasia of the cecum and colon were observed in males and females exposed to 5,000 or 10,000 ppm senna. These intestinal lesions were not considered to be of sufficient severity to cause mortality and, thus, in the p53(+/-) mouse 40-week study, the high dose of 10,000 ppm was selected. Significant increases in the incidences of epithelial hyperplasia of the colon and cecum were observed at 10,000 ppm in p53(+/-) males and females, and the incidence of hyperplasia of the colon was significantly increased at 3,000 ppm in females. In conclusion, the large intestine was the major target of senna-induced toxicity in both wild-type and the p53(+/-) mouse model. There was no neoplastic change when senna was administered to p53(+/-) mouse. C1 [Surh, Inok; Brix, Amy; French, John E.; Collins, Bradley J.; Sanders, J. Michael; Vallant, Molly; Dunnick, June K.] NIEHS, Res Triangle Pk, NC 27709 USA. [Surh, Inok] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. RP Dunnick, JK (reprint author), NIEHS, POB 12233,MD K2-13, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU NIEHS [N01-ES-65406, N01-ES-55536] FX This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). However, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U.S. government. We greatly acknowledge the expert review by Ms. Kristine Witt and Dr. Arun Pandiri. The in life phase of the study was conducted under NIEHS contracts N01-ES-65406 and N01-ES-55536. The authors would like to thank Drs. Milton Hejtmancik, Diane Gerken, Daphne Vasconcelos, and other staff at Battelle Memorial Institute for helping to conduct these studies. NR 66 TC 0 Z9 0 U1 1 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2013 VL 41 IS 5 BP 770 EP 778 DI 10.1177/0192623312464304 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 169FK UT WOS:000320764000007 PM 23125117 ER PT J AU Xi, ZX Li, X Li, J Peng, XQ Song, R Gaal, J Gardner, EL AF Xi, Zheng-Xiong Li, Xia Li, Jie Peng, Xiao-Qing Song, Rui Gaal, Jozsef Gardner, Eliot L. TI Blockade of dopamine D-3 receptors in the nucleus accumbens and central amygdala inhibits incubation of cocaine craving in rats SO ADDICTION BIOLOGY LA English DT Article DE Cocaine; craving; D-3 receptor; dopamine; drug seeking; incubation; relapse; SB-277011A ID SELF-ADMINISTERED COCAINE; INDUCED CONDITIONED LOCOMOTION; CUE-INDUCED REINSTATEMENT; DRUG-SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; DORSAL STRIATUM; D-AMPHETAMINE; EXCITOTOXIC LESIONS; HUMAN BRAIN; EXTRACELLULAR DOPAMINE AB Cue-induced drug seeking progressively increases over time of withdrawal from drug self-administration in rats, a phenomenon called incubation of craving'. The underlying mechanisms have been linked to increased expression of brain-derived neurotrophic factor and GluR2-lacking AMPA receptors in the mesolimbic dopamine (DA) system and also to increased extracellular signal-regulated kinase activation in the central amygdala (CeA). However, it remains unclear whether any DA mechanism is also involved in incubation of craving. Recent research demonstrates that cue-induced cocaine seeking appears to parallel increased DA D3, but not D1 or D2, receptor expression in the nucleus accumbens (NAc) of rats over time of withdrawal, suggesting possible involvement of D3 receptors (D3Rs) in incubation of cocaine craving. Here, we report that systemic or local administration of SB-277011A, a highly selective D3R antagonist, into the NAc (core and shell) or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2-30 days of withdrawal from previous cocaine self-administration but had no effect on sucrose-seeking behavior in rats after 10-30 days of withdrawal. These data suggest that DA D3Rs in both the NAc and the CeA play an important role in incubation of cocaine craving in rats and support the potential utility of D3R antagonists in the treatment of cocaine addiction. C1 [Xi, Zheng-Xiong; Li, Xia; Li, Jie; Peng, Xiao-Qing; Song, Rui; Gardner, Eliot L.] NIDA, Intramural Res Program, Baltimore, MD USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, Baltimore, MD USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU US National Institute on Drug Abuse Intramural Research Program FX This work was supported by the US National Institute on Drug Abuse Intramural Research Program. NR 82 TC 12 Z9 13 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2013 VL 18 IS 4 BP 665 EP 677 DI 10.1111/j.1369-1600.2012.00486.x PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 169IW UT WOS:000320774700007 PM 22913325 ER PT J AU Hoofnagle, JH Van Natta, ML Kleiner, DE Clark, JM Kowdley, KV Loomba, R Neuschwander-Tetri, BA Sanyal, AJ Tonascia, J AF Hoofnagle, J. H. Van Natta, M. L. Kleiner, D. E. Clark, J. M. Kowdley, K. V. Loomba, R. Neuschwander-Tetri, B. A. Sanyal, A. J. Tonascia, J. CA Non-alcoholic Steatohepatitis TI Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FATTY LIVER-DISEASE; RANDOMIZED CONTROLLED-TRIAL; TERM-FOLLOW-UP; E-DEFICIENCY; NATURAL-HISTORY; CANCER; PIOGLITAZONE; PREVENTION; SUPPLEMENTATION; EPIDEMIOLOGY AB Background Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. Aim To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. Methods The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to 40U/L and by 30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. Results ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P<0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P<0.001), but not fibrosis scores (P=0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P<0.05). Weight loss (2kg) was also associated with ALT response (P<0.001), improvements in NAS (P <0.001) and fibrosis (P<0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (2kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Conclusions Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622. C1 [Hoofnagle, J. H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. [Van Natta, M. L.; Clark, J. M.; Tonascia, J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kowdley, K. V.] Virginia Mason Med Ctr, Inst Digest Dis, Seattle, WA 98101 USA. [Loomba, R.] Univ Calif San Diego, Div Gastroenterol & Epidemiol, San Diego, CA 92103 USA. [Neuschwander-Tetri, B. A.] St Louis Univ, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. [Sanyal, A. J.] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. RP Hoofnagle, JH (reprint author), NIH, Room 644,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov RI Vaughn, Ivana/B-6138-2016; OI Vaughn, Ivana/0000-0002-7201-0289; Kleiner, David/0000-0003-3442-4453 FU Daiichi Sankyo Inc.; Bayer-Onxy; Exhalenz; Genentech; Gilead; Gore; Ikaria; Intercept; Salix; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK0 61738, U01DK061730, U01DK061713]; General Clinical Research Centers or Clinical and Translational Science Awards [UL1RR024989, UL1RR025761, M01RR00188, UL1RR 024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, UL1RR 031980]; National Institute of Child Health and Human Development (NICHD); National Cancer (NCI); NIDDK; Takeda Pharmaceuticals North America; Pharmavite FX Declaration of personal interests: JHH, MLVN, DEK, JMC, KVK, RL, BANT and JT have no conflicts of interest to report. RL serves as a consultant to Gilead, Corgenix and Daiichi Sankyo Inc and has received research grant support from Daiichi Sankyo Inc. AJS serves as a consultant to Abbott, Genfit, Ikaria, Merck, Norgene, Salix and Roche and has research grant support from Bayer-Onxy, Exhalenz, Genentech, Gilead, Gore, Ikaria, Intercept and Salix and receives royalties from Uptodate. Declaration of funding interests: The NASH CRN is a multicentre prospective study of the natural history and treatment of non-alcoholic steatohepatitis funded as a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant numbers: U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK0 61738, U01DK061730, U01DK061713). In conduct of the NASH CRN studies, several clinical centres use support from General Clinical Research Centers or Clinical and Translational Science Awards (Grant numbers: UL1RR024989, UL1RR025761, M01RR00188, UL1RR 024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, UL1RR 031980). Further support is provided by the National Institute of Child Health and Human Development (NICHD) and by the intramural programme of the National Cancer (NCI). The PIVENS trial was conducted by the NASH CRN and supported in part by Collaborative Research and Development Agreement (CRADA) between NIDDK and Takeda Pharmaceuticals North America (for pioglitazone and placebo tablets and for additional financial support) and a Clinical Trial Agreement between NIDDK and Pharmavite (for vitamin E and placebo capsules). Full membership of the NASH CRN is listed in the Table S1. NR 27 TC 47 Z9 49 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL PY 2013 VL 38 IS 2 BP 134 EP 143 DI 10.1111/apt.12352 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 165GV UT WOS:000320472400006 PM 23718573 ER PT J AU Consonni, D Matteis, SD Pesatori, AC Cattaneo, A Cavallo, DM Lubin, JH Tucker, M Bertazzi, PA Caporaso, NE Wacholder, S Landi, MT AF Consonni, Dario Matteis, Sara De Pesatori, Angela C. Cattaneo, Andrea Cavallo, Domenico M. Lubin, Jay H. Tucker, Margaret Bertazzi, Pier Alberto Caporaso, Neil E. Wacholder, Sholom Landi, Maria Teresa TI Increased lung cancer risk among bricklayers in an italian population-based case-control study (vol 55, pg 423, 2012) SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Correction C1 Dept Prevent Med, Epidemiol Unit, Fondazione IRCCS Ca Granda Osped Maggiore Policli, Milan, Italy. Univ Studi Milano, Dept Occupat & Environm Hlth, Milan, Italy. Univ Studi dellInsubria, Dept Chem & Environm Sci, Como, Italy. Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. RP Consonni, D (reprint author), Dept Prevent Med, Epidemiol Unit, Fondazione IRCCS Ca Granda Osped Maggiore Policli, Via San Barnaba, I-820122 Milan, Italy. RI Cavallo, Domenico Maria/F-9881-2013; Tucker, Margaret/B-4297-2015; Consonni, Dario/K-7943-2016; bertazzi, pietro alberto/D-5039-2017 OI Cavallo, Domenico Maria/0000-0003-1853-2999; Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449 NR 1 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 2013 VL 56 IS 7 BP 825 EP 825 DI 10.1002/ajim.22154 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 165GM UT WOS:000320471400010 ER PT J AU Gilbert, JR Pillai, AS Horwitz, B AF Gilbert, Jessica R. Pillai, Ajay S. Horwitz, Barry TI Assessing crossmodal matching of abstract auditory and visual stimuli in posterior superior temporal sulcus with MEG SO BRAIN AND COGNITION LA English DT Article DE Crossmodal matching; Audio-visual processing; pSTS; Magnetoencephalography ID MULTISENSORY INTEGRATION; AUDIOVISUAL SPEECH; BRAIN OSCILLATIONS; MEMORY; CORTEX; FMRI; TIME; MAGNETOENCEPHALOGRAPHY; SYNCHRONIZATION; INFORMATION AB Associating crossmodal auditory and visual stimuli is an important component of perception, with the posterior superior temporal sulcus (pSTS) hypothesized to support this. However, recent evidence has argued that the pSTS serves to associate two stimuli irrespective of modality. To examine the contribution of pSTS to crossmodal recognition, participants (N = 13) learned 12 abstract, non-linguistic pairs of stimuli over 3 weeks. These paired associates comprised four types: auditory-visual (AV), auditory-auditory (AA), visual-auditory (VA), and visual-visual (VV). At week four, participants were scanned using magnetoencephalography (MEG) while performing a correct/incorrect judgment on pairs of items. Using an implementation of synthetic aperture magnetometry that computes real statistics across trials (SAMspm), we directly contrasted crossmodal (AV and VA) with unimodal (AA and VV) pairs from stimulus-onset to 2 s in theta (4-8 Hz), alpha (9-15 Hz), beta (16-30 Hz), and gamma (31-50 Hz) frequencies. We found pSTS showed greater desynchronization in the beta frequency for crossmodal compared with unimodal trials, suggesting greater activity during the crossmodal pairs, which was not influenced by congruency of the paired stimuli. Using a sliding window SAM analysis, we found the timing of this difference began in a window from 250 to 750 ms after stimulus-onset. Further, when we directly contrasted all sub-types of paired associates from stimulus-onset to 2 s, we found that pSTS seemed to respond to dynamic, auditory stimuli, rather than crossmodal stimuli per se. These findings support an early role for pSTS in the processing of dynamic, auditory stimuli, and do not support claims that pSTS is responsible for associating two stimuli irrespective of their modality. Published by Elsevier Inc. C1 [Gilbert, Jessica R.; Pillai, Ajay S.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Bethesda, MD 20892 USA. RP Gilbert, JR (reprint author), Natl Inst Deafness & Other Commun Disorders NIDCD, NIH, Brain Imaging & Modeling Sect, 10 Ctr Dr,Room 5039, Bethesda, MD 20892 USA. EM jessica.gilbert@nih.gov FU National Institute on Deafness and Other Communication Disorders of the National Institutes of Health FX This work was supported by the intramural program of the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. The authors thank Tom Holroyd, Fred Carver, and Jason Smith for technical advice and helpful discussions. NR 37 TC 0 Z9 0 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUL PY 2013 VL 82 IS 2 BP 161 EP 170 DI 10.1016/j.bandc.2013.03.004 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 160WZ UT WOS:000320152500005 PM 23665947 ER PT J AU Zhou, Q Gil-Krzewska, A Peruzzi, G Borrego, F AF Zhou, Q. Gil-Krzewska, A. Peruzzi, G. Borrego, F. TI Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE monoclonal antibody; NK cell; polyfunctionality; tumour immunotherapy ID VIRUS TYPE-1 INFECTION; IFN-GAMMA; TUMOR-DEVELOPMENT; FC-RECEPTORS; NK CELLS; T-CELLS; IN-VIVO; IGG FC; CD16; CANCER AB Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) function. Using an in-vitroADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3 and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. C1 [Zhou, Q.; Gil-Krzewska, A.; Borrego, F.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bethesda, MD 20892 USA. [Peruzzi, G.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, Rockville, MD USA. RP Borrego, F (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bldg 29B,Room 3NN18,29 Lincoln Dr,HFD 123, Bethesda, MD 20892 USA. EM Francisco.BorregoRabasco@osakidetza.net OI Peruzzi, Giovanna/0000-0002-6517-9107 FU US Food and Drug Administration; NCI-FDA Interagency Oncology Task Force fellowship programme FX This work was supported by the intramural programme of the US Food and Drug Administration and by the NCI-FDA Interagency Oncology Task Force fellowship programme. The authors would like to thank Dr Wen Jin Wu and Dr Milos Dokmanovic for their generous gift of trastuzumab. NR 42 TC 20 Z9 20 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2013 VL 173 IS 1 BP 131 EP 139 DI 10.1111/cei.12095 PG 9 WC Immunology SC Immunology GA 159GA UT WOS:000320032400015 PM 23607800 ER PT J AU Chinn, IK Milner, JD Scheinberg, P Douek, DC Markert, ML AF Chinn, I. K. Milner, J. D. Scheinberg, P. Douek, D. C. Markert, M. L. TI Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3-T cells in complete DiGeorge anomaly SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE DiGeorge; FoxP3; repertoire; thymus; transplantation ID REGULATORY T-CELLS; EXPRESSION; IMMUNODEFICIENCY; ENTEROPATHY AB The development of T cells with a regulatory phenotype after thymus transplantation has not been examined previously in complete DiGeorge anomaly (cDGA). Seven athymic infants with cDGA and non-maternal pretransplantation T cell clones were assessed. Pretransplantation forkhead box protein 3 (Foxp3)+ T cells were detected in five of the subjects. Two subjects were studied in greater depth. T cell receptor variable chain (TCR-V) expression was assessed by flow cytometry. In both subjects, pretransplantation FoxP3+ and total CD4+ T cells showed restricted TCR-V expression. The development of naive T cells and diverse CD4+ TCR-V repertoires following thymic transplantation indicated successful thymopoiesis from the thymic tissue grafts. Infants with atypical cDGA develop rashes and autoimmune phenomena before transplantation, requiring treatment with immunosuppression, which was discontinued successfully subsequent to the observed thymopoiesis. Post-transplantation, diverse TCR-V family expression was also observed in FoxP3+ CD4+ T cells. Interestingly, the percentages of each of the TCR-V families expressed on FoxP3+ and total CD4+ T cells differed significantly between these T lymphocyte subpopulations before transplantation. By 16 months post-transplantation, however, the percentages of expression of each TCR-V family became significantly similar between FoxP3+ and total CD4+ T cells. Sequencing of TCRBV DNA confirmed the presence of clonally amplified pretransplantation FoxP3+ and FoxP3- T cells. After thymus transplantation, increased polyclonality was observed for both FoxP3+ and FoxP3- cells, and pretransplantation FoxP3+ and FoxP3- clonotypes essentially disappeared. Thus, post-transplantation thymic function was associated with the development of a diverse repertoire of FoxP3+ T cells in cDGA, corresponding with immunological and clinical recovery. C1 [Chinn, I. K.; Markert, M. L.] Duke Univ, Med Ctr, Dept Pediat, Div Allergy & Immunol, Durham, NC 27710 USA. [Markert, M. L.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Milner, J. D.] NIAID, Lab Allerg Dis, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheinberg, P.; Douek, D. C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheinberg, P.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chinn, IK (reprint author), Duke Univ, Med Ctr, Box 103020, Durham, NC 27710 USA. EM chinn001@mc.duke.edu OI Scheinberg, Phillip/0000-0002-9047-4538 FU American Academy of Allergy, Asthma and Immunology Senior Allergy/Immunology Fellow Transition Award; NIH [R01 AI 047040, R01 AI 054843, M03 RR 30, T32 AI 007062 28A2, 2 K12 HD043494 06]; National Institute of Allergy and Infectious Diseases FX This work was supported by the American Academy of Allergy, Asthma and Immunology 2008 Senior Allergy/Immunology Fellow Transition Award and NIH grants R01 AI 047040, R01 AI 054843, M03 RR 30 (General Clinical Research Center, National Center for Research Resources), T32 AI 007062 28A2 and 2 K12 HD043494 06. This effort was also supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases. The authors appreciate the assistance of Dr J. Michael Cook of the Duke Comprehensive Cancer Center flow cytometry facility in processing samples. The statistical support provided by Dr Yi-Ju Li of the Duke Translational Medicine Institute is kindly acknowledged. The authors express gratitude to Dr Gregory D. Sempowski of the Duke Human Vaccine Institute for assistance with reviewing the manuscript. The authors thank Dr Blythe H. Devlin, Jie Li, Chia-San Hsieh, Dr Bin Li, Stephanie E. Gupton, Elizabeth A. McCarthy, Michele E. Cox and Judy Stelling for technical, laboratory and clinical research support. The clinical care of the subjects provided by the Duke Pediatric Allergy and Immunology faculty and fellows is appreciated. The authors are grateful for the efforts of the referring physicians in obtaining and sending blood samples and data for the research. NR 32 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2013 VL 173 IS 1 BP 140 EP 149 DI 10.1111/cei.12088 PG 10 WC Immunology SC Immunology GA 159GA UT WOS:000320032400016 PM 23607606 ER PT J AU Zhao, Z Moley, KH Gronowski, AM AF Zhao, Zhen Moley, Kelle H. Gronowski, Ann M. TI Diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases SO CLINICAL BIOCHEMISTRY LA English DT Review DE miRNA; Pregnancy; Biomarker ID RECURRENT SPONTANEOUS-ABORTION; CIRCULATING MICRORNAS; MATERNAL CIRCULATION; ECTOPIC PREGNANCY; HUMAN PLACENTAS; UNITED-STATES; PREECLAMPSIA; EXPRESSION; PLASMA; GROWTH AB Discovery of circulating miRNAs in maternal blood has not only facilitated the understanding of their role in normal pregnancy, but also paved new avenues for biomarker discovery to detect pregnancy-associated complications, such as preeclampsia, ectopic pregnancy, gestational diabetes mellitus, fetal growth restriction, recurrent pregnancy loss, and preterm delivery. In this review, we summarize the studies to date of miRNAs in maternal circulation and placental tissue in human. This brief review does not cover all aspects of this intriguing field but focuses on some new and interesting findings of diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Zhao, Zhen] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Moley, Kelle H.; Gronowski, Ann M.] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Gronowski, Ann M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Gronowski, AM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, Box 8118,660 S Euclid, St Louis, MO 63110 USA. EM gronowski@wustl.edu NR 47 TC 31 Z9 32 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD JUL PY 2013 VL 46 IS 10-11 SI SI BP 953 EP 960 DI 10.1016/j.clinbiochem.2013.01.026 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 163PS UT WOS:000320350000015 PM 23396163 ER PT J AU Roux, A Mourin, G Fastenackels, S Almeida, JR Iglesias, MC Boyd, A Gostick, E Larsen, M Price, DA Sacre, K Douek, DC Autran, B Picard, C de Miranda, S Sauce, D Stern, M Appay, V AF Roux, Antoine Mourin, Gisele Fastenackels, Solene Almeida, Jorge R. Iglesias, Maria Candela Boyd, Anders Gostick, Emma Larsen, Martin Price, David A. Sacre, Karim Douek, Daniel C. Autran, Brigitte Picard, Clement de Miranda, Sandra Sauce, Delphine Stern, Marc Appay, Victor TI CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation SO CLINICAL IMMUNOLOGY LA English DT Article DE Cytomegalovirus; T-lymphocyte; Immune activation; Lung transplantation; Acute rejection ID CYTOMEGALOVIRUS-SPECIFIC CD4(+); ALLOGRAFT-REJECTION; PREVENT CYTOMEGALOVIRUS; ANTIGEN-EXPRESSION; IMMUNE-RESPONSE; INFECTION; RECIPIENTS; DISEASE; DIFFERENTIATION; LYMPHOCYTES AB Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. (C) 2013 Elsevier Inc. All rights reserved. C1 [Roux, Antoine; Mourin, Gisele; Fastenackels, Solene; Iglesias, Maria Candela; Larsen, Martin; Sacre, Karim; Autran, Brigitte; Sauce, Delphine; Appay, Victor] Univ Paris 06, Hop La Pitie Salpetriere, INSERM, UMR S 945, F-75013 Paris, France. [Roux, Antoine; Picard, Clement; de Miranda, Sandra; Stern, Marc] Hop Foch, Serv Pneumol, F-92151 Suresnes, France. [Almeida, Jorge R.; Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Boyd, Anders] Univ Paris 06, Hop St Antoine, INSERM, UMR S 707, F-75012 Paris, France. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Autran, Brigitte; Appay, Victor] Grp Hosp Pitie Salpetriere, AP HP, Lab Immunol Cellulaire & Tissulaire, F-75013 Paris, France. RP Roux, A (reprint author), Hop La Pitie Salpetriere, INSERM, U945, F-75013 Paris, France. EM a.roux@hopital-foch.org; victor.appay@upmc.fr RI Price, David/C-7876-2013; sauce, delphine/H-1990-2014; Larsen, Martin/A-7316-2014; OI Price, David/0000-0001-9416-2737; sauce, delphine/0000-0003-4596-7373; Larsen, Martin/0000-0003-1375-4816; Ramos de Almeida, Jorge/0000-0002-5009-8478; STERN, Marc/0000-0001-5275-6959 FU Vaincre la Mucoviscidose (VLM); National Institutes of Allergy and Infectious Diseases; Fondation pour la Recherche Medicate (FRM) FX This work was supported by Vaincre la Mucoviscidose (VLM), as well as by the Intramural Program of the National Institutes of Allergy and Infectious Diseases (DCD and JRA). AR is supported by VLM and the Fondation pour la Recherche Medicate (FRM). NR 55 TC 7 Z9 8 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2013 VL 148 IS 1 BP 16 EP 26 DI 10.1016/j.clim.2013.03.012 PG 11 WC Immunology SC Immunology GA 164RN UT WOS:000320427300003 PM 23644452 ER PT J AU Degheidy, HA Gadalla, SM Farooqui, MZH Abbasi, F Arthur, DC Bauer, SR Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Gadalla, Shahinaz M. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Bauer, Steven R. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Bcl-2 level as a biomarker for 13q14 deletion in CLL SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; Bcl-2; flow cytometry; del 13q14; hemizygous; homozygous deletion ID CHRONIC-LYMPHOCYTIC-LEUKEMIA; B-CELLS; EXPRESSION; APOPTOSIS; MICRORNAS; SURVIVAL; ASSOCIATION; GENES; RNA; ACCUMULATION AB Background Deletion 13q14.3 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL). Previously it was reported that miR-15/16 is the target of 13q14 deletions and plays a tumor suppressor role by suppressing Bcl-2. Therefore, Bcl-2 expression was examined more closely to determine whether it would predict 13q14 deletion status. Methods A multi-color flow panel consisting of anti-Bcl-2/anti-lambda/anti-kappa/CD19/CD5/CD3/CD20 was performed. The ability of Bcl-2 to predict 13q14 deletion was tested using the conventional Bcl-2 index (c-index): mean fluorescence intensity (MFI) of CLL clone/MFI of residual T cells. Fifty-four untreated CLL/MBL patients were studied. Bimodal Bcl-2 expression was evaluated to test the ability of Bcl-2 to detect intraclonal heterogeneity. Other CLL prognostic markers including CD38, CD49d, CD26, and CD69 were evaluated. FISH was performed on selected sorted populations. Results The Bcl-2 c-index strongly predicts del13q14 P < 0.0001. A statistically significant association was observed between the percentage of cells carrying the deletion and the level of Bcl-2 expression P < 0.05. Cells sorted based on Bcl-2 expression showed enrichment of both hemizygous and homozygous del 13q14 cells. Also, we observed that an alteration in Bcl-2 level over time predicts changes in 13q14 deletion status. And a statistically significant correlation between the bimodal pattern of CD69 expression and the presence of 13q14 deletion was found P < 0.0001. Conclusion Bcl-2 expression using the c-index strongly predicts 13q14 deletion and can be used to distinguish homozygous, heterozygous, and diploid CLL clonal cells. Further systematic studies of this biomarker are needed for confirmation and expansion of these findings. Published 2013 Wiley-Periodicals, Inc. C1 [Degheidy, Heba A.; Abbasi, Fatima; Bauer, Steven R.; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Degheidy, Heba A.; Marti, Gerald E.] Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gadalla, Shahinaz M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gemarti@mac.com OI Bauer, Steven/0000-0003-2831-846X FU Oak Ridge Institute for Science and Education through US DOE; Oak Ridge Institute for Science and Education through US FDA; National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute FX Grant sponsor: Oak Ridge Institute for Science and Education through US DOE and US FDA (Heba Degheidy's appointment to the Research Participation Program at CBER); Intramural Research Program of the National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute. NR 39 TC 6 Z9 7 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL-AUG PY 2013 VL 84B IS 4 BP 237 EP 247 DI 10.1002/cyto.b.21090 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 168VC UT WOS:000320732900006 PM 23674504 ER PT J AU Paul, R Minniti, CP Nouraie, M Luchtman-Jones, L Campbell, A Rana, S Onyekwere, O Darbari, DS Ajayi, O Arteta, M Ensing, G Sable, C Dham, N Kato, GJ Gladwin, MT Castro, OL Gordeuk, VR AF Paul, Rabindra Minniti, Caterina P. Nouraie, Mehdi Luchtman-Jones, Lori Campbell, Andrew Rana, Sohail Onyekwere, Onyinye Darbari, Deepika S. Ajayi, Olaid Arteta, Manuel Ensing, Gregory Sable, Craig Dham, Niti Kato, Gregory J. Gladwin, Mark T. Castro, Oswaldo L. Gordeuk, Victor R. TI Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain ID ACUTE CHEST SYNDROME; REGURGITANT JET VELOCITY; SOCIETY-OF-ECHOCARDIOGRAPHY; RISK-FACTORS; TASK-FORCE; HYPERTENSION; ANEMIA; ASTHMA; COMPLICATIONS; ASSOCIATION AB Objectives We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study. Methods Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20yrs were studied at four centers in a cross-sectional manner. A subgroup (n=293) was followed for a median of 21months (range 9-35). Results A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (P<0.0001), older age (P=0.001), >3 severe pain episodes in the preceding 12months (P=0.002), higher tricuspid regurgitation velocity (TRV) (P=0.028), and higher white blood cell (WBC) count (P=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (P=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.0; P<0.0001) and younger age (odds ratio 0.9; P=0.007) were independently associated with developing a new episode during follow-up. Conclusions Asthma history, frequent pain, and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD. C1 [Paul, Rabindra; Nouraie, Mehdi; Rana, Sohail; Onyekwere, Onyinye; Ajayi, Olaid; Castro, Oswaldo L.] Howard Univ, Washington, DC 20059 USA. [Minniti, Caterina P.; Darbari, Deepika S.; Kato, Gregory J.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Luchtman-Jones, Lori; Darbari, Deepika S.; Sable, Craig; Dham, Niti] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Campbell, Andrew; Arteta, Manuel; Ensing, Gregory] Univ Michigan, Ann Arbor, MI 48109 USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Gordeuk, Victor R.] Univ Illinois, Chicago, IL 60612 USA. RP Gordeuk, VR (reprint author), Univ Illinois, Sickle Cell Ctr M C 712, Suite 172,Clin Sci Bldg,820 South Wood St, Chicago, IL 60612 USA. EM vgordeuk@uic.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU NHLBI [2 R25 HL003679-08, 1 R01 HL079912-02]; Howard University GCRC from NCRR, NIH, Bethesda, MD [2MOI RR10284-10]; NIH [1 ZIA HL006016-03] FX Supported in part by grant nos. 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by NIH intramural funding 1 ZIA HL006016-03. NR 38 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUL PY 2013 VL 91 IS 1 BP 62 EP 68 DI 10.1111/ejh.12118 PG 7 WC Hematology SC Hematology GA 168QO UT WOS:000320720800008 PM 23560516 ER PT J AU Orjuela-Sanchez, P Sa, JM Brandi, MCC Rodrigues, PT Bastos, MS Amaratunga, C Duong, S Fairhurst, RM Ferreira, MU AF Orjuela-Sanchez, Pamela Sa, Juliana M. Brandi, Michelle C. C. Rodrigues, Priscila T. Bastos, Melissa S. Amaratunga, Chanaki Duong, Socheat Fairhurst, Rick M. Ferreira, Marcelo U. TI Higher microsatellite diversity in Plasmodium vivax than in sympatric Plasmodium falciparum populations in Pursat, Western Cambodia SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Plasmodium vivax; Plasmodium falciparum; Population structure; Genetic diversity; Microsatellites ID GENETIC DIVERSITY; RURAL AMAZONIA; MALARIA; INFECTIONS; MARKERS; DYNAMICS; SAMPLES; REGION; PREVALENCE; FREQUENCY AB Previous microsatellite analyses of sympatric populations of Plasmodium vivax and Plasmodium falciparum in Brazil revealed higher diversity in the former species. However, it remains unclear whether regional species-specific differences in prevalence and transmission levels might account for these findings. Here, we examine sympatric populations of P. vivax (n = 87) and P. falciparum (n = 164) parasites from Pursat province, Western Cambodia, where both species are similarly prevalent. Using 10 genome-wide microsatellites for P. falciparum and 13 for P. vivax, we found that the P. vivax population was more diverse than the sympatric P. falciparum population (average virtual heterozygosity [H-E], 0.87 vs. 0.66, P = 0.003), with more multiple-clone infections (89.6% vs. 47.6%) and larger mean number of alleles per marker (16.2 vs. 11.1, P = 0.07). Both populations showed significant multi-locus linkage disequilibrium suggestive of a predominantly clonal mode of parasite reproduction. The higher microsatellite diversity found in P. vivax isolates, compared to sympatric P. falciparum isolates, does not necessarily result from local differences in transmission level and may reflect differences in population history between species or increased mutation rates in P. vivax. (C) 2013 Elsevier Inc. All rights reserved. C1 [Orjuela-Sanchez, Pamela; Brandi, Michelle C. C.; Rodrigues, Priscila T.; Bastos, Melissa S.; Ferreira, Marcelo U.] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, Brazil. [Orjuela-Sanchez, Pamela] La Jolla Bioengn Inst, San Diego, CA USA. [Sa, Juliana M.; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Duong, Socheat] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. RP Ferreira, MU (reprint author), Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, Brazil. EM muferrei@usp.br RI Ferreira, Marcelo/G-8289-2011 OI Ferreira, Marcelo/0000-0002-5293-9090 FU National Institutes of Health (NIH) [RO1 AI 075416]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [470570/2006-7]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [07/51199-0]; National Institute of Allergy and Infectious Diseases (NIAID), NIH; CNPq; FAPESP FX This research was supported by funds from the National Institutes of Health (NIH) Grant RO1 AI 075416 to M.U.F., the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) Grant 470570/2006-7 to M.U.F. and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) Grant 07/51199-0 to M.U.F. This study was supported in part by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, provided to R.M.F. P.O.S. and M.U.F. received scholarships from CNPq, and P.T.R. received a scholarship from FAPESP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the patients from Pursat province for their cooperation, and Seila Suon and Sokunthea Sreng for their collaborative efforts in Pursat. We also thank Carmen S. A. Takata, Marcio M. Yamamoto, Erika S. Phelps and Michael A. Krause for laboratory and analytical support. NR 41 TC 21 Z9 21 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUL PY 2013 VL 134 IS 3 BP 318 EP 326 DI 10.1016/j.exppara.2013.03.029 PG 9 WC Parasitology SC Parasitology GA 165JX UT WOS:000320481300009 PM 23562882 ER PT J AU Egervari, K Potter, G Guzman-Hernandez, ML Salmon, P Balla, T Wehrle-Haller, B Kiss, JZ AF Egervari, K. Potter, G. Guzman-Hernandez, M. -L. Salmon, P. Balla, T. Wehrle-Haller, B. Kiss, J. Z. TI INTRACELLULAR TRAFFICKING, MATRIX ASSOCIATION AND FUNCTION OF VEGF IN ASTROGLIAL CELLS SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Egervari, K.; Potter, G.; Salmon, P.; Wehrle-Haller, B.; Kiss, J. Z.] Univ Geneva, Geneva, Switzerland. [Guzman-Hernandez, M. -L.; Balla, T.] NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S88 EP S88 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400273 ER PT J AU Fields, RD AF Fields, R. D. TI REGULATION OF SCHWANN CELL DEVELOPMENT AND MYELINATION BY ACTION POTENTIALS SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Fields, R. D.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S47 EP S47 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400144 ER PT J AU Gao, H Zhou, H Hong, JS AF Gao, H. Zhou, H. Hong, J. -S. TI PATTERN RECOGNITION-RELATED INFLAMMATORY OXIDATIVE INSULT FROM MICROGLIA MEDIATES CHRONIC NEURODEGENERATION SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Gao, H.] Nanjing Univ, Nanjing 210008, Jiangsu, Peoples R China. [Zhou, H.; Hong, J. -S.] NIEHS, NIH, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S19 EP S19 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400041 ER PT J AU Tata, AM Uggenti, C De Stefano, ME Pisano, A Costantino, M Loreti, S Talora, C Wess, J Magnaghi, V Ricordy, R AF Tata, A. M. Uggenti, C. De Stefano, M. E. Pisano, A. Costantino, M. Loreti, S. Talora, C. Wess, J. Magnaghi, V. Ricordy, R. TI ACETYLCHOLINE AND M2 MUSCARINIC RECEPTOR CONTRIBUTE TO MODULATE SCHWANN CELL PROLIFERATION AND DIFFERENTIATION SO GLIA LA English DT Meeting Abstract CT 11th European Meeting on Glial Cell Function in Health and Disease CY JUL 03-06, 2013 CL Berlin, GERMANY C1 [Tata, A. M.; Uggenti, C.; De Stefano, M. E.; Pisano, A.; Costantino, M.; Loreti, S.; Talora, C.] Univ Roma La Sapienza, I-00185 Rome, Italy. [Wess, J.] NIDDK, NIH, Bethesda, MD 20892 USA. [Magnaghi, V.] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Ricordy, R.] CNR, Biol & Mol Pathol 3Inst, Rome, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 SU 1 BP S47 EP S48 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 164KQ UT WOS:000320408400147 ER PT J AU Zhang, CL Bao, W Rong, Y Yang, HX Bowers, K Yeung, E Kiely, M AF Zhang, Cuilin Bao, Wei Rong, Ying Yang, Huixia Bowers, Katherine Yeung, Edwina Kiely, Michele TI Genetic variants and the risk of gestational diabetes mellitus: a systematic review SO HUMAN REPRODUCTION UPDATE LA English DT Article DE gestational diabetes mellitus; single nucleotide polymorphism; gene; genetic factors ID GENOME-WIDE ASSOCIATION; BETA(3)-ADRENERGIC RECEPTOR GENE; POLYCYSTIC-OVARY-SYNDROME; INSULIN-SECRETION; TCF7L2 GENE; TRANSCRIPTION-FACTOR-7-LIKE-2 TCF7L2; TRP(64)ARG POLYMORPHISM; MEXICAN-AMERICANS; GREEK POPULATION; GLUCOKINASE GENE AB Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies. Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNPGDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95 confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity. Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95 CIs) of 1.44 (1.291.60, P 0.001) per T allele of rs7903146 and 1.46 (1.151.84, P 0.002) per T allele of rs12255372. In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion. C1 [Zhang, Cuilin; Bao, Wei; Bowers, Katherine; Yeung, Edwina; Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Rong, Ying] Huazhong Univ Sci & Technol, Dept Nutr & Food Hyg, Hubei Key Lab Food Nutr & Safety, Sch Publ Hlth,Tongji Med Coll, Wuhan 430030, Peoples R China. [Yang, Huixia] Peking Univ, Hosp 1, Dept Obstet & Gynecol, Beijing 100034, Peoples R China. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov; wei.bao@nih.gov RI Yeung, Edwina/F-5992-2015; Bowers, Katherine/N-5226-2015; OI Yeung, Edwina/0000-0002-3851-2613; Bao, Wei/0000-0002-7301-5786 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX W.B., K.B., E.Y., M.K. and C.Z. are supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 70 TC 52 Z9 55 U1 0 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 EI 1460-2369 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD JUL-AUG PY 2013 VL 19 IS 4 BP 376 EP 390 DI 10.1093/humupd/dmt013 PG 15 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 165DP UT WOS:000320463500006 PM 23690305 ER PT J AU Bourbakis, N Makrogiannis, SK Dakopoulos, D AF Bourbakis, Nikolaos Makrogiannis, Sokratis K. Dakopoulos, Dimitrios TI A System-Prototype Representing 3D Space via Alternative-Sensing for Visually Impaired Navigation SO IEEE SENSORS JOURNAL LA English DT Article DE 2-D vibration arrays; alternative sensing; assistive technologies; blind's navigation; high-to-low image representation; human computer interface; motion detection ID BLIND; AID; TECHNOLOGY; WATERSHEDS AB Offering an alternative mode of interaction with the surrounding 3-D space to the visually impaired for collision free navigation is a goal of great significance that includes several key challenges. In this paper, we study the alternative 3-D space sensation that is interpreted by our computer vision prototype system and transferred to the user via a vibration array. There are two main tasks for conducting such a study. The first task is to detect obstacles in close proximity, and motion patterns in image sequences, both important issues for a safe navigation in a 3-D dynamic space. To achieve this task, the images from the left and right cameras are acquired to produce new stereo images, followed by video stabilization as a preprocessing stage, a nonlinear spatio-temporal diffusion and kernel based density estimation method to assess the motion activity, and finally watershed-based detection of moving regions (or obstacles) of interest. The second task is to efficiently represent the information of the captured static and dynamic visual scenes as 3-D detectable patterns of vibrations applied on the human body to create a 3-D sensation of the space during navigation. To accomplish this task, considering the current limitations imposed by the technology, we create a high-to-low (H-L) image resolution representation scheme to facilitate the mapping onto a low-resolution 2-D array of vibrators. The H-L scheme uses pyramidal modeling to obtain low-resolution images of interest-preserving motion and obstacles-that are mapped onto a vibration array. These patterns are utilized to train and test the performance of the users in free space navigation. Thus, in this paper we study the synergy of these two important schemes to offer an alternative sensation of the 3-D space to the visually impaired via an array of vibrators. Particularly, the motion component is employed as an element for the identification of visual information of interest to be retained during the H-L transformation. The role of the array vibrators is to create a small-scale front representation of the space via various levels of vibrations. Thus, 3-D vibrations applied on the user's body (chest, abdomen) offer a 3-D sensation of the surrounding space and the motion in it. In addition, we present experimental results that indicate the efficiency of this navigation scheme in creating low-resolution 3-D views of the free navigation space and detecting obstacles and moving areas. C1 [Bourbakis, Nikolaos; Dakopoulos, Dimitrios] Wright State Univ, Assist Technol Res Ctr, Dayton, OH 45435 USA. [Makrogiannis, Sokratis K.] NIA, NIH, Baltimore, MD 21225 USA. RP Bourbakis, N (reprint author), Wright State Univ, Assist Technol Res Ctr, Dayton, OH 45435 USA. EM nikolaos.bourbakis@wright.edu; makrogianniss@mail.nih.gov; dakopoulos.2@wright.edu FU NSF; AIIS Inc. FX Manuscript received November 5, 2012; revised January 29, 2013; accepted March 11, 2013. Date of publication March 19, 2013; date of current version May 29, 2013. This work was supported by NSF and AIIS Inc. for the Tyflos Project. The associate editor coordinating the review of this paper and approving it for publication was Prof. Subhas C. Mukhopadhyay. NR 34 TC 8 Z9 8 U1 0 U2 17 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1530-437X EI 1558-1748 J9 IEEE SENS J JI IEEE Sens. J. PD JUL PY 2013 VL 13 IS 7 BP 2535 EP 2547 DI 10.1109/JSEN.2013.2253092 PG 13 WC Engineering, Electrical & Electronic; Instruments & Instrumentation; Physics, Applied SC Engineering; Instruments & Instrumentation; Physics GA 158VF UT WOS:000320001100005 ER PT J AU Vahedi, G Kanno, Y Sartorelli, V O'Shea, JJ AF Vahedi, Golnaz Kanno, Yuka Sartorelli, Vittorio O'Shea, John J. TI Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers SO IMMUNOLOGY LA English DT Review DE enhancers; epigenomics; master regulators; STATs; T helper cells ID ENHANCER LANDSCAPE; DIFFERENTIATION; SPECIFICATION AB Naive T cells differentiate and become distinct subsets in response to changes in the cytokine milieu. Such specialization arises through a complex and dynamic utilization of cis-regulatory enhancer elements. In this brief essay, we review recent findings on the relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription family transcription factors, master regulators', and other transcription factors in the enhancer architecture of T cells. These findings provide new insights into how signal transduction impinges upon the genome. C1 [Vahedi, Golnaz; Kanno, Yuka; O'Shea, John J.] Mol Immunol & Inflammat Branch, Lymphocyte Cell Biol Sect, Bethesda, MD USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Vahedi, G (reprint author), 10 Ctr Dr,Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM vahedig@mail.nih.gov; osheaj@arb.niams.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 NR 17 TC 16 Z9 16 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD JUL PY 2013 VL 139 IS 3 BP 294 EP 298 DI 10.1111/imm.12113 PG 5 WC Immunology SC Immunology GA 164EU UT WOS:000320392500004 PM 23586907 ER PT J AU Kim, SH Thurm, A Shumway, S Lord, C AF Kim, So Hyun Thurm, Audrey Shumway, Stacy Lord, Catherine TI Multisite Study of New Autism Diagnostic Interview-Revised (ADI-R) Algorithms for Toddlers and Young Preschoolers SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Early diagnosis; Autism spectrum disorders; Autism diagnostic interview-revised ID SPECTRUM DISORDERS; OBSERVATION SCHEDULE; AGREEMENT; VALIDITY; CHILDREN; ADOS AB Using two independent datasets provided by National Institute of Health funded consortia, the Collaborative Programs for Excellence in Autism and Studies to Advance Autism Research and Treatment (n = 641) and the National Institute of Mental Health (n = 167), diagnostic validity and factor structure of the new Autism Diagnostic Interview (ADI-R) algorithms for toddlers and young preschoolers were examined as a replication of results with the 2011 Michigan sample (Kim and Lord in J Autism Dev Disord 42(1): 82-93, 2012). Sensitivities and specificities and a three-factor solution were replicated. Results suggest that the new ADI-R algorithms can be appropriately applied to existing research databases with children from 12 to 47 months and down to nonverbal mental ages of 10 months for diagnostic grouping. C1 [Kim, So Hyun] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06510 USA. [Thurm, Audrey; Shumway, Stacy] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Lord, Catherine] Weill Cornell Med Coll, Ctr Autism & Developing Brain, White Plains, NY 10605 USA. RP Kim, SH (reprint author), Yale Univ, Sch Med, Yale Child Study Ctr, 40 Temple St,Suite 7-D, New Haven, CT 06510 USA. EM so-hyun.kim@yale.edu OI Manwaring, Stacy/0000-0002-0835-9398 FU Intramural NIH HHS; NIMH NIH HHS [R25MH067723, F32 MH066469, R01MH066469, R25 MH067723] NR 31 TC 13 Z9 13 U1 4 U2 29 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUL PY 2013 VL 43 IS 7 BP 1527 EP 1538 DI 10.1007/s10803-012-1696-4 PG 12 WC Psychology, Developmental SC Psychology GA 165TO UT WOS:000320507200004 PM 23114567 ER PT J AU Atsawasuwan, P Lu, X Ito, Y Chen, Y Gopinathan, G Evans, CA Kulkarni, AB Gibson, CW Luan, X Diekwisch, TGH AF Atsawasuwan, P. Lu, X. Ito, Y. Chen, Y. Gopinathan, G. Evans, C. A. Kulkarni, A. B. Gibson, C. W. Luan, X. Diekwisch, T. G. H. TI Expression and Function of Enamel-related Gene Products in Calvarial Development SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE amelogenin; ameloblastin; osteoblast; calvaria; evolution; suture ID BONE-MARROW; AMELOGENIN; CELLS; AMELOBLASTIN; PROTEIN; PROLIFERATION; OSTEOCLASTOGENESIS; DIFFERENTIATION; EVOLUTION; MICE AB Enamel-related gene products (ERPs) are detected in non-enamel tissues such as bone. We hypothesized that, if functional, ERP expression corresponds with distinct events during osteoblast differentiation and affects bone development and mineralization. In mouse calvariae and MC3T3 cells, expression profiles of enamel-related gene products (ERPs) correlated with key events in post-natal calvarial development and MC3T3 cell mineralization. Developing skulls from both Amel- and Ambn-deficient animals were approximately 15% shorter when compared with those of wild-type controls, and their sutures remained patent for a longer period of time. Analysis of Amel- and Ambn-deficient calvariae and calvarial osteoblast cultures revealed a dramatic reduction in mineralized nodules, a significant reduction in Runx2, Sp7, Ibsp, and Msx2 expression, and a reduction in Alx4 in Amel-deficient calvariae vs. an increase in Alx4 in Ambn-deficient calvariae. Analysis of these data indicates that ERP expression follows defined developmental profiles and affects osteoblast differentiation, mineralization, and calvarial bone development. We propose that, in parallel to their role in the developing enamel matrix, ERPs have retained an evolutionary conserved function related to the biomineralization of bones. C1 [Atsawasuwan, P.; Lu, X.; Ito, Y.; Gopinathan, G.; Luan, X.; Diekwisch, T. G. H.] Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60612 USA. [Atsawasuwan, P.; Chen, Y.; Evans, C. A.; Luan, X.; Diekwisch, T. G. H.] Univ Illinois, Dept Orthodont, Chicago, IL 60612 USA. [Luan, X.; Diekwisch, T. G. H.] Coll Dent, UIC Dept Oral Biol, Chicago, IL USA. [Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gibson, C. W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. RP Diekwisch, TGH (reprint author), Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60612 USA. EM tomdkw@uic.edu OI Atsawasuwan, Phimon/0000-0002-2576-060X FU NIDCR [DE18057, DE19155, DE18900]; Thomas M. Graber AAOF fellowship FX This study was supported by the NIDCR (grants DE18057 and DE19155 to XL; grant DE18900 to TGHD) and by the Thomas M. Graber AAOF fellowship (to PA). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 26 TC 13 Z9 14 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2013 VL 92 IS 7 BP 622 EP 628 DI 10.1177/0022034513487906 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 164TH UT WOS:000320432100009 PM 23625374 ER PT J AU Zadeh, ES Lungu, AO Cochran, EK Brown, RJ Ghany, MG Heller, T Kleiner, DE Gorden, P AF Zadeh, Elika Safar Lungu, Andreea O. Cochran, Elaine K. Brown, Rebecca J. Ghany, Marc G. Heller, Theo Kleiner, David E. Gorden, Phillip TI The liver diseases of lipodystrophy: The long-term effect of leptin treatment SO JOURNAL OF HEPATOLOGY LA English DT Article DE Lipodystrophy; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Leptin; Metabolic syndrome ID NONALCOHOLIC FATTY LIVER; INSULIN-RESISTANCE; METABOLIC SYNDROME; STEATOHEPATITIS; MODELS AB Background & Aims: Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. Methods: This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N = 50) and after leptin replacement (N = 27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A(1c), and liver enzymes were measured at baseline and at the time of the final liver biopsy. Results: In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 +/- 3.7 months (mean SE, p = 0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p <0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. Conclusions: The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Zadeh, Elika Safar; Lungu, Andreea O.; Cochran, Elaine K.; Brown, Rebecca J.; Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Ghany, Marc G.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), NIDDK, NIH, Clin Res Ctr, Room 6-5952,10 Ctr Dr, Bethesda, MD 20892 USA. EM PhillipG@intra.niddk.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX This work was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. NR 25 TC 36 Z9 37 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2013 VL 59 IS 1 BP 131 EP 137 DI 10.1016/j.jhep.2013.02.007 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 165KF UT WOS:000320482100021 ER PT J AU Emmert, S Kraemer, KH AF Emmert, Steffen Kraemer, Kenneth H. TI Do Not Underestimate Nucleotide Excision Repair: It Predicts Not Only Melanoma Risk but Also Survival Outcome SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID CUTANEOUS MELANOMA; XERODERMA-PIGMENTOSUM; POLYMORPHISMS; LIGHT AB Nucleotide excision repair (NER) removes UV-induced DNA damage and other bulky DNA lesions, thereby maintaining genomic integrity. Dr Qingyi Wei's group demonstrated over the last decade that NER fidelity and single-nucleotide polymorphisms (SNPs) in NER genes constitute melanoma risk biomarkers. In this issue, Li et al. provide evidence that SNPs in NER genes may also predict melanoma survival. C1 [Emmert, Steffen] Univ Med Ctr Gottingen, Dept Dermatol Venerol & Allergol, Gottingen, Germany. [Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Intramural NIH HHS [Z01 BC004517-31] NR 11 TC 2 Z9 2 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 EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2013 VL 133 IS 7 BP 1713 EP 1717 DI 10.1038/jid.2013.72 PG 5 WC Dermatology SC Dermatology GA 164RY UT WOS:000320428400006 PM 23760049 ER PT J AU Sengupta, A Lichti, UF Carlson, BA Cataisson, C Ryscavage, AO Mikulec, C Conrad, M Fischer, SM Hatfield, DL Yuspa, SH AF Sengupta, Aniruddha Lichti, Ulrike F. Carlson, Bradley A. Cataisson, Christophe Ryscavage, Andrew O. Mikulec, Carol Conrad, Marcus Fischer, Susan M. Hatfield, Dolph L. Yuspa, Stuart H. TI Targeted Disruption of Glutathione Peroxidase 4 in Mouse Skin Epithelial Cells Impairs Postnatal Hair Follicle Morphogenesis that Is Partially Rescued through Inhibition of COX-2 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID THIOREDOXIN REDUCTASE; LIPID-PEROXIDATION; CHOLESTEROL HYDROPEROXIDES; CYCLOOXYGENASE-2; EXPRESSION; PHGPX; MICE; GENE; CARCINOGENESIS; SELENIUM AB Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4-knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. C1 [Sengupta, Aniruddha; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Lichti, Ulrike F.; Cataisson, Christophe; Ryscavage, Andrew O.; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mikulec, Carol; Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Dept Mol Carcinogenesis, Smithville, TX USA. [Conrad, Marcus] DZNE German Ctr Neurodegenerat Dis, Munich, Germany. [Conrad, Marcus] Helmholtz Ctr, Munich, Germany. [Conrad, Marcus] German Res Ctr Environm Hlth, Inst Dev Genet, Neuherberg, Germany. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM yuspas@dc37a.nci.nih.gov OI Conrad, Marcus/0000-0003-1140-5612 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; Deutsche Forschungsgemeinschaft (DFG) [CO 291/2-3]; DFG-Priority Program [SPP1087] FX We thank Histoserv, Germantown, MD, for preparation of tissue sections, and members of the Pathology/Histotechnology Laboratory, Center for Cancer Research, NCI, Frederick, MD, for their help with immunohistochemical analysis. The help from Raghunath Chatterjee and Petra Tsuji, NCI, NIH, with the Ingenuity Pathway Analysis is also acknowledged. This research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to DLH and SHY), and by the Deutsche Forschungsgemeinschaft (DFG) CO 291/2-3 and the DFG-Priority Program SPP1087 (MC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2013 VL 133 IS 7 BP 1731 EP 1741 DI 10.1038/jid.2013.52 PG 11 WC Dermatology SC Dermatology GA 164RY UT WOS:000320428400010 PM 23364477 ER PT J AU Perdivara, I Perera, L Sricholpech, M Terajima, M Pleshko, N Yamauchi, M Tomer, KB AF Perdivara, Irina Perera, Lalith Sricholpech, Marnisa Terajima, Masahiko Pleshko, Nancy Yamauchi, Mitsuo Tomer, Kenneth B. TI Unusual Fragmentation Pathways in Collagen Glycopeptides SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Collagen; Glycopeptide; Hydroxyproline; Galactosylhydroxylysine; Tandem mass spectrometry; Fragmentation pathway; Mobile proton ID TANDEM MASS-SPECTROMETRY; O-GLYCOSYLATION SITES; TRIPLE-HELICAL DOMAIN; SEQUENCE-ANALYSIS; CROSS-LINKING; I COLLAGEN; GELATINASE-B; AMINO-ACID; PEPTIDE; DISSOCIATION AB Collagens are the most abundant glycoproteins in the body. One characteristic of this protein family is that the amino acid sequence consists of repeats of three amino acids -(X-Y-Gly)(n). Within this motif, the Y residue is often 4-hydroxyproline (HyP) or 5-hydroxylysine (HyK). Glycosylation in collagen occurs at the 5-OH group in HyK in the form of two glycosides, galactosylhydroxylysine (Gal-HyK) and glucosyl galactosylhydroxylysine (GlcGal-HyK). In collision induced dissociation (CID), collagen tryptic glycopeptides exhibit unexpected gas-phase dissociation behavior compared to typical N- and O-linked glycopeptides (i.e., in addition to glycosidic bond cleavages, extensive cleavages of the amide bonds are observed). The Gal- or GlcGal- glycan modifications are largely retained on the fragment ions. These features enable unambiguous determination of the amino acid sequence of collagen glycopeptides and the location of the glycosylation site. This dissociation pattern was consistent for all analyzed collagen glycopeptides, regardless of their length or amino acid composition, collagen type or tissue. The two fragmentation pathways-amide bond and glycosidic bond cleavage-are highly competitive in collagen tryptic glycopeptides. The number of ionizing protons relative to the number of basic sites (i.e., Arg, Lys, HyK, and N-terminus) is a major driving force of the fragmentation. We present here our experimental results and employ quantum mechanics calculations to understand the factors enhancing the labile character of the amide bonds and the stability of hydroxylysine glycosides in gas phase dissociation of collagen glycopeptides. C1 [Perdivara, Irina; Tomer, Kenneth B.] NIEHS, Mass Spectrometry Grp, NIH, Res Triangle Pk, NC 27709 USA. [Perera, Lalith] NIEHS, Computat Chem Grp, NIH, Res Triangle Pk, NC 27709 USA. [Sricholpech, Marnisa] Srinakharinwirot Univ, Fac Dent, Bangkok, Thailand. [Terajima, Masahiko; Yamauchi, Mitsuo] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Philadelphia, PA 19122 USA. RP Perdivara, I (reprint author), NIEHS, Mass Spectrometry Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM perdivarai@niehs.nih.gov; tomer@niehs.nih.gov OI Sricholpech, Marnisa/0000-0003-2139-0688 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES050171, ES043010]; NIH [AR060978, R01 AR056145] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES050171 to K. B. T. and ES043010 to L. P.), and by the NIH grants AR060978 (M.Y.) and R01 AR056145 (N.P.). The authors acknowledge Dr. Joshua Sharp (CCRC, Athens, GA) and Dr. Lee Pedersen (NIEHS/NIH) for the critical review of the manuscript, and the NIEHS Protein Microcharacterization Core Facility for the assistance with the in-gel digests. NR 51 TC 8 Z9 9 U1 3 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD JUL PY 2013 VL 24 IS 7 BP 1072 EP 1081 DI 10.1007/s13361-013-0624-y PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 162RW UT WOS:000320284000013 PM 23633013 ER PT J AU Fair, C Wiener, L Zadeh, S Albright, J Mellins, CA Mancilla, M Tepper, V Trexler, C Purdy, J Osherow, J Lovelace, S Kapetanovic, S AF Fair, Cynthia Wiener, Lori Zadeh, Sima Albright, Jamie Mellins, Claude Ann Mancilla, Michael Tepper, Vicki Trexler, Connie Purdy, Julia Osherow, Janet Lovelace, Susan Kapetanovic, Suad TI Reproductive Health Decision-Making in Perinatally HIV-Infected Adolescents and Young Adults SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE HIV and reproductive health; Perinatal HIV; HIV-infected youth; Adolescent reproductive health ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; ANTIRETROVIRAL THERAPY; FERTILITY DESIRES; POSITIVE WOMEN; NEURODEVELOPMENTAL OUTCOMES; MEDICATION ADHERENCE; VASCULAR DYSFUNCTION; PREGNANT-WOMEN; CHILDREN AB With widespread access to antiretroviral therapy in the United States, many perinatally HIV-infected (PHIV+) children are surviving into adolescence and adulthood, becoming sexually active and making decisions about their reproductive health. The literature focusing on the reproductive decisions of individuals behaviorally infected with HIV can serve as a springboard for understanding the decision-making process of PHIV+ youth. Yet, there are many differences that critically distinguish reproductive health and related decision-making of PHIV+ youth. Given the potential public health implications of their reproductive decisions, better understanding of factors influencing the decision-making process is needed to help inform the development of salient treatment and prevention interventions. To begin addressing this understudied area, a "think tank" session, comprised of clinicians, medical providers, and researchers with expertise in the area of adolescent HIV, was held in Bethesda, MD, on September 21, 2011. The focus was to explore what is known about factors that influence the reproductive decision-making of PHIV+ adolescents and young adults, determine what important data are needed in order to develop appropriate intervention for PHIV+ youth having children, and to recommend future directions for the field in terms of designing and carrying out collaborative studies. In this report, we summarize the findings from this meeting. The paper is organized around the key themes that emerged, including utilizing a developmental perspective to create an operational definition of reproductive decision-making, integration of psychosocial services with medical management, and how to design future research studies. Case examples are presented and model program components proposed. C1 [Fair, Cynthia; Albright, Jamie] Elon Univ, Elon, NC 27244 USA. [Wiener, Lori] NCI, Ctr Canc Res, Pediat Clin SE 1, Bethesda, MD 20892 USA. [Zadeh, Sima] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Mellins, Claude Ann] Columbia Univ, HIV Ctr Clin & Behav Studies, Dept Psychiat, New York, NY 10032 USA. [Mellins, Claude Ann] Columbia Univ, HIV Ctr Clin & Behav Studies, Dept Sociomed Sci, New York, NY 10032 USA. [Mellins, Claude Ann] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Mancilla, Michael] Childrens Natl Med Ctr, Burgess SIS Clin, Washington, DC 20010 USA. [Tepper, Vicki] Univ Maryland, Sch Med, Pediat AIDS Program, Baltimore, MD 21201 USA. [Trexler, Connie] Childrens Natl Med Ctr, Burgess Clin, Washington, DC 20010 USA. [Purdy, Julia] NIH, Ctr Clin, CCMD, Bethesda, MD 20892 USA. [Osherow, Janet] Georgetown Univ Hosp, Pediat Infect Dis Dept, PHC, Washington, DC 20007 USA. [Lovelace, Susan] Univ Maryland, Baltimore, MD 21201 USA. [Kapetanovic, Suad] NIMH, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Fair, C (reprint author), Elon Univ, CB 2338, Elon, NC 27244 USA. EM cfair@elon.edu; wienerl@mail.nih.gov; zadehsl@Mail.nih.gov; jalbright6@elon.edu; cmellins@gmail.com; MMancill@cnmc.org; vtepper@peds.umaryland.edu; ctrexler@childrensnational.org; purdyj@cc.nih.gov; JXO10@gunet.georgetown.edu; slovelac@peds.umaryland.edu; suad.kapetanovic@nih.gov FU Intramural NIH HHS; NIMH NIH HHS [R01 MH069133] NR 105 TC 10 Z9 10 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2013 VL 17 IS 5 BP 797 EP 808 DI 10.1007/s10995-012-1070-3 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 163FK UT WOS:000320321100004 PM 22736033 ER PT J AU El-Mohandes, AAE Windsor, R Tan, S Perry, DC Gantz, MG Kiely, M AF El-Mohandes, Ayman A. E. Windsor, Richard Tan, Sylvia Perry, David C. Gantz, Marie G. Kiely, Michele TI A Randomized Clinical Trial of Trans-Dermal Nicotine Replacement in Pregnant African-American Smokers SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Pregnancy; African-Americans; Smoking; Nicotine replacement therapy ID SMOKING-CESSATION; BIRTH-WEIGHT; THERAPY AB We compared acceptability, adherence and efficacy of trans-dermal nicotine patches and cognitive behavioral therapy (Group 1) to cognitive behavioral therapy alone (Group 2) in minority pregnant smokers. This is a randomized controlled trial. 52 women were recruited during pregnancy with a mean gestational age 18.5 +/- A 5.0 weeks and followed through delivery. Randomization was by site and initial cotinine levels. Interventionists and interviewers were blinded to group assignment. Two different nicotine replacement therapy dosing regiments were administered according to the baseline salivary cotinine level. A process evaluation model summarized patient adherence. The main outcome measure was self-report of cessation since last visit, confirmed by exhaled carbon monoxide. Analyses of categorical and continuous measures were conducted as well as linear trend tests of salivary cotinine levels. Women lost to follow-up were considered treatment failures. Participants were on average 27.5 +/- A 5.4 years old, 81 % were single, 69 % unemployed and 96 % were Medicaid eligible. A process evaluation indicated patients in both groups were adherent to scheduled program procedures through Visit 4, but not for Visits 5 and 6. Confirmed quit rates were: at visit 3, 23 (Group 1) and 0 % (Group 2) (p = 0.02); at visits 4 and 5, no difference; at visit 6, 19 (Group 1) and 0 % (Group 2) (p = 0.05). Group 1 delivered infants with a mean gestational age of 39.4 weeks versus 38.4 weeks in Group 2 (p = 0.02). 73 % (52/71) of the eligible smokers agreed to participate and 65 % (17/26) of Group 1 completed the protocol (i.e. attended 6 visits). A comparison of Group 1 and 2 quit rates confirmed a non-significant difference. C1 [El-Mohandes, Ayman A. E.] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. [Windsor, Richard] George Washington Univ, Sch Publ Hlth, Washington, DC USA. [Tan, Sylvia; Gantz, Marie G.] RTI Int, Rockville, MD USA. [Perry, David C.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Kiely, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Rm 7B-05, Rockville, MD 20852 USA. EM kielym@nih.gov FU Intramural NIH HHS; NICHD NIH HHS [U10 HD036104, U18 HD031206, U18 HD031206-07] NR 27 TC 4 Z9 4 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2013 VL 17 IS 5 BP 897 EP 906 DI 10.1007/s10995-012-1069-9 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 163FK UT WOS:000320321100014 PM 22761006 ER PT J AU Scharf, M Neef, S Freund, R Geers-Knorr, C Franz-Wachtel, M Brandis, A Krone, D Schneider, H Groos, S Menon, MB Chang, KC Kraft, T Meissner, JD Boheler, KR Maier, LS Gaestel, M Scheibe, RJ AF Scharf, Madeleine Neef, Stefan Freund, Robert Geers-Knoerr, Cornelia Franz-Wachtel, Mirita Brandis, Almuth Krone, Dorothee Schneider, Heike Groos, Stephanie Menon, Manoj B. Chang, Kin-Chow Kraft, Theresia Meissner, Joachim D. Boheler, Kenneth R. Maier, Lars S. Gaestel, Matthias Scheibe, Renate J. TI Mitogen-Activated Protein Kinase-Activated Protein Kinases 2 and 3 Regulate SERCA2a Expression and Fiber Type Composition To Modulate Skeletal Muscle and Cardiomyocyte SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GENE-EXPRESSION; RETICULUM CA2+-ATPASE; TWITCH MUSCLE; HEART-FAILURE; SLOW-TWITCH; P38 MAPK; TRANSCRIPTIONAL COACTIVATOR; METABOLIC ADAPTATION; GAMMA COACTIVATOR-1; SIGNAL-TRANSDUCTION AB The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3(-/-)) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3(-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3(-/-) soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3(-/-) mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function. C1 [Scharf, Madeleine; Freund, Robert; Krone, Dorothee; Schneider, Heike; Menon, Manoj B.; Gaestel, Matthias; Scheibe, Renate J.] Hannover Med Sch, Dept Biochem, Hannover, Germany. [Neef, Stefan; Maier, Lars S.] Univ Gottingen, Dept Cardiol & Pneumol, D-37073 Gottingen, Germany. [Geers-Knoerr, Cornelia; Kraft, Theresia] Hannover Med Sch, Dept Mol & Cellular Physiol, Hannover, Germany. [Franz-Wachtel, Mirita] Univ Tubingen, Proteome Ctr Tubingen, Interfac Inst Cell Biol, Tubingen, Germany. [Brandis, Almuth] Hannover Med Sch, Dept Pathol, Hannover, Germany. [Groos, Stephanie] Hannover Med Sch, Inst Cell Biol, Ctr Anat, Hannover, Germany. [Chang, Kin-Chow] Univ Nottingham, Sch Vet Med & Sci, Loughborough, England. [Meissner, Joachim D.] Hannover Med Sch, Dept Vegetat Physiol, Hannover, Germany. [Boheler, Kenneth R.] NIA, Mol Cardiol & Stem Cell Unit, NIH, Baltimore, MD 21224 USA. [Boheler, Kenneth R.] Univ Hong Kong, Li Ka Shing Fac Med, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China. RP Scheibe, RJ (reprint author), Hannover Med Sch, Dept Biochem, Hannover, Germany. EM scheibe.renate@mh-hannover.de RI Menon, Manoj/P-1543-2015 OI Menon, Manoj/0000-0001-5859-0347 FU Deutsche Forschungsgemeinschaft [SCHE 309/5-1] FX This work was supported by the Deutsche Forschungsgemeinschaft (SCHE 309/5-1). NR 83 TC 15 Z9 15 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2013 VL 33 IS 13 BP 2586 EP 2602 DI 10.1128/MCB.01692-12 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FN UT WOS:000320030900007 PM 23608535 ER PT J AU Kondilis-Mangum, HD Wade, PA AF Kondilis-Mangum, Hrisavgi D. Wade, Paul A. TI Epigenetics and the adaptive immune response SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE T cells; B cells; Adaptive immunity; Memory; Secondary immune response; Epigenetics; Histone modifications; DNA methylation; DNA methyltransferase ID T-CELL DEVELOPMENT; BETA ALLELIC EXCLUSION; HEAVY-CHAIN GENE; DNA METHYLTRANSFERASE 1; IFN-GAMMA PROMOTER; V(D)J RECOMBINATION; CHROMATIN-STRUCTURE; HISTONE H3; CYTIDINE DEAMINASE; B-LYMPHOCYTES AB Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathogens. While the immune system benefits from the dynamic nature of the epigenome, such benefit comes at a cost - increased likelihood of disease-causing mutation. Published by Elsevier Ltd. C1 [Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr MD D4-04, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [ES101965] FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (ES101965 to P.A.W.). We thank the members of the Wade laboratory for useful discussions throughout the course of preparation of this manuscript. We apologize to our many colleagues whose work could not be cited here due to space constraints. NR 102 TC 13 Z9 13 U1 5 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD JUL-AUG PY 2013 VL 34 IS 4 SI SI BP 813 EP 825 DI 10.1016/j.mam.2012.06.008 PG 13 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 165KI UT WOS:000320482400004 PM 22789989 ER PT J AU Liao, XH Buggey, J Lee, YK Kimmel, AR AF Liao, Xin-Hua Buggey, Jonathan Lee, Yun Kyung Kimmel, Alan R. TI Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DIRECTIONAL CELL-MOVEMENT; HETEROTRIMERIC G-PROTEINS; MEDIATED CGMP RESPONSE; ADENYLYL-CYCLASE; LEADING-EDGE; SPATIOTEMPORAL REGULATION; EUKARYOTIC CHEMOTAXIS; RAS ACTIVATION; DISCOIDEUM; CAMP AB Global stimulation of Dictyostelium with different chemoattractants elicits multiple transient signaling responses, including synthesis of cAMP and cGMP, actin polymerization, activation of kinases ERK2, TORC2, and phosphatidylinositide 3-kinase, and Ras-GTP accumulation. Mechanisms that down-regulate these responses are poorly understood. Here we examine transient activation of TORC2 in response to chemically distinct chemoattractants, cAMP and folate, and suggest that TORC2 is regulated by adaptive, desensitizing responses to stimulatory ligands that are independent of downstream, feedback, or feedforward circuits. Cells with acquired insensitivity to either folate or cAMP remain fully responsive to TORC2 activation if stimulated with the other ligand. Thus TORC2 responses to cAMP or folate are not cross-inhibitory. Using a series of signaling mutants, we show that folate and cAMP activate TORC2 through an identical GEF/Ras pathway but separate receptors and G protein couplings. Because the common GEF/Ras pathway also remains fully responsive to one chemoattractant after desensitization to the other, GEF/Ras must act downstream and independent of adaptation to persistent ligand stimulation. When initial chemoattractant concentrations are immediately diluted, cells rapidly regain full responsiveness. We suggest that ligand adaptation functions in upstream inhibitory pathways that involve chemoattractant-specific receptor/G protein complexes and regulate multiple response pathways. C1 [Liao, Xin-Hua; Buggey, Jonathan; Lee, Yun Kyung; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Kimmel, AR (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM alank@helix.nih.gov FU Intramural Research Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX We thank dictyBase (Fey et al., 2009) and colleagues for various strains. We thank Leung Kim, Pascale Charest, Rick Firtel, and Shi Shu for providing the Ras-related reagents. This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. NR 51 TC 3 Z9 4 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 1 PY 2013 VL 24 IS 13 BP 2146 EP 2155 DI 10.1091/mbc.E13-03-0130 PG 10 WC Cell Biology SC Cell Biology GA 175AP UT WOS:000321201800008 PM 23657816 ER PT J AU Moon, K Six, DA Lee, HJ Raetz, CRH Gottesman, S AF Moon, Kyung Six, David A. Lee, Hyun-Jung Raetz, Christian R. H. Gottesman, Susan TI Complex transcriptional and post-transcriptional regulation of an enzyme for lipopolysaccharide modification SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI LIPOPOLYSACCHARIDE; SMALL RNA; SALMONELLA-ENTERICA; ENVELOPE-STRESS; OUTER-MEMBRANE; SIGMA-FACTOR; LIPID-A; SYSTEM; PHOSPHORYLATION; CHROMOSOME AB The PhoQ/PhoP two-component system activates many genes for lipopolysaccharide (LPS) modification when cells are grown at low Mg2+ concentrations. An additional target of PhoQ and PhoP is MgrR, an Hfq-dependent small RNA that negatively regulates expression of eptB, also encoding a protein that carries out LPS modification. Examination of LPS confirmed that MgrR effectively silences EptB; the phosphoethanolamine modification associated with EptB is found in mgrR::kan but not mgrR+ cells. Sigma E has been reported to positively regulate eptB, although the eptB promoter does not have the expected Sigma E recognition motifs. The effects of Sigma E and deletion of mgrR on levels of eptB mRNA were independent, and the same 5 end was found in both cases. In vitro transcription and the behaviour of transcriptional and translational fusions demonstrate that Sigma E acts directly at the level of transcription initiation for eptB, from the same start point as Sigma 70. The results suggest that when Sigma E is active, synthesis of eptB transcript outstrips MgrR-dependent degradation; presumably the modification of LPS is important under these conditions. Adding to the complexity of eptB regulation is a second sRNA, ArcZ, which also directly and negatively regulates eptB. C1 [Moon, Kyung; Lee, Hyun-Jung; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Six, David A.; Raetz, Christian R. H.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov RI Six, David/D-6523-2011 OI Six, David/0000-0002-9013-1711 FU NIH, National Cancer Institute, Center for Cancer Research; NIH [GM-51310]; LIPID MAPS Large Scale Collaborative from NIH [GM-069338] FX We thank V. Rhodius for his thoughts on the eptB promoter, Dale Lewis for help with the in vitro transcription experiments, H. Nikaido for discussions, and K. Potrykus and M. Cashel for providing Sigma E protein. We thank M. S. Trent, D. Schu, S. Tong, N. De Lay and K. Ramamurthi for advice and comments on this article. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by NIH Grant GM-51310 to C.R.H.R. The mass spectrometry facility in the Department of Biochemistry of the Duke University Medical Center is supported by the LIPID MAPS Large Scale Collaborative Grant number GM-069338 from NIH. D.A.S. and S.G. dedicate this article to the memory of co-author Christian R. H. Raetz, whose deep knowledge and interest played a key role in bringing this work to fruition. NR 37 TC 14 Z9 16 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2013 VL 89 IS 1 BP 52 EP 64 DI 10.1111/mmi.12257 PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 168TN UT WOS:000320728800004 PM 23659637 ER PT J AU Penet, MF Artemov, D Farahani, K Bhujwalla, ZM AF Penet, Marie-France Artemov, Dmitri Farahani, Keyvan Bhujwalla, Zaver M. TI MR - eyes for cancer: looking within an impenetrable disease SO NMR IN BIOMEDICINE LA English DT Article DE MR probes; cancer; tumor microenvironment; receptors imaging; theranostics ID MAGNETIC-RESONANCE-SPECTROSCOPY; LYMPH-NODE METASTASES; SUPERPARAMAGNETIC IRON-OXIDE; TUMOR-ASSOCIATED MACROPHAGES; HUMAN BREAST-CANCER; IN-VIVO; EXTRACELLULAR PH; NONINVASIVE DETECTION; NMR-SPECTROSCOPY; PROSTATE-CANCER AB Probe development is a critical component in cancer imaging, and novel probes are making major inroads in several aspects of cancer detection and image-guided treatments. Intrinsic MR probes such as signals from metabolites and their chemical shifts have been used for more than a decade to understand cancer physiology and metabolism. Through the integration of technology, molecular biology, and chemistry, the last few years have witnessed an explosion of extrinsic probes for molecular and functional imaging of cancer that, together with techniques such as CEST and hyperpolarization, have significantly expanded the repertoire of MR techniques in basic and translational investigations of many different aspects of cancer. Furthermore, incorporation of MR probes into multifunctional nanoparticles and multimodality imaging platforms have opened new opportunities for MR in image-guided diagnosis and therapy of cancer. Here we have provided an overview of recent innovations that have occurred in the development of MRI probes for molecular and functional imaging of cancer. Although most of these novel probes are not clinically available, they offer significant promise for future translational applications. In this review, we have highlighted the areas of future development that are likely to have a profound impact on cancer detection and treatment. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Penet, Marie-France; Artemov, Dmitri; Bhujwalla, Zaver M.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, JHU ICMIC Program,Div Canc Imaging Res, Baltimore, MD 21218 USA. [Artemov, Dmitri; Bhujwalla, Zaver M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD USA. [Farahani, Keyvan] NCI, Image Guided Intervent Branch, Canc Imaging Program, Bethesda, MD 20892 USA. RP Bhujwalla, ZM (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, JHU ICMIC Program,Div Canc Imaging Res, Baltimore, MD 21218 USA. EM zaver@mri.jhu.edu FU NIH [P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R01 CA138264]; Honorable Tina Brozman Foundation FX Support from NIH P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R01 CA138264 and the Honorable Tina Brozman Foundation (MFP) is gratefully acknowledged. NR 86 TC 5 Z9 5 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2013 VL 26 IS 7 SI SI BP 745 EP 755 DI 10.1002/nbm.2980 PG 11 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 168UC UT WOS:000320730300004 PM 23784955 ER PT J AU Baidoo, KE Milenic, DE Brechbiel, MW AF Baidoo, Kwamena E. Milenic, Diane E. Brechbiel, Martin W. TI Methodology for labeling proteins and peptides with lead-212 (Pb-212) SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Radioimmunotherapy; Alpha targeted therapy; Lead-212; Trastuzumab; Cancer therapy ID DISSEMINATED PERITONEAL DISEASE; ALPHA-PARTICLE RADIOIMMUNOTHERAPY; DNA-DAMAGE REPAIR; CANCER-THERAPY; MONOCLONAL-ANTIBODY; GASTRIC-CANCER; TARGETING HER2; IN-VIVO; TUMOR; RADIATION AB Introduction: Alpha particles possess an exquisite degree of cytotoxicity when employed for targeted alpha-particle therapy (TAT) or radioimmunotherapy (RIT). Pb-212, which acts as an in vivo generator of the alpha-emitting nuclide Bi-212 has shown great promise in pre-clinical studies when used to label the HER2 binding antibody, trastuzumab. Currently, the first RIT clinical trial employing Pb-212 radiolabeled trastuzumab is in progress. This report provides detailed current protocol operations and steps that were generated for use in the clinical trial as well as the relevant pre-clinical experimentation, and describes in detail the labeling of proteins or peptides with Pb-212 as provided via a Ra-224 based generator system. Methods: Pb-212 was eluted from the Ra-224/Pb-212 generator using hydrochloric acid (2 M). The generator eluate was evaporated and digested with nitric acid (8 M) followed by extraction of the Pb-212 with dilute nitric acid (0.1 M). The dilute nitric acid solution of Pb-212 was used to label the immunoconjugate Trastuzumab-TCMC (2-(4-isothiocyanatobenzyl-1,4,7,10-tetraaza-1,4,7,10,tetra-(2-carbamonylmethyl)-cyclododecane) at pH 5.5. Results: Elution of Pb-212 from the generator was efficient yielding>90% of available Pb-212. Trastuzumab-TCMC was efficiently labeled with a radiochemical yield of 94% +/- 4% (n = 7) by ITLC and an isolated yield of 73% +/- 3% (n = 7). Conclusions: The results show the feasibility of generating radioimmunoconjugates and peptide conjugates for use as in vivo alpha generator systems in the clinic. The technology holds promise in applications involving the treatment of minimal disease such as micrometastases and residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers, such as ovarian cancer. Published by Elsevier Inc. C1 [Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.] NCI, NIH, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. RP Baidoo, KE (reprint author), NCI, NIH, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. EM baidook@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 41 TC 8 Z9 8 U1 0 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 592 EP 599 DI 10.1016/j.nucmedbio.2013.01.010 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800002 PM 23602604 ER PT J AU Kang, CS Song, HA Milenic, DE Baidoo, KE Brechbiel, MW Chong, HS AF Kang, Chi Soo Song, Hyun A. Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. Chong, Hyun-Soon TI Preclinical evaluation of NETA-based bifunctional ligand for radioimmunotherapy applications using Bi-212 and Bi-213: Radiolabeling, serum stability, and biodistribution and tumor uptake studies SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Bi-212; Bi-213; Bifunctional chelator; Serum stability, biodistribution; Radiolabeling ID IN-VIVO EVALUATION; MONOCLONAL-ANTIBODY; LEUKEMIA; THERAPY; CANCER; LU-177; ACID AB Introduction: Despite the great potential of targeted alpha-radioimmunotherapy (RIT) as demonstrated by preclinical and clinical trials, limited progress has been made on the improvement of chelation chemistry for Bi-212 and Bi-213. A new bifunctional ligand 3p-C-NETA was evaluated for targeted alpha RIT using Bi-212 and Bi-213. Methods: Radiolabeling of 3p-C-NETA with Bi-205/6, a surrogate of Bi-212 and Bi-213, was evaluated at pH 5.5 and room temperature. In vitro stability of the Bi-205/6-3p-C-NETA-trastuzumab conjugate was evaluated using human serum (pH 7, 37 degrees C). Immunoreactivity and specific activity of the Bi-205/6-3p-C-NETA-trastuzumab conjugate were measured. An in vivo biodistribution study was performed to evaluate the in vivo stability and tumor targeting properties of the Bi-205/6-3p-C-NETA-trastuzumab conjugate in athymic mice bearing subcutaneous LS174T tumor xenografts. Result: The 3p-C-NETA-trastuzumab conjugate was extremely rapid in complexing with Bi-205/6, and the corresponding Bi-205/6-3p-C-NETA-trastuzumab was stable in human serum. Bi-205/6-3p-C-NETA-trastuzumab was prepared with a high specific activity and retained immunoreactivity. Bi-205/6-3p-C-NETA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low normal organ and high tumor uptake. Conclusion: The results of the in vitro and in vivo studies indicate that 3p-C-NETA is a promising chelator for RIT applications using Bi-212 and Bi-213. Further detailed in vivo evaluations of 3p-C-NETA for targeted alpha RIT are warranted. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kang, Chi Soo; Song, Hyun A.; Chong, Hyun-Soon] IIT, Biol & Chem Sci Dept, Div Chem, Chicago, IL 60616 USA. [Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] Natl Canc Inst, NIH, Ctr Canc Res, Radiat Oncol Branch,Radioimmune & Inorgan Chem Se, Bethesda, MD USA. RP Chong, HS (reprint author), IIT, Biol & Chem Sci Dept, Div Chem, Chicago, IL 60616 USA. EM chong@iit.edu FU National Institutes of Health [R01CA112503]; NIH FX Supported by National Institutes of Health (R01CA112503) and NIH intramural research program. NR 22 TC 11 Z9 11 U1 4 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 600 EP 605 DI 10.1016/j.nucmedbio.2013.01.012 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800003 PM 23541026 ER PT J AU Peterson, KL Reid, WC Freeman, AF Holland, SM Pettigrew, RI Gharib, AM Hammoud, DA AF Peterson, Kristin L. Reid, William C. Freeman, Alexandra F. Holland, Steven M. Pettigrew, Roderic I. Gharib, Ahmed M. Hammoud, Dima A. TI The use of C-14-FIAU to predict bacterial thymidine kinase presence: Implications for radiolabeled FIAU bacterial imaging SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Bacterial imaging; PET; FIAU; Thymidine kinase ID POSITRON-EMISSION-TOMOGRAPHY; HYPER-IGE SYNDROMES; INFECTIONS AB Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with I-124-FIAU-PET. Methods: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with C-14-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter. Results: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of C-14-FIAU uptake, except for P. aeruginosa. Conclusion: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all retain FIAU. Our technique is simple, and can be easily used to assess whether a certain bacterial strain of interest can or cannot be visualized using radiolabeled FIAU. Published by Elsevier Inc. C1 [Peterson, Kristin L.; Reid, William C.; Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20814 USA. [Pettigrew, Roderic I.; Gharib, Ahmed M.] NIDDK, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, NIH, Immunopathogenesis Sect, LCID, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Clin, Bethesda, MD 20814 USA. EM hammoudd@cc.nih.gov RI Hammoud, Dima/C-2286-2015; Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Peterson, Kristin/0000-0003-0796-3611 FU National Institutes of Health FX National Institutes of Health, Bench to Bedside intramural research grant (2011-2012). NR 21 TC 5 Z9 6 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2013 VL 40 IS 5 BP 638 EP 642 DI 10.1016/j.nucmedbio.2013.01.005 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161TS UT WOS:000320216800008 PM 23541824 ER PT J AU Bowers, K Laughon, SK Kim, S Mumford, SL Brite, J Kiely, M Zhang, CL AF Bowers, Katherine Laughon, S. Katherine Kim, Sungduk Mumford, Sunni L. Brite, Jennifer Kiely, Michele Zhang, Cuilin TI The Association between a Medical History of Depression and Gestational Diabetes in a Large Multi-ethnic Cohort in the United States SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE depression; pregnancy; gestational diabetes ID INCREASING PREVALENCE; MELLITUS; PREGNANCY; WOMEN; HEALTH; RISK AB Background Both major depression and gestational diabetes mellitus (GDM) are prevalent among women of reproductive age. Our objective was to determine whether a medical history of depression is related to subsequent development of GDM. Methods The Consortium on Safe Labor was a US retrospective cohort study of 228562 births between 2002 and 2008. Exclusion criteria for the present analysis included multiple gestation pregnancies (n=5059), pre-existing diabetes (n=12771), deliveries <24 weeks (n=395), site GDM prevalence (<1%) (n=20721) and missing data on pre-pregnancy body mass index (BMI) (n=61321). Using generalised estimating equations, we estimated the association between a history of depression and a pregnancy complicated by GDM. Results The final analytic population included 121260 women contributing 128295 pregnancies, of which 5606 were affected by GDM. A history of depression was significantly associated with an increased risk of developing GDM (multivariate odds ratio [aOR]=1.42 [95% confidence interval (CI) 1.26, 1.60]). Adjusting for pre-pregnancy BMI and weight gain during pregnancy attenuated the association, although it remained statistically significant (aOR=1.17 [95% CI 1.03, 1.33]). Conclusions A history of depression was significantly associated with an increased GDM risk among a large multi-ethnic US cohort of women. If the association is confirmed, depression presents a potentially modifiable risk factor of GDM and provides additional clues to the underlying pathophysiology of GDM. C1 [Bowers, Katherine; Laughon, S. Katherine; Kim, Sungduk; Mumford, Sunni L.; Kiely, Michele; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Bowers, Katherine] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Brite, Jennifer] CUNY, Sch Publ Hlth, New York, NY 10021 USA. RP Bowers, K (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, 3333 Burnet Ave,MLC 5041, Cincinnati, OH 45229 USA. EM katherine.bowers@cchmc.org; zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this paper were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. Institutions involved in the Consortium include, in alphabetical order, Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Inter-mountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH.; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville MD (Data Coordinating Center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and the University of Texas Health Science Center at Houston, Houston, TX. The named authors alone are responsible for the views expressed in this manuscript, which does not necessarily represent the decisions or the stated policy of the NICHD. NR 23 TC 10 Z9 10 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2013 VL 27 IS 4 BP 323 EP 328 DI 10.1111/ppe.12057 PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 165HQ UT WOS:000320474700002 PM 23772933 ER PT J AU Jin, TC Curry, J Smith, P Jiang, JS Xiao, TS AF Jin, Tengchuan Curry, James Smith, Patrick Jiang, Jiansheng Xiao, T. Sam TI Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE NLRP1; CARD; death domain fold; electrostatic attraction ID INFLAMMASOME; ACTIVATION; PLATFORM; NALP1 AB The NLRP1 inflammasome responds to microbial challenges such as Bacillus anthracis infection and is implicated in autoimmune disease such as vitiligo. Human NLRP1 contains both an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain (CARD), with the latter being essential for its association with the downstream effector procaspase-1. Here we report a 2.0 angstrom crystal structure of the human NLRP1 CARD as a fusion with the maltose-binding protein. The structure reveals the six-helix bundle fold of the NLRP1 CARD, typical of the death domain superfamily. The charge surface of the NLRP1 CARD structure and a procaspase-1 CARD model suggests potential mechanisms for their association through electrostatic attraction. Proteins 2013; 81:1266-1270. (c) 2013 Wiley Periodicals, Inc. C1 [Jin, Tengchuan; Curry, James; Smith, Patrick; Jiang, Jiansheng; Xiao, T. Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Xiao, TS (reprint author), NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, 4 Mem Dr,Bldg 4,Room 228, Bethesda, MD 20892 USA. EM xiaot@niaid.nih.gov RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010; Jin, Tengchuan/B-5883-2014 OI Xiao, Tsan/0000-0001-9688-475X; Jin, Tengchuan/0000-0002-1395-188X FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; US Department of Energy [DE-AC02-06CH11357]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX Grant sponsor: National Cancer Institute; Grand number: Y1-CO-1020; Grant sponsor: National Institute of General Medical Sciences; Grand number: Y1-GM-1104; Grant sponsor: US Department of Energy; Grand number: DE-AC02-06CH11357; Grant sponsor: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 18 TC 17 Z9 17 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUL PY 2013 VL 81 IS 7 BP 1266 EP 1270 DI 10.1002/prot.24287 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 165HK UT WOS:000320474100016 PM 23508996 ER PT J AU Ling, D Liu, BY Jawad, S Thompson, IA Nagineni, CN Dailey, J Chien, J Sredni, B Nussenblatt, RB AF Ling, Diamond Liu, Baoying Jawad, Shayma Thompson, Ian A. Nagineni, Chandrasekharam N. Dailey, Jennifer Chien, Jason Sredni, Benjamin Nussenblatt, Robert B. TI The tellurium redox immunomodulating compound AS101 inhibits IL-1 beta-activated inflammation in the human retinal pigment epithelium SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID NF-KAPPA-B; MACULAR DEGENERATION; GENE-EXPRESSION; CELLS; IL-6; MECHANISMS; SECRETION; UVEITIS; MICE AB Purpose AS101 is a non-toxic organotellurium-IV compound with demonstrated immunomodulating activity in vitro and in vivo. Inflammatory responses are attributed to the pathophysiology of numerous ocular diseases. In this study, we wished to elucidate whether AS101 could mitigate pro-inflammatory activity in human retinal pigment epithelial (RPE) cells, which are heavily involved in ocular immune responses, induced by pro-inflammatory IL-beta activity. Methods Primary and transformed RPE cells treated with varying concentrations of AS101 were used in this study. Real-time PCR and ELISA assays were used to detect cytokine/chemokine mRNA expression and protein production. Western blot was used to detect changes in the NF kappa B pathway. Cell viability and proliferation were detected using a Vi-Cell XR cell counter. To measure the cytoprotective capacity of AS101, cell numbers were compared between cells treated with IL-1 beta or lipopolysaccharide (LPS) and cells treated with IL-1 beta or LPS in the presence of AS101. Results AS101 inhibited IL-1 beta-induced mRNA expression and protein production of IL-6 and IL-8 in RPE cells. The viability of RPE cells treated with IL-1 beta and LPS was unaffected. AS101 slightly inhibited RPE cell growth in the presence of higher levels of IL-1 beta. Also, AS101 downregulated the IL-1 beta activity by inhibiting the phosphorylation of p65, an NF kappa B subunit. Conclusions The results demonstrate that AS101 reduces IL-1 beta-induced inflammatory responses in the RPE. In previous studies, AS101 exhibited therapeutic effects in various disease models and was a safe profile in clinical trials. These results suggest that AS101 may have potent anti-inflammatory potential in the eye and confer the downregulation of RPE inflammatory responses in a pathological environment. C1 [Ling, Diamond; Liu, Baoying; Jawad, Shayma; Thompson, Ian A.; Nagineni, Chandrasekharam N.; Dailey, Jennifer; Chien, Jason; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Sredni, Benjamin] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, Tel Aviv, Israel. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU Intramural Research Program of NIH, National Eye Institute, Bethesda, USA FX This research was supported by the Intramural Research Program of NIH, National Eye Institute, Bethesda, USA. NR 25 TC 5 Z9 6 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUL PY 2013 VL 97 IS 7 BP 934 EP 938 DI 10.1136/bjophthalmol-2012-301962 PG 5 WC Ophthalmology SC Ophthalmology GA 161YH UT WOS:000320229800028 PM 23624272 ER PT J AU Chen, D Chen, Y Forrest, D Bremner, R AF Chen, D. Chen, Y. Forrest, D. Bremner, R. TI E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3 SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE retinoblastoma; E2f; p53; cone photoreceptor; retina ID LENS FIBER CELLS; S-PHASE ENTRY; E2F1-INDUCED APOPTOSIS; DNA-SYNTHESIS; MUTANT MICE; MOUSE MODEL; RB; RETINOBLASTOMA; P53; CYCLE AB The 'activating' E2fs (E2f1-3) are transcription factors that potently induce quiescent cells to divide. Work on cultured fibroblasts suggested they were essential for division, but in vivo analysis in the developing retina and other tissues disproved this notion. The retina, therefore, is an ideal location to assess other in vivo adenovirus E2 promoter binding factor (E2f) functions. It is thought that E2f1 directly induces apoptosis, whereas other activating E2fs only induce death indirectly by upregulating E2f1 expression. Indeed, mouse retinoblastoma (Rb)-null retinal neuron death requires E2f1, but not E2f2 or E2f3. However, we report an entirely distinct mechanism in dying cone photoreceptors. These neurons survive Rb loss, but undergo apoptosis in the cancer-prone retina lacking both Rb and its relative p107. We show that while E2f1 killed Rb/p107 null rod, bipolar and ganglion neurons, E2f2 was required and sufficient for cone death, independent of E2f1 and E2f3. Moreover, whereas E2f1-dependent apoptosis was p53 and p73-independent, E2f2 caused p53-dependent cone death. Our in vivo analysis of cone photoreceptors provides unequivocal proof that E2f-induces apoptosis independent of E2f1, and reveals distinct E2f1- and E2f2-activated death pathways in response to a single tumorigenic insult. C1 [Chen, D.; Chen, Y.; Bremner, R.] Univ Toronto, Dept Ophthalmol & Visual Sci, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Chen, D.; Chen, Y.; Bremner, R.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Chen, D.; Chen, Y.; Bremner, R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Chen, D.] Sichuan Univ, Dept Ophthalmol, Ophthalm Lab, Mol Med Res Ctr, Chengdu 610064, Peoples R China. [Chen, D.] Sichuan Univ, Torsten Wiesel Res Inst, World Eye Org, State Key Lab Biotherapy,West China Hosp, Chengdu 610064, Peoples R China. [Forrest, D.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. RP Bremner, R (reprint author), Univ Toronto, Toronto Western Res Inst, Dept Genet & Dev, 399 Bathurst St,Room Mc6-424, Toronto, ON M5T 2S8, Canada. EM rbremner@uhnres.utoronto.ca RI Bremner, Rod/I-6490-2012 OI Bremner, Rod/0000-0001-9184-7212 FU Canadian Institutes for Health Research; Foundation Fighting Blindness Canada FX We thank G Leone and L van Parijs for plasmids; CM Craft, PA Hargrave, T Mak and R Molday for antibodies; G Leone and F McKeon for mice and P Monnier and R Slack for comments on the manuscript. This work was supported by grants from the Canadian Institutes for Health Research and the Foundation Fighting Blindness Canada to RB. NR 60 TC 10 Z9 10 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2013 VL 20 IS 7 BP 931 EP 940 DI 10.1038/cdd.2013.24 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 160EO UT WOS:000320100000013 PM 23558950 ER PT J AU Cahoon, EK Rozhko, A Hatch, M Polyanskaya, O Ostroumova, E Tang, M Nadirov, E Yauseyenka, V Savasteeva, I McConnell, RJ Pfeiffer, RM Brenner, AV AF Cahoon, Elizabeth K. Rozhko, Alexander Hatch, Maureen Polyanskaya, Olga Ostroumova, Evgenia Tang, Min Nadirov, Eldar Yauseyenka, Vasilina Savasteeva, Irina McConnell, Robert J. Pfeiffer, Ruth M. Brenner, Alina V. TI Factors associated with serum thyroglobulin levels in a population living in Belarus SO CLINICAL ENDOCRINOLOGY LA English DT Article ID DIFFERENTIATED THYROID-CANCER; CHERNOBYL ACCIDENT; IODINE DEFICIENCY; HEALTHY-SUBJECTS; MARKER; TG; RADIOIMMUNOASSAY; AUTOANTIBODIES; CARCINOMA; DISEASE AB Objective Serum thyroglobulin (Tg) has been associated with a number of thyroid disorders and has been proposed as an indicator of iodine deficiency in a population. However, few studies have addressed the epidemiology of Tg in a population-based setting or in the context of exposure to radioactive iodine-131 (I-131). Our objective was to evaluate baseline levels of Tg in relation to sociodemographic characteristics, iodine status and thyroid function for individuals exposed to I-131. Design A population-based cohort assembled in Belarus following the Chornobyl accident provided demographic factors, clinical data and physiological measurements. Participants Our analytical sample included 10344 subjects of whom 7890 had no thyroid disease and 2454 had evidence of structural or functional thyroid abnormality. Measurements Standardized assays were used to measure serum Tg, urinary iodine, TSH and antibodies to Tg and thyroid peroxidase. Ultrasound was used to assess the presence of nodules and estimate thyroid volume. Results In the fully adjusted model, percent change in Tg was significantly increased among females, smokers and subjects of older age and Tg increased with decreasing urinary iodine concentration, increasing serum TSH and increasing thyroid volume (P-values for trend <0 center dot 0001), and presence of thyroid nodules (P<0 center dot 05). We found a complex interaction between region of residence, rural/urban living, presence/absence of thyroid abnormalities and serum Tg (P<0 center dot 0001). Conclusions In residents of Belarus, serum Tg is significantly related to presence of thyroid abnormalities as well as indicators of thyroid function and iodine deficiency and, therefore, could be used to characterize the iodine status and thyroid function of individuals in the context of epidemiological study. C1 [Cahoon, Elizabeth K.; Hatch, Maureen; Ostroumova, Evgenia; Brenner, Alina V.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. [Rozhko, Alexander; Polyanskaya, Olga; Nadirov, Eldar; Yauseyenka, Vasilina; Savasteeva, Irina] Republican Ctr Radiat Med & Human Ecol, Res Dept, Gomel, Byelarus. [Tang, Min] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tang, Min] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McConnell, Robert J.] Columbia Univ, Coll Phys & Surg, Dept Med, Thyroid Ctr, New York, NY USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. RP Cahoon, EK (reprint author), 6120 Execut Blvd,EPS,Room 7053,MSC 7238, Bethesda, MD 20892 USA. EM khaykine@mail.nih.gov FU Intramural NIH HHS [ZIA CP010132-17] NR 35 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JUL PY 2013 VL 79 IS 1 BP 120 EP 127 DI 10.1111/cen.12107 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158SP UT WOS:000319993500018 PM 23190420 ER PT J AU Schoonveld, C Donsante, A del Gaudio, D Waggoner, D Das, S Kaler, SG AF Schoonveld, C. Donsante, A. del Gaudio, D. Waggoner, D. Das, S. Kaler, S. G. TI Prenatal diagnostic conundrum involving anovel ATP7A duplication SO CLINICAL GENETICS LA English DT Letter ID DISEASES C1 [Schoonveld, C.] Univ Minnesota, Med Ctr, Fairview Hlth Serv, Minneapolis, MN 55455 USA. [Donsante, A.; Kaler, S. G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD USA. [del Gaudio, D.; Waggoner, D.; Das, S.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Kaler, SG (reprint author), NICHD, Program Mol Med, NIH, Bldg 10,Room 10N313,MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU Intramural NIH HHS [ZIA HD008768-10] NR 7 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUL PY 2013 VL 84 IS 1 BP 97 EP 98 DI 10.1111/cge.12041 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 160QE UT WOS:000320133500019 PM 23151012 ER PT J AU Williams, KW Word, C Streck, MR Titus, MO AF Williams, Kelli W. Word, Carolyn Streck, Maria R. Titus, M. Olivia TI Parental Education on Asthma Severity in the Emergency Department and Primary Care Follow-up Rates SO CLINICAL PEDIATRICS LA English DT Article DE asthma; severity; education; emergency department; follow-up ID INNER-CITY CHILDREN; NATIONAL GUIDELINES; RANDOMIZED-TRIAL; VISIT; BARRIERS; MANAGEMENT; EXACERBATIONS; MEDICATION; INITIATION; ADHERENCE AB Asthma is the most prevalent chronic condition affecting children and a common chief complaint in emergency departments (EDs). We aimed to improve parents' understanding of their child's asthma severity on accessing our pediatric ED for an acute asthma exacerbation. A retrospective chart review was conducted to determine outpatient follow-up rates from our ED in 2010-2011. In an attempt to educate parents at ED discharge about their child's asthma severity at presentation, we included a visual severity scale on their discharge instructions. Postdischarge telephone interviews were completed to determine postintervention follow-up rates. Asthma follow-up rates at 1 week improved from 20.8% to 50% after intervention. This difference was statistically significant after controlling for age and clinical asthma score with logistic regression (P < .0001). Offering predischarge education about a child's initial asthma severity is a simple intervention that significantly improved follow-up rates for children seen in the ED for asthma exacerbation. C1 [Williams, Kelli W.; Word, Carolyn; Streck, Maria R.; Titus, M. Olivia] Med Univ S Carolina, Charleston, SC 29425 USA. RP Williams, KW (reprint author), NIAID, ICMOB, DCR, NIH, 10 Ctr Dr,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM kelli.williams@nih.gov RI Webster, Susan/C-7360-2015 OI Webster, Susan/0000-0002-0684-4226 NR 24 TC 3 Z9 3 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUL PY 2013 VL 52 IS 7 BP 612 EP 619 DI 10.1177/0009922813479163 PG 8 WC Pediatrics SC Pediatrics GA 156IW UT WOS:000319816300006 PM 23471520 ER PT J AU Mandemakers, W Abuhatzira, L Xu, H Caromile, LA Hebert, SS Snellinx, A Morais, VA Matta, S Cai, T Notkins, AL De Strooper, B AF Mandemakers, W. Abuhatzira, L. Xu, H. Caromile, L. A. Hebert, S. S. Snellinx, A. Morais, V. A. Matta, S. Cai, T. Notkins, A. L. De Strooper, B. TI Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 beta: identification of miR-153 target genes with functions related to IA-2 beta in pancreas and brain SO DIABETOLOGIA LA English DT Article DE Diabetes; Glucose stimulation; IA-2 beta; MicroRNA; miR-153; Neurodegeneration ID AMYLOID PRECURSOR PROTEIN; INSULIN-SECRETION; MONOCLONAL-ANTIBODIES; EXPRESSION; PHOSPHATASE; DISRUPTION; MICE; GRANULES; PHOGRIN; ROLES AB We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2 beta. We also identified miR-153 target genes that correlated with IA-2 beta localisation and function. A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2 beta, quantitative PCR analysis of miR-153 and Ia-2 beta (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2 beta single knockout and Ia-2/Ia-2 beta double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2 beta, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2 beta in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2 beta knockout and Ia-2/Ia-2 beta double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2 beta expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels. This study suggests the involvement of miR-153, IA-2 beta and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release. C1 [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] VIB Ctr Biol Dis, Gasthuisberg O&N4, B-3000 Louvain, Belgium. [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] KULeuven, Ctr Human Genet, LIND, Louvain, Belgium. [Mandemakers, W.; Hebert, S. S.; Snellinx, A.; Morais, V. A.; Matta, S.; De Strooper, B.] KULeuven, Univ Ziekenhuizen, Louvain, Belgium. [Abuhatzira, L.; Xu, H.; Caromile, L. A.; Cai, T.; Notkins, A. L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [De Strooper, B.] VIB Ctr Biol Dis VIB11, Ctr Human Genet CB4, Gasthuisberg O&N4, B-3000 Louvain, Belgium. RP De Strooper, B (reprint author), VIB Ctr Biol Dis VIB11, Ctr Human Genet CB4, Gasthuisberg O&N4, Herestr 49 Bus 602, B-3000 Louvain, Belgium. EM bart.destrooper@cme.vib-kuleuven.be RI Caromile, Leslie/Q-2980-2016 OI Caromile, Leslie/0000-0003-2193-5190 FU National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA; Marie Curie Intra-European Fellowship (EIF) [041333]; Flemish community; University of Leuven, Belgium; European Research Commission (ERC) grant (EU Commission) FX This work was supported, in part, by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, a Marie Curie Intra-European Fellowship (EIF proposal number 041333) awarded to W. Mandemakers, and a Methusalem grant (Flemish community and University of Leuven, Belgium) and European Research Commission (ERC) grant (EU Commission) to B. De Strooper. NR 48 TC 13 Z9 13 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2013 VL 56 IS 7 BP 1547 EP 1556 DI 10.1007/s00125-013-2901-5 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 157FL UT WOS:000319881300012 PM 23595248 ER PT J AU Goedert, JJ AF Goedert, James J. TI The microbiota and human health: beyond exploration SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID DIVERSITY C1 NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov FU Intramural NIH HHS [ZIA CP010214-03] NR 5 TC 3 Z9 3 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUL PY 2013 VL 43 IS 7 BP 657 EP 659 DI 10.1111/eci.12100 PG 3 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 160NW UT WOS:000320127400001 PM 23611431 ER PT J AU Bataller, R Gao, B AF Bataller, Ramon Gao, Bin TI Dissecting the role of CB1 receptors on chronic liver diseases SO GUT LA English DT Editorial Material ID MICE C1 [Bataller, Ramon] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Bataller, Ramon] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Bataller, R (reprint author), Univ N Carolina, Dept Med, 2209 McGavran Greenberg, Chapel Hill, NC 27599 USA. EM bataller@med.unc.edu; bgao@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999, ZIA AA000369-11] NR 9 TC 1 Z9 1 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD JUL PY 2013 VL 62 IS 7 BP 957 EP 958 DI 10.1136/gutjnl-2012-303664 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 158MO UT WOS:000319975900002 PM 23197412 ER PT J AU Narendra, DP Wang, CX Youle, RJ Walker, JE AF Narendra, Derek P. Wang, Chunxin Youle, Richard J. Walker, John E. TI PINK1 rendered temperature sensitive by disease-associated and engineered mutations SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECESSIVE PARKINSONISM; DAMAGED MITOCHONDRIA; ACTIVATION SEGMENT; CRYSTAL-STRUCTURE; PROTEIN-KINASES; MITOPHAGY; RECRUITMENT; P62/SQSTM1; RECOGNITION; PROTEASOME AB Mutations in Parkin or PINK1 are the most common cause of recessively inherited parkinsonism. Parkin and PINK1 function in a conserved mitochondrial quality control pathway, in which PINK1, a putative mitochondrial kinase, directs Parkin, a cytosolic E3 ubiquitin ligase, selectively to dysfunctional mitochondria to promote their isolation, immobilization and degradation by macroautophagy (hereafter, mitophagy). As Parkin recruitment to mitochondria is robustly induced by PINK1 expression on the outer mitochondrial membrane, Parkin recruitment to mitochondria was used as an assay for PINK1 function. Unexpectedly, mutation of serine residues within the activation segment of PINK1 uncovered a temperature-sensitive variant of PINK1 (tsPINK1). tsPINK1 allowed for the first time the disassociation of PINK1 activity from its expression and localization. Additionally, extensive mutagenesis identified three disease-associated variants in the activation segment and one in an -helix N-terminal to kinase domain (Q126P) that are similarly thermally labile, suggesting that their activity could be restored post-translationally (e.g. by reducing the temperature or by a chemical or pharmacologic chaperone). Together, these findings suggest that tsPINK1 may represent a valuable tool for the analysis of the PINK1/Parkin pathway in human cells; additionally, as the serine residue promoting thermal lability is conserved among Mus musculus, Danio rerio, Drosophila melanogaster and Caenorhabditis elegans, it may serve as the basis for developing other temperature-sensitive models for the study of recessive parkinsonism and mitophagy. Finally, these results suggest that PINK1 kinase function could be restored for a subset of patients with PINK1 mutations, and perhaps alter the course of their disease. C1 [Narendra, Derek P.; Walker, John E.] MRC, Mitochondrial Biol Unit, Cambridge CB0 2XY, England. [Narendra, Derek P.; Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Walker, JE (reprint author), MRC Mitochondrial Biol Unit, Wellcome Trust MRC Bldg,Hills Rd, Cambridge CB2 OXY, England. EM john.walker@mrc-mbu.cam.ac.uk RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU Medical Research Council; National Institute of Neurological Disorders and Stroke; NIH [1F30AG039185-01] FX This work received funding support from the Medical Research Council (J.E.W. and D.P.N.), the intramural program at the National Institute of Neurological Disorders and Stroke (R.J.Y. and D.P.N.) and NIH training grant 1F30AG039185-01 (D.P.N.). NR 42 TC 9 Z9 10 U1 5 U2 11 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 JUL 1 PY 2013 VL 22 IS 13 BP 2572 EP 2589 DI 10.1093/hmg/ddt106 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100003 PM 23459931 ER PT J AU Schumacher, FR Wang, ZM Skotheim, RI Koster, R Chung, CC Hildebrandt, MAT Kratz, CP Bakken, AC Bishop, DT Cook, MB Erickson, RL Fossa, SD Greene, MH Jacobs, KB Kanetsky, PA Kolonel, LN Loud, JT Korde, LA Le Marchand, L Lewinger, JP Lothe, RA Pike, MC Rahman, N Rubertone, MV Schwartz, SM Siegmund, KD Skinner, EC Turnbull, C Van den Berg, DJ Wu, XF Yeager, M Nathanson, KL Chanock, SJ Cortessis, VK McGlynn, KA AF Schumacher, Fredrick R. Wang, Zhaoming Skotheim, Rolf I. Koster, Roelof Chung, Charles C. Hildebrandt, Michelle A. T. Kratz, Christian P. Bakken, Anne C. Bishop, D. Timothy Cook, Michael B. Erickson, R. Loren Fossa, Sophie D. Greene, Mark H. Jacobs, Kevin B. Kanetsky, Peter A. Kolonel, Laurence N. Loud, Jennifer T. Korde, Larissa A. Le Marchand, Loic Lewinger, Juan Pablo Lothe, Ragnhild A. Pike, Malcolm C. Rahman, Nazneen Rubertone, Mark V. Schwartz, Stephen M. Siegmund, Kimberly D. Skinner, Eila C. Turnbull, Clare Van den Berg, David J. Wu, Xifeng Yeager, Meredith Nathanson, Katherine L. Chanock, Stephen J. Cortessis, Victoria K. McGlynn, Katherine A. TI Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 SO HUMAN MOLECULAR GENETICS LA English DT Article ID CANCER; RISK; GENES; POLYMORPHISMS; METABOLISM; EXPRESSION; VARIANTS; RECEPTOR; URIDINE; TRENDS AB Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four casecontrol studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (P-Combined 6.0 10(9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (P-FBAT 2.3 10(3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk. C1 [Schumacher, Fredrick R.; Lewinger, Juan Pablo; Siegmund, Kimberly D.; Van den Berg, David J.; Cortessis, Victoria K.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Wang, Zhaoming; Chung, Charles C.; Cook, Michael B.; Greene, Mark H.; Jacobs, Kevin B.; Loud, Jennifer T.; Korde, Larissa A.; Yeager, Meredith; Chanock, Stephen J.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin B.; Yeager, Meredith] NCI Frederick, Canc Genome Res Lab, Div Canc Epidemiol & Genet, Adv Technol Program,SAIC Frederick Inc, Frederick, MD USA. [Skotheim, Rolf I.; Bakken, Anne C.; Lothe, Ragnhild A.] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Canc Prevent, Oslo, Norway. [Skotheim, Rolf I.; Bakken, Anne C.; Lothe, Ragnhild A.] Univ Oslo, Fac Med, Ctr Canc Biomed, Oslo, Norway. [Koster, Roelof; Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Kratz, Christian P.] Hannover Med Sch, Dept Pediat Hematol & Oncol, Ctr Pediat & Adolescent Med, Hannover, Germany. [Bishop, D. Timothy] St James Univ Hosp, Canc Res UK Clin Ctr Leeds, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds LS9 7TF, W Yorkshire, England. [Erickson, R. Loren] Walter Reed Army Inst Res, Silver Spring, MD USA. [Fossa, Sophie D.] Univ Oslo, Norwegian Radium Hosp, Oslo Univ Hosp, Dept Oncol, Oslo, Norway. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Korde, Larissa A.] Univ Washington, Div Med Oncol, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Div Canc Genet, Sutton, Surrey, England. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Silver Spring, MD USA. [Schwartz, Stephen M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Schwartz, Stephen M.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Skinner, Eila C.] Stanford Univ, Dept Urol, Stanford, CA 94305 USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM preethi.raj@nih.gov; mcglynnk@mail.nih.gov RI Cook, Michael/A-5641-2009; Koster, Roelof/E-2158-2016; OI Cook, Michael/0000-0002-0533-7302; Koster, Roelof/0000-0003-1424-8579; Schwartz, Stephen/0000-0001-7499-8502; Nathanson, Katherine/0000-0002-6740-0901; Bishop, Tim/0000-0002-8752-8785 FU Intramural Research Program of the National Cancer Institute; Westat, Inc.; California Cancer Research Program [99-00505V-10260, 03-00174VRS-30021]; National Cancer Institute [1R01 CA102042-01A1]; Whittier Foundation; Abramson Cancer Center at the University of Pennsylvania; National Institutes of Health [R01CA114478, R01CA085914]; MD Anderson Senior Research Trust Fellowship; Movember; Cancer Research UK; [HHSN261200655004C] FX A portion of this work was supported by the Intramural Research Program of the National Cancer Institute and by support services contract HHSN261200655004C with Westat, Inc. Support was also provided as follows: USC GWAS controls were supported by the Multiethnic Cohort Study (NCI U01-CA98758). USC GWAS testicular cases and Familial Study were supported by the California Cancer Research Program (99-00505V-10260, 03-00174VRS-30021) and National Cancer Institute (1R01 CA102042-01A1) grants to V. K. C. and a Whittier Foundation award to the Norris Comprehensive Cancer Center. Replication effort for the TestPAC study was supported by the Abramson Cancer Center at the University of Pennsylvania and National Institutes of Health grant R01CA114478 to P. A. K. and K.L.N. Replication effort for the ATLAS study was supported by the National Institutes of Health grant R01CA085914 to S. M. S. MD Anderson: Center for Translational and Public Health Genomics of the Duncan Family Institute for Cancer Prevention and Risk Assessment and by MD Anderson Senior Research Trust Fellowship to X. W. The UK Genetics of Testicular Cancer Study was supported by Movember and Cancer Research UK. NR 33 TC 29 Z9 30 U1 0 U2 11 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 JUL 1 PY 2013 VL 22 IS 13 BP 2748 EP 2753 DI 10.1093/hmg/ddt109 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100017 PM 23462292 ER PT J AU Stambolian, D Wojciechowski, R Oexle, K Pirastu, M Li, XH Raffel, LJ Cotch, MF Chew, EY Klein, B Klein, R Wong, TY Simpson, CL Klaver, CCW van Duijn, CM Verhoeven, VJM Baird, PN Vitart, V Paterson, AD Mitchell, P Saw, SM Fossarello, M Kazmierkiewicz, K Murgia, F Portas, L Schache, M Richardson, A Xie, J Wang, JJ Rochtchina, E Viswanathan, AC Hayward, C Wright, AF Polasek, O Campbell, H Rudan, I Oostra, BA Uitterlinden, AG Hofman, A Rivadeneira, F Amin, N Karssen, LC Vingerling, JR Hosseini, SM Doring, A Bettecken, T Vatavuk, Z Gieger, C Wichmann, HE Wilson, JF Fleck, B Foster, PJ Topouzis, F McGuffin, P Sim, XL Inouye, M Holliday, EG Attia, J Scott, RJ Rotter, JI Meitinger, T Bailey-Wilson, JE AF Stambolian, Dwight Wojciechowski, Robert Oexle, Konrad Pirastu, Mario Li, Xiaohui Raffel, Leslie J. Cotch, Mary Frances Chew, Emily Y. Klein, Barbara Klein, Ronald Wong, Tien Y. Simpson, Claire L. Klaver, Caroline C. W. van Duijn, Cornelia M. Verhoeven, Virginie J. M. Baird, Paul N. Vitart, Veronique Paterson, Andrew D. Mitchell, Paul Saw, Seang Mei Fossarello, Maurizio Kazmierkiewicz, Krista Murgia, Federico Portas, Laura Schache, Maria Richardson, Andrea Xie, Jing Wang, Jie Jin Rochtchina, Elena Viswanathan, Ananth C. Hayward, Caroline Wright, Alan F. Polasek, Ozren Campbell, Harry Rudan, Igor Oostra, Ben A. Uitterlinden, Andre G. Hofman, Albert Rivadeneira, Fernando Amin, Najaf Karssen, Lennart C. Vingerling, Johannes R. Hosseini, S. M. Doring, Angela Bettecken, Thomas Vatavuk, Zoran Gieger, Christian Wichmann, H. -Erich Wilson, James F. Fleck, Brian Foster, Paul J. Topouzis, Fotis McGuffin, Peter Sim, Xueling Inouye, Michael Holliday, Elizabeth G. Attia, John Scott, Rodney J. Rotter, Jerome I. Meitinger, Thomas Bailey-Wilson, Joan E. CA DCCT EDIC Res Grp TI Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error SO HUMAN MOLECULAR GENETICS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; HIGH-GRADE MYOPIA; BEAVER DAM EYE; FAMILIAL AGGREGATION; SUSCEPTIBILITY LOCUS; OCULAR REFRACTION; OUTDOOR ACTIVITY; POPULATION; HERITABILITY; CHILDREN AB Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (Cooperative Health Research in the Region of Augsburg); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P 3.9 10(9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. C1 [Stambolian, Dwight; Kazmierkiewicz, Krista] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Bethesda, MD USA. [Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] NHGRI, Bethesda, MD 20892 USA. [Cotch, Mary Frances; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Oexle, Konrad; Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Pirastu, Mario; Murgia, Federico; Portas, Laura] Natl Res Council Italy, Inst Populat Genet, Sassari, Italy. [Li, Xiaohui; Raffel, Leslie J.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Klein, Barbara; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Saw, Seang Mei] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Yong Loo Lin Sch Med, Singapore 117548, Singapore. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. [Klaver, Caroline C. W.; Verhoeven, Virginie J. M.; Vingerling, Johannes R.] Erasmus MC, Dept Ophthalmol & Epidemiol, Rotterdam, Netherlands. [van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Baird, Paul N.; Schache, Maria; Richardson, Andrea; Xie, Jing; Wang, Jie Jin] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, IGMM, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Paterson, Andrew D.; Hosseini, S. M.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Mitchell, Paul; Wang, Jie Jin; Rochtchina, Elena] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Mitchell, Paul; Wang, Jie Jin; Rochtchina, Elena] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Fossarello, Maurizio] Univ Cagliari, Clin Oculist, Dipartimento Sci Chirurg, Cagliari, Italy. [DCCT EDIC Res Grp] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London EC1V 2PD, England. [Viswanathan, Ananth C.; Foster, Paul J.] UCL Inst Ophthalmol, London EC1V 2PD, England. [Polasek, Ozren] Univ Split Med Sch, Croatian Ctr Global Hlth, Split, Croatia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Doring, Angela; Gieger, Christian; Wichmann, H. -Erich] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Bettecken, Thomas; Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Vatavuk, Zoran] Hosp Sestre Milosrdnice, Dept Ophthalmol, Zagreb, Croatia. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Topouzis, Fotis] Aristotle Univ Thessaloniki, AHEPA Hosp, Sch Med, Dept Ophthalmol, GR-54006 Thessaloniki, Greece. [McGuffin, Peter] Kings Coll London, Inst Psychiat, MRC Social Genet & Dev Psychiat Res Ctr, London WC2R 2LS, England. [Inouye, Michael] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Inouye, Michael] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Holliday, Elizabeth G.; Attia, John; Scott, Rodney J.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Holliday, Elizabeth G.; Attia, John; Scott, Rodney J.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Scott, Rodney J.] Univ Newcastle, Ctr Informat Based Med, Newcastle, NSW 2300, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW 2300, Australia. [Scott, Rodney J.] John Hunter Hosp, Div Genet, Hunter Area Pathol Serv, Newcastle, NSW, Australia. RP Bailey-Wilson, JE (reprint author), NHGRI, NIH, 333 Cassell Dr Suite 1200, Baltimore, MD 21131 USA. EM jebw@mail.nih.gov RI McGuffin, Peter/A-1565-2012; Attia, John/F-5376-2013; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Klaver, Caroline/A-2013-2016; Paterson, Andrew/A-4088-2011; Rudan, Igor/I-1467-2012; Hayward, Caroline/M-8818-2016 OI Bailey-Wilson, Joan/0000-0002-9153-2920; Wojciechowski, Robert/0000-0002-9593-4652; Baird, Paul/0000-0002-1305-3502; Cotch, Mary Frances/0000-0002-2046-4350; Gieger, Christian/0000-0001-6986-9554; Klein, Ronald/0000-0002-4428-6237; Fossarello, Maurizio/0000-0003-1520-7760; Karssen, Lennart C./0000-0002-1959-342X; McGuffin, Peter/0000-0002-9888-2907; Hosseini, Mohsen/0000-0003-3626-9928; Attia, John/0000-0001-9800-1308; Wang, Jie Jin/0000-0001-9491-4898; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Paterson, Andrew/0000-0002-9169-118X; Rudan, Igor/0000-0001-6993-6884; Hayward, Caroline/0000-0002-9405-9550 FU Intramural Research Program of the National Human Genome Research Institute; National Eye Institute; National Institutes of Health; NIH [RO1EY020483, K08EY022943]; Helmholtz Center Munich; German Federal Ministry of Education and Research (BMBF); National Heart, Lung and Blood Institute (NHLBI); MESA; NHLBI [N02-HL-6-4278]; Intramural Research Program of the National Eye Institute [ZIAEY000403]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences [UL1TR000124]; Australian National Health & Medical Research Council (NHMRC) [974159, 991407, 211069, 457349]; Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye [529923]; Australian NHMRC project [512423, 475604, 529912, 590204]; Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/08/Z]; NHMRC fellowship scheme [631096, 1028444, 358702, 632909]; Victorian government; Italian Ministry of Education, University and Research (MIUR) [5571/DSPAR/2002]; Italian Ministry of Education, University and Research (FIRB) [718/Ric/2005]; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-6-2204, R01-DK-077510]; Netherlands Organization of Scientific Research (NWO) [Vidi 91796357]; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Rotterdam Eye Hospital Research Foundation; Topcon Europe; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; EU [LSHG-CT-2006-018947]; Chief Scientist Office of the Scottish Government; Royal Society; Medical Research Council Human Genetics Unit; European Union framework program 6 EURO-SPAN project [LSHG-CT-2006-018947]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX This work was funded in part by the Intramural Research Program of the National Human Genome Research Institute (J.E.B.W., R. W., C. L. S.) and the National Eye Institute (M. C., E.Y.C.), National Institutes of Health and NIH RO1EY020483 (D. S., J.E.B.W.) and K08EY022943 (R. W.). The KORA Study is supported by funds from Helmholtz Center Munich and the German Federal Ministry of Education and Research (BMBF). The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Funding for the collection of RE data was supported by the Intramural Research Program of the National Eye Institute (ZIAEY000403). Support was also provided by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. The Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NHMRC) project grants (IDs 974159, 991407, 211069 and 457349) and Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye (ID 529923). The Blue Mountains Eye Study GWAS and genotyping costs were supported by Australian NHMRC project grants (IDs 512423, 475604, 529912 and 590204), and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (grant IDs 085475/B/08/Z and 085475/08/Z). E. G. H. (631096), P.N.B. (1028444) and J.W. (358702 and 632909) are supported by the NHMRC fellowship scheme. The Center for Eye Research Australia receives Operational Infrastructure Support from the Victorian government. OGP-Talana was supported by grants from the Italian Ministry of Education, University and Research (MIUR) No. 5571/DSPAR/2002 and (FIRB) D. M no. 718/Ric/2005. The DCCT Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, N01-DK-6-2204, R01-DK-077510) and the National Institutes of Health. A. D. P. holds a Canada Research Chair in the Genetics of Complex Diseases. The Rotterdam Study and ERF were supported by the Netherlands Organization of Scientific Research (NWO) (Vidi 91796357); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; the Rotterdam Eye Hospital Research Foundation and Topcon Europe.; The Croatian studies were funded by grants from the Medical Research Council (UK), from the Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302). We acknowledge the Wellcome Trust Clinical facility (Edinburgh) for the genotyping of the CROATIA-Vis study, an EU framework 6 project EUROSPAN (contract no LSHG-CT-2006-018947) for the genotyping of the CROATIA-Korcula study that was performed at the Helmholtz Zentrum Munchen (Munich, Germany). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the Medical Research Council Human Genetics Unit and the European Union framework program 6 EURO-SPAN project (contract no. LSHG-CT-2006-018947). NR 57 TC 20 Z9 21 U1 0 U2 12 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 JUL 1 PY 2013 VL 22 IS 13 BP 2754 EP 2764 DI 10.1093/hmg/ddt116 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 160MZ UT WOS:000320125100018 PM 23474815 ER PT J AU Salehi, B Preuss, N van der Veen, JW Shen, J Neumeister, A Drevets, WC Hodgkinson, C Goldman, D Wendland, JR Singleton, A Gibbs, JR Cookson, MR Hasler, G AF Salehi, Basira Preuss, Nora van der Veen, Jan Willem Shen, Jun Neumeister, Alexander Drevets, Wayne C. Hodgkinson, Colin Goldman, David Wendland, Jens R. Singleton, Andrew Gibbs, Jesse R. Cookson, Mark R. Hasler, Gregor TI Age-modulated association between prefrontal NAA and the BDNF gene SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE BDNF; genetic variation; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP ID MAGNETIC-RESONANCE-SPECTROSCOPY; N-ACETYL-ASPARTATE; MAJOR DEPRESSIVE DISORDER; AMINOBUTYRIC-ACID LEVELS; NEUROTROPHIC FACTOR; ALZHEIMERS-DISEASE; IN-VIVO; BIPOLAR DISORDER; METABOLITE CHANGES; MOOD DISORDERS AB Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p=0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 x age interaction on NAA level (p=0.031). Specifically, the effect of rs1519480 on NAA level became significant at age >= 34.17 yr. NAA level decreased with advancing age for genotype TT (p=0.001) but not for genotype CT (p=0.82) or CC (p=0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions. C1 [Salehi, Basira; Hasler, Gregor] Univ Bern, Psychiat Univ Hosp, Bern, Switzerland. [Preuss, Nora] Univ Bern, Dept Psychol, Bern, Switzerland. [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spect Core, Bethesda, MD 20892 USA. [Neumeister, Alexander] NYU, Sch Med, New York, NY USA. [Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Laureate Inst Brain Res, Tulsa, OK USA. [Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Wendland, Jens R.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew; Gibbs, Jesse R.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), Psychiat Univ Hosp, Bolligenstr 111, CH-3000 Bern 60, Switzerland. EM g.hasler@bluewin.ch RI Singleton, Andrew/C-3010-2009; Hasler, Gregor/E-4845-2012; Goldman, David/F-9772-2010 OI Hasler, Gregor/0000-0002-8311-0138; Goldman, David/0000-0002-1724-5405 FU Lundebck; Servier; Lilly; Bistol-Myers Squibb; GlaxoSmithKline; Astra Zeneca; Johnson Johnson; Myriad/Rules Based Medicine; Pfizer; Eisai FX G. H. received honoraria or consulting fees from Lundebck, Servier, Lilly, Bistol-Myers Squibb, GlaxoSmithKline and Astra Zeneca for projects unrelated to this study. W. C. D. received consulting fees from Johnson & Johnson, Myriad/Rules Based Medicine, Pfizer and Eisai for projects unrelated to this study. J.R.W. is a current employee of F. Hoffmann-La Roche. NR 54 TC 2 Z9 3 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2013 VL 16 IS 6 BP 1185 EP 1193 DI 10.1017/S1461145712001204 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 158LS UT WOS:000319973200001 PM 23253771 ER PT J AU Yap, MNF Bernstein, HD AF Yap, Mee-Ngan F. Bernstein, Harris D. TI Mutations in the Escherichia coli Ribosomal Protein L22 Selectively Suppress the Expression of a Secreted Bacterial Virulence Factor SO JOURNAL OF BACTERIOLOGY LA English DT Article ID NASCENT POLYPEPTIDE; TRANSLATION ARREST; EXIT TUNNEL; ERYTHROMYCIN RESISTANCE; STRUCTURAL BASIS; GENE-EXPRESSION; SECA REGULATION; OUTER-MEMBRANE; RNA; RECOGNITION AB Mutations in the ribosomal protein L22 that impair peptide-mediated translation arrest in Escherichia coli have been shown to reduce the expression of several genes, including secA, which encodes an ATPase that drives protein export via the Sec pathway. Here, we used a comparative proteomic approach to obtain insight into the global effects of the L22(Delta 82-84) mutation on gene expression and protein synthesis. While the mutation did not affect or modestly affected the level of most soluble proteins, it dramatically reduced the level of antigen 43 (Ag43), a secreted virulence factor that promotes autoaggregation. The reduced protein concentration correlated with a sharp decrease in the abundance and stability of Ag43 mRNA. We found that the overexpression of secA or the inactivation of genes that encode presecretory and membrane proteins restored Ag43 production in the L22 mutant strain. Furthermore, impairment of the Sec pathway in a wild-type strain reduced Ag43 production but did not significantly affect the synthesis of other presecretory proteins. Taken together, these results indicate that Ag43 gene expression is exquisitely sensitive to the status of the Sec machinery and strongly suggest that the L22 mutation decreases the Ag43 concentration indirectly by reducing secA expression. Our results imply the existence of a novel regulatory mechanism in which the efficiency of protein export is coupled to gene expression and help to explain the modulation of SecA synthesis that has been observed in response to secretion stress. C1 [Yap, Mee-Ngan F.; Bernstein, Harris D.] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Yap, Mee-Ngan F.] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM myap1@slu.edu; harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences [R00GM094212] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by grant R00GM094212 (National Institute of General Medical Sciences) to M.-N.F.Y. NR 54 TC 3 Z9 3 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2013 VL 195 IS 13 BP 2991 EP 2999 DI 10.1128/JB.00211-13 PG 9 WC Microbiology SC Microbiology GA 160HH UT WOS:000320109000005 PM 23625843 ER PT J AU Gungor, D Bornstein, MH De Leersnyder, J Cote, L Ceulemans, E Mesquita, B AF Gungor, Derya Bornstein, Marc H. De Leersnyder, Jozefien Cote, Linda Ceulemans, Eva Mesquita, Batja TI Acculturation of Personality: A Three-Culture Study of Japanese, Japanese Americans, and European Americans SO JOURNAL OF CROSS-CULTURAL PSYCHOLOGY LA English DT Article DE personality; acculturation; Japanese Americans; cultural fit ID SOJOURNER ADJUSTMENT; PARENTING COGNITIONS; MATERNAL PERSONALITY; UNITED-STATES; CULTURAL FIT; TRAITS; PROFILES; SELF; PERSPECTIVE; UNIVERSAL AB The present study tests the hypothesis that involvement with a new culture instigates changes in personality of immigrants that result in (a) better fit with the norms of the culture of destination and (b) reduced fit with the norms of the culture of origin. Participants were 40 Japanese first-generation immigrants to the United States, 57 Japanese monoculturals, and 60 U.S. monoculturals. All participants completed the Jackson Personality Inventory as a measure of the Big Five; immigrants completed the Japanese American Acculturation Scale. Immigrants' fits with the cultures of destination and origin were calculated by correlating Japanese American mothers' patterns of ratings on the Big Five with the average patterns of ratings of European Americans and Japanese on the same personality dimensions. Japanese Americans became more American and less Japanese in their personality as they reported higher participation in the U.S. culture. The results support the view that personality can be subject to cultural influence. C1 [Gungor, Derya; De Leersnyder, Jozefien; Ceulemans, Eva; Mesquita, Batja] Univ Louvain, B-3000 Louvain, Belgium. [Bornstein, Marc H.; Cote, Linda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US Dept HHS, Bethesda, MD USA. [Cote, Linda] Marymount Univ, Arlington, VA USA. RP Gungor, D (reprint author), Univ Louvain, Ctr Social & Cultural Psychol, Tiensestr 102,Bus 3727, B-3000 Louvain, Belgium. EM Derya.Gungor@ppw.kuleuven.be OI De Leersnyder, Jozefien/0000-0002-4486-878X FU Intramural NIH HHS [ZIA HD001119-25, ZIA HD001119-24] NR 62 TC 8 Z9 8 U1 3 U2 35 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0221 J9 J CROSS CULT PSYCHOL JI J. Cross-Cult. Psychol. PD JUL PY 2013 VL 44 IS 5 BP 701 EP 718 DI 10.1177/0022022112470749 PG 18 WC Psychology, Social SC Psychology GA 158OZ UT WOS:000319983200003 PM 23935211 ER PT J AU Hobbs, CV Tanaka, TQ Muratova, O Van Vliet, J Borkowsky, W Williamson, KC Duffy, PE AF Hobbs, Charlotte V. Tanaka, Takeshi Q. Muratova, Olga Van Vliet, Jillian Borkowsky, William Williamson, Kim C. Duffy, Patrick E. TI HIV Treatments Have Malaria Gametocyte Killing and Transmission Blocking Activity SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; malaria; antiretrovirals; TMP-SMX; gametocytes; transmission ID PLASMODIUM-FALCIPARUM GAMETOCYTES; TYPE-1 PROTEASE INHIBITORS; SULFADOXINE-PYRIMETHAMINE; COTRIMOXAZOLE PROPHYLAXIS; ANTIMALARIAL-DRUGS; GENE-EXPRESSION; IN-VITRO; SULFAMETHOXAZOLE; TRIMETHOPRIM; MOSQUITO AB Background. Millions of individuals being treated for human immunodeficiency virus (HIV) live in malaria-endemic areas, but the effects of these treatments on malaria transmission are unknown. While drugs like HIV protease inhibitors (PIs) and trimethoprim-sulfamethoxazole (TMP-SMX) have known activity against parasites during liver or asexual blood stages, their effects on transmission stages require further study. Methods. The HIV PIs lopinavir and saquinavir, the nonnucleoside reverse-transcriptase inhibitor nevirapine, and the antibiotic TMP-SMX were assessed for activity against Plasmodium falciparum transmission stages. The alamarBlue assay was used to determine the effects of drugs on gametocyte viability, and exflagellation was assessed to determine the effects of drugs on gametocyte maturation. The effects of drug on transmission were assessed by calculating the mosquito oocyst count as a marker for infectivity, using standard membrane feeding assays. Results. Lopinavir and saquinavir have gametocytocidal and transmission blocking activities at or approaching clinically relevant treatment levels, while nevirapine does not. TMP-SMX is not gametocytocidal, but at prophylactic levels it blocks transmission. Conclusions. Specific HIV treatments have gametocyte killing and transmission-blocking effects. Clinical studies are warranted to evaluate these findings and their potential impact on eradication efforts. C1 [Hobbs, Charlotte V.; Muratova, Olga; Van Vliet, Jillian; Duffy, Patrick E.] NIAID, Lab Malaria Vaccinol & Immunol, NIH, Bethesda, MD 20892 USA. [Tanaka, Takeshi Q.; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Borkowsky, William] NYU, Dept Pediat, Div Infect Dis & Immunol, New York, NY 10016 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. RP Hobbs, CV (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM charlotte.hobbs@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; US Public Health Service, National Institute of Allergy and Infectious Disease, National Institutes of Health [AI069314] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; and by the US Public Health Service, National Institute of Allergy and Infectious Disease, National Institutes of Health (grant AI069314). NR 47 TC 12 Z9 13 U1 0 U2 17 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 JUL 1 PY 2013 VL 208 IS 1 BP 139 EP 148 DI 10.1093/infdis/jit132 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300019 PM 23539746 ER PT J AU Moormann, AM Sumba, PO Chelimo, K Fang, H Tisch, DJ Dent, AE John, CC Long, CA Vulule, J Kazura, JW AF Moormann, Ann M. Sumba, Peter Odada Chelimo, Kiprotich Fang, Hua Tisch, Daniel J. Dent, Arlene E. John, Chandy C. Long, Carole A. Vulule, John Kazura, James W. TI Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human immunity; Merozoite Surface Protein 1; humoral immunity; cellular immunity; interferongamma; interleukin-10; sickle cell trait; longitudinal study; observational study ID NATURALLY ACQUIRED-IMMUNITY; MALARIA VACCINE; ANTIBODY-RESPONSES; INTERFERON-GAMMA; KENYAN ADULTS; CHILDREN; FRAGMENT; ANTIGEN; AREA; TRANSMISSION AB Background. Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts. Methods. The relationship between immunoglobulin G (IgG) antibody and both interferon gamma (IFN-gamma) and interleukin 10 (IL-10) responses to the 42-kD C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 (MSP142) and the risk of (re) infection were examined following drug-mediated clearance of parasitemia in 94 adults and 95 children in an area of holoendemicity of western Kenya. Results. Positive IFN-gamma enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot assay (ELISPOT) responses to MSP1(42) 3D7 were associated with delayed time to (re) infection, whereas high-titer IgG antibodies to MSP1(42) 3D7 or FVO alleles were not independently predictive of the risk of (re) infection. When IFN-gamma and IL-10 responses were both present, the protective effect of IFN-gamma was abrogated. A Cox proportional hazard model including IFN-gamma, IL-10, MSP1(42) 3D7 IgG antibody responses, hemoglobin S genotype, age, and infection status at baseline showed that the time to blood-stage infection correlated positively with IFN-gamma responses and negatively with IL-10 responses, younger age, and asymptomatic parasitemia. Conclusions. Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone. C1 [Moormann, Ann M.; Tisch, Daniel J.; Dent, Arlene E.; Kazura, James W.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Dent, Arlene E.] Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Moormann, Ann M.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. [Moormann, Ann M.; Fang, Hua] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [John, Chandy C.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Sumba, Peter Odada; Chelimo, Kiprotich; Vulule, John] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Kisumu, Kenya. [Chelimo, Kiprotich] Maseno Univ, Dept Biomed Sci & Technol, Kisumu, Kenya. RP Moormann, AM (reprint author), Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. EM ann.moormann@umassmed.edu FU National Institutes of Health [RO1 AI43906, R01 CA134051]; Fogarty International Center [1D43TW006576]; Burroughs Wellcome Fund [1006818, UL1RR031982]; National Center for Research Resources; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health RO1 AI43906 (J. W. K.), R01 CA134051 (A. M. M.), Fogarty International Center 1D43TW006576 (P. O. S., K. C.), Burroughs Wellcome Fund 1006818 (A. E. D.), UL1RR031982, National Center for Research Resources (H. J. F.) and the intramural research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (C.L.). NR 50 TC 16 Z9 16 U1 0 U2 14 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 JUL 1 PY 2013 VL 208 IS 1 BP 149 EP 158 DI 10.1093/infdis/jit134 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300020 PM 23539744 ER PT J AU Kutty, G England, KJ Kovacs, JA AF Kutty, Geetha England, Katherine J. Kovacs, Joseph A. TI Expression of Pneumocystis jirovecii Major Surface Glycoprotein in Saccharomyces cerevisiae SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Pneumocystis jirovecii; major surface glycoprotein; upstream conserved sequence; antigenic variation; GPI anchored protein ID CULTURED LUNG-CELLS; CARINII; PROTEINS; SEQUENCE; GENES; WALL; SITE; VARIANTS; ANTIGEN; REGION AB The major surface glycoprotein (Msg), which is the most abundant protein expressed on the cell surface of Pneumocystis organisms, plays an important role in the attachment of this organism to epithelial cells and macrophages. In the present study, we expressed Pneumocystis jirovecii Msg in Saccharomyces cerevisiae, a phylogenetically related organism. Full-length P. jirovecii Msg was expressed with a DNA construct that used codons optimized for expression in yeast. Unlike in Pneumocystis organisms, recombinant Msg localized to the plasma membrane of yeast rather than to the cell wall. Msg expression was targeted to the yeast cell wall by replacing its signal peptide, serine-threonine-rich region, and glycophosphatidylinositol anchor signal region with the signal peptide of cell wall protein a-agglutinin of S. cerevisiae, the serine-threonine-rich region of epithelial adhesin (Epa1) of Candida glabrata, and the carboxyl region of the cell wall protein (Cwp2) of S. cerevisiae, respectively. Immunofluorescence analysis and treatment with beta-1,3 glucanase demonstrated that the expressed Msg fusion protein localized to the yeast cell wall. Surface expression of Msg protein resulted in increased adherence of yeast to A549 alveolar epithelial cells. Heterologous expression of Msg in yeast will facilitate studies of the biologic properties of Pneumocystis Msg. C1 [Kutty, Geetha; England, Katherine J.; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@mail.nih.gov FU National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 33 TC 2 Z9 3 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2013 VL 208 IS 1 BP 170 EP 179 DI 10.1093/infdis/jit131 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 156NX UT WOS:000319830300022 PM 23532098 ER PT J AU Kiesel, BF Parise, RA Tjornelund, J Christensen, MK Loza, E Tawbi, H Chu, E Kummar, S Beumer, JH AF Kiesel, Brian F. Parise, Robert A. Tjornelund, Jette Christensen, Mette K. Loza, Einars Tawbi, Hussein Chu, Edward Kummar, Shivaani Beumer, Jan H. TI LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE HDAC; Belinostat; Tandem mass spectrometry; Metabolites; Assay; Validation ID HISTONE DEACETYLASE; CANCER AB The histone deacetylase inhibitor belinostat is being evaluated clinically as a single agent in the treatment of peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered belinostat IV at a dose of 400 mg/m(2). The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of belinostat in the ongoing liver organ dysfunction as well as other studies that investigate belinostat with other anticancer agents. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kiesel, Brian F.; Parise, Robert A.; Tawbi, Hussein; Chu, Edward; Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. [Parise, Robert A.; Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Tjornelund, Jette; Christensen, Mette K.] Topotarget AS, Copenhagen, Denmark. [Loza, Einars] Latvian Inst Organ Synth, Riga, Latvia. [Chu, Edward] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. [Kummar, Shivaani] NCI, Bethesda, MD 20892 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Inst Canc, Room G27E,Hillman Res Pavilion,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM beumerj@gmail.com OI Beumer, Jan/0000-0002-8978-9401 FU Spectrum Pharmaceuticals Inc.; Topotarget A/S [U01-CA099168, N01-CM62209]; [P30-CA47904] FX Support: Spectrum Pharmaceuticals Inc., Topotarget A/S, grant U01-CA099168 and contract N01-CM62209 (NCI-CTEP). This project used the UPCI Clinical Pharmacology Analytical Facility (CPAF) and was supported in part by award P30-CA47904. NR 8 TC 6 Z9 6 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JUL-AUG PY 2013 VL 81-82 BP 89 EP 98 DI 10.1016/j.jpba.2013.03.025 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 156AX UT WOS:000319793500013 PM 23644904 ER PT J AU Barrett, MO Sesma, JI Ball, CB Jayasekara, PS Jacobson, KA Lazarowski, ER Harden, TK AF Barrett, Matthew O. Sesma, Juliana I. Ball, Christopher B. Jayasekara, P. Suresh Jacobson, Kenneth A. Lazarowski, Eduardo R. Harden, T. Kendall TI A Selective High-Affinity Antagonist of the P2Y(14) Receptor Inhibits UDP-Glucose-Stimulated Chemotaxis of Human Neutrophils SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; PHOSPHOLIPASE-C; MOLECULAR-MECHANISMS; GPR105 KIAA0001; NUCLEOTIDE; CELLS; ATP; RELEASE; PATHOPHYSIOLOGY; IDENTIFICATION AB The nucleotide-sugar-activated P2Y(14) receptor (P2Y(14)-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y(14)-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y(14)-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a K-B of 434 pM observed. In contrast, 1 mu M PPTN exhibited no agonist or antagonist effect at the P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11), P2Y(12), or P2Y(13) receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the K-B determined with recombinant P2Y(14)-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y(14)-R that is useful for interrogating the action of this receptor in physiologic systems. C1 [Barrett, Matthew O.; Ball, Christopher B.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Sesma, Juliana I.; Lazarowski, Eduardo R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Jayasekara, P. Suresh; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM tkh@med.unc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health National Institute of General Medical Sciences [GM38213]; National Institutes of Health National Heart, Lung, and Blood Institute [HL34322]; Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases] FX This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM38213]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL34322]; and the Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases]. NR 43 TC 23 Z9 23 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2013 VL 84 IS 1 BP 41 EP 49 DI 10.1124/mol.113.085654 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163YF UT WOS:000320373900004 PM 23592514 ER PT J AU Cullinane, AR Schaffer, AA Huizing, M AF Cullinane, Andrew R. Schaeffer, Alejandro A. Huizing, Marjan TI The BEACH Is Hot: A LYST of Emerging Roles for BEACH-Domain Containing Proteins in Human Disease SO TRAFFIC LA English DT Review DE autophagy; LRBA; NBEA; NBEAL1; NBEAL2; NSMAF; WDFY3; WDFY4; WDR81 ID CHEDIAK-HIGASHI-SYNDROME; GRAY PLATELET SYNDROME; PLECKSTRIN HOMOLOGY DOMAINS; NEUTRAL SPHINGOMYELINASE ACTIVATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; WD-REPEAT PROTEINS; UNDIAGNOSED DISEASES; AGGREGATED PROTEINS; CRYSTAL-STRUCTURE; DIVERSE FUNCTIONS AB BEACH (named after Beige and Chediak-Higashi') is a conserved approximate to 280 residue domain, present in nine human BEACH domain containing proteins (BDCPs). Most BDCPs are large, containing a PH-like domain for membrane association preceding their BEACH domain, and containing WD40 and other domains for ligand binding. Recent studies found that mutations in individual BDCPs cause several human diseases. BDCP alterations affect lysosome size (LYST and NSMAF), apoptosis (NSMAF), autophagy (LYST, WDFY3, LRBA), granule size (LYST, NBEAL2, NBEA) or synapse formation (NBEA). However, the roles of each BDCP in these membrane events remain controversial. After reviewing studies on individual BDCPs, we propose a unifying hypothesis that BDCPs act as scaffolding proteins that facilitate membrane events, including both fission and fusion, determined by their binding partners. BDCPs may also bind each other, enabling fusion or fission of vesicles that are not necessarily of the same type. Such mechanisms explain why different BDCPs may have roles in autophagy; each BDCP is specific for the cell type or the cargo, but not necessarily specific for attaching to the autophagosome. Further elucidation of these mechanisms, preferably carrying out the same experiment on multiple BDCPs, and possibly using patients' cells, may identify potential targets for therapy. C1 [Cullinane, Andrew R.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Natl Biotechnol Ctr, US Dept HHS, Bethesda, MD 20894 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov FU National Institutes of Health; NHGRI; NLM FX We thank Dr Murat Sincam for his skillful assistance with identifying genetic variants in human BDCPs. We thank the NIH Undiagnosed Diseases program for providing access to their exome sequencing database. We thank two reviewers for their helpful corrections and suggestions. This research was supported by the Intramural Research Programs of the National Institutes of Health, NHGRI and NLM. NR 80 TC 35 Z9 35 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 J9 TRAFFIC JI Traffic PD JUL PY 2013 VL 14 IS 7 BP 749 EP 766 DI 10.1111/tra.12069 PG 18 WC Cell Biology SC Cell Biology GA 161GL UT WOS:000320180400002 PM 23521701 ER PT J AU Hermone, AR Gussio, R AF Hermone, Ann R. Gussio, Rick TI Calculation Methods for the Enhancement of Pharmaceutical Properties in Small Molecules: Estimating the Cationic pK(a) SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Solvation energy; continuum dielectric; scoring function; training set; pK(a) calculations; cations; physical chemical properties; computational chemistry; small molecules; pharmaceutics ID AQUEOUS-SOLUTION; PREDICTING PK(A); AB-INITIO; COMPUTER-SIMULATIONS; CHEMICAL-PROCESSES; FREE-ENERGIES; AMINO-ACIDS; SOLVATION; MODEL; CONTINUUM AB In this review, a summary of methodologies is covered to enable medicinal chemists to access an overview of pK(a) estimation devices. In order to stave overutilization of costly synthetic resources, the chemist requires an accurate and computationally tractable solution for estimating a pK(a) of a candidate molecule. We focus on the cationic moieties, since they are so fundamentally important in the chemistry of drugs, and possess unique requirements to obtain a reasonably reliable pK(a) estimation. C1 [Hermone, Ann R.] NCI, Computat Drug Dev Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. [Gussio, Rick] NCI, Informat Technol Branch, Computat Drug Dev Grp, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Hermone, AR (reprint author), NCI, Computat Drug Dev Grp, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM hermonea@mail.nih.gov; gussior@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 48 TC 1 Z9 1 U1 1 U2 36 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD JUL PY 2013 VL 19 IS 23 BP 4310 EP 4315 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 148SC UT WOS:000319266600012 PM 23170887 ER PT J AU Kabirov, KK Kapetanovic, IM Benbrook, DM Dinger, N Mankovskaya, I Zakharov, A Detrisac, C Pereira, M Martin-Jimenez, T Onua, E Banerjee, A van Breemen, RB Nikolic, D Chen, L Lyubimov, AV AF Kabirov, Kasim K. Kapetanovic, Izet M. Benbrook, Doris M. Dinger, Nancy Mankovskaya, Irina Zakharov, Alexander Detrisac, Carol Pereira, Marcia Martin-Jimenez, Tomas Onua, Emmanuel Banerjee, Aryamitra van Breemen, Richard B. Nikolic, Dejan Chen, Lian Lyubimov, Alexander V. TI Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs SO DRUG AND CHEMICAL TOXICOLOGY LA English DT Article DE SHetA2; chemoprevention; toxicity; pharmacokinetic; rat; Beagle dog ID RETINOIC ACID RECEPTOR; FLEXIBLE-HETEROAROTINOIDS; INDUCE APOPTOSIS; CANCER CELLS; MITOCHONDRIA; SUFFICIENT; CARCINOMA AB SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol (R) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day. C1 [Kabirov, Kasim K.; Dinger, Nancy; Mankovskaya, Irina; Zakharov, Alexander; Onua, Emmanuel; Banerjee, Aryamitra; Lyubimov, Alexander V.] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. [Kapetanovic, Izet M.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. [Benbrook, Doris M.] Univ Oklahoma HSC, Dept Obstet & Gynecol, Gynecol Oncol Sect, Oklahoma City, OK USA. [Benbrook, Doris M.] Univ Oklahoma HSC, Dept Biochem & Mol Biol, Oklahoma City, OK USA. [Detrisac, Carol] Charles River Co, Chicago Div, Pathol Associates Int, Chicago, IL USA. [Pereira, Marcia] Histo Sci Res Labs, Mt Jackson, VA USA. [Martin-Jimenez, Tomas] Univ Tennessee, Coll Vet Med, Knoxville, TN USA. [van Breemen, Richard B.; Nikolic, Dejan; Chen, Lian] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. RP Lyubimov, AV (reprint author), Univ Illinois, Toxicol Res Lab, 808 South Wood St, Chicago, IL 60612 USA. EM lyubimov@uic.edu RI Chen, Lian/C-5948-2017 FU National Cancer Institute, Division of Cancer Prevention [N01-CN-43306] FX These studies were supported by contract number N01-CN-43306 from the National Cancer Institute, Division of Cancer Prevention. NR 21 TC 2 Z9 2 U1 0 U2 50 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0148-0545 J9 DRUG CHEM TOXICOL JI Drug Chem. Toxicol. PD JUL PY 2013 VL 36 IS 3 BP 284 EP 295 DI 10.3109/01480545.2012.710632 PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy; Toxicology SC Chemistry; Pharmacology & Pharmacy; Toxicology GA 154RB UT WOS:000319692500004 PM 22947079 ER PT J AU Trabert, B Graubard, BI Erickson, RL Zhang, YW McGlynn, KA AF Trabert, Britton Graubard, Barry I. Erickson, Ralph L. Zhang, Yawei McGlynn, Katherine A. TI Second to fourth digit ratio, handedness and. testicular germ cell tumors SO EARLY HUMAN DEVELOPMENT LA English DT Article DE Case-control; Testicular cancer; Hand pattern; Left-handed dominance; Digit ratio ID BREAST-CANCER RISK; 2D 4D; WOMEN; TESTOSTERONE; LENGTH; COHORT; DIETHYLSTILBESTROL; LATERALIZATION; LANGUAGE; SIZE AB Background: Research on early life exposures and testicular germ cell tumors (TGCT) risk has focused on a possible perinatal etiology with a well-known hypothesis suggesting that hormonal involvement during fetal life is associated with risk. Second-to-fourth digit ratio (2D:4D) and left-hand dominance have been proposed as markers of prenatal hormone exposure. Aim: To evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (Delta(R-L)), and left-hand dominance and TGCT in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. Methods: A total of 246 TGCT cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Associations between digit ratio, hand dominance and TGCT were estimated using unconditional logistic regression adjusting for identified covariates. Results: Right 2D:4D was not associated with TGCT [odds ratio (OR) for a one-standard deviation (SD) increase in right-hand 2D:4D: 1.12, 95% confidence interval (CI): 0.93-1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left-hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in Delta(R-L): 1.03,95% CI: 0.87-1.23]. Compared to men who reported right-hand dominance, ambidexterity [OR (95% CI) = 0.65 (0.30-1.41)] and left-hand dominance [OR (95% Cl) = 0.79 (0.44-1.44)] were not associated with risk. Conclusions: These results do not support the hypothesis that prenatal hormonal imbalance is associated with TGCT risk. Given the limited sample size, further evaluation of the relationship between TGCT and prenatal hormonal factors using digit ratio, Delta(R-L), or left-hand dominance and larger sample size are warranted. Published by Elsevier Ireland Ltd. C1 [Trabert, Britton; McGlynn, Katherine A.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch,DHHS, Rockville, MD 20852 USA. [Graubard, Barry I.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Zhang, Yawei] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Trabert, B (reprint author), Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch,DHHS, Suite 550,6120 Execut Blvd, Rockville, MD 20852 USA. EM trabertbl@mail.nih.gov RI Trabert, Britton/F-8051-2015 FU National Cancer Institute [CA130110] FX This work was supported by the Intramural Research Program of the National Cancer Institute and by grant CA130110 from the National Cancer Institute. NR 34 TC 2 Z9 2 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-3782 J9 EARLY HUM DEV JI Early Hum. Dev. PD JUL PY 2013 VL 89 IS 7 BP 463 EP 466 DI 10.1016/j.earlhumdev.2013.04.001 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 154YV UT WOS:000319713500004 PM 23623693 ER PT J AU Ranguelova, K Rice, AB Lardinois, OM Triquigneaux, M Steinckwich, N Deterding, LJ Garantziotis, S Mason, RP AF Ranguelova, Kalina Rice, Annette B. Lardinois, Olivier M. Triquigneaux, Mathilde Steinckwich, Natacha Deterding, Leesa J. Garantziotis, Stavros Mason, Ronald P. TI Sulfite-mediated oxidation of myeloperoxidase to a free radical: Immuno-spin trapping detection in human neutrophils SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Human neutrophils; Immuno-spin trapping; Sulfite radicals; Sulfite toxicity; Free radicals ID HYDROGEN-PEROXIDE; SULFUR-DIOXIDE; EOSINOPHIL PEROXIDASE; CATALYZED OXIDATION; ASTHMATIC-PATIENTS; REDOX PROPERTIES; SO5-RADICALS; OXIDASE; INVOLVEMENT; ACTIVATION AB Previous studies focused on catalyzed oxidation of (bi)sulfite, leading to the formation of the reactive sulfur trioxide ((SO3-)-S-center dot), peroxymonosulfate ((-O3SOO center dot)), and sulfate (SO4(center dot-)) anion radicals, which can damage target proteins and oxidize them to protein radicals. It is known that these very reactive sulfur- and oxygen-centered radicals can be formed by oxidation of (bi)sulfite by peroxidases. Myeloperoxidase (MPO), an abundant heme protein secreted from activated neutrophils that play a central role in host defense mechanisms, allergic reactions, and asthma, is a likely candidate for initiating the respiratory damage caused by sulfur dioxide. The objective of this study was to examine the oxidative damage caused by (bi)sulfite-derived free radicals in human neutrophils through formation of protein radicals. We used immuno-spin trapping and confocal microscopy to study the protein oxidations driven by sulfite-derived radicals. We found that the presence of sulfite can cause MPO-catalyzed oxidation of MPO to a protein radical in phorbol 12-myristate 13-acetate-activated human neutrophils. We trapped the MPO-derived radicals in situ using the nitrone spin trap 5,5-dimethyl-1-pyrroline N- oxide and detected them immunologically as nitrone adducts in cells. Our present study demonstrates that myeloperoxidase initiates (bi)sulfite oxidation leading to MPO radical damage, possibly leading to (bi)sulfite-exacerbated allergic reactions. Published by Elsevier Inc. C1 [Ranguelova, Kalina; Triquigneaux, Mathilde; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Rice, Annette B.; Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, Res Triangle Pk, NC 27709 USA. [Lardinois, Olivier M.; Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Steinckwich, Natacha] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU NIH, NIEHS FX The authors thank Mrs. Mary J. Mason and Dr. Ann Motten for their help in the preparation of the manuscript and Jason Williams, Katina Johnson, and Andrea Adams from the protein micro characterization core facility of NIEHS for helpful suggestions and assistance. Also, we thank Ms. Brenda Yingling and Ms. Jamie D. Marshburn for their technical assistance. This work was supported by the Intramural Research Program of the NIH, NIEHS. NR 50 TC 8 Z9 9 U1 3 U2 35 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 98 EP 106 DI 10.1016/j.freeradbiomed.2013.01.022 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500013 PM 23376232 ER PT J AU Valente, AJ Yoshida, T Clark, RA Delafontaine, P Siebenlist, U Chandrasekar, B AF Valente, Anthony J. Yoshida, Tadashi Clark, Robert A. Delafontaine, Patrice Siebenlist, Ulrich Chandrasekar, Bysani TI Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE AOPPs; TRAF3IP2; Oxidative stress; Cell death; Myocardial injury; Free radicals ID GLYCATION END-PRODUCTS; NF-KAPPA-B; ACUTE CORONARY SYNDROMES; C-REACTIVE PROTEIN; NADPH OXIDASE; OXIDIZED LDL; ARTERY-DISEASE; NOX FAMILY; CIKS ACT1; APOPTOSIS AB Advanced oxidation protein products (AOPPs) are formed during chronic oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants. Their levels are elevated during various cardiovascular diseases. Because elevated AOPPs serve as independent risk factors for ischemic heart disease, and cardiomyocyte death is a hallmark of ischemic heart disease, we hypothesized that AOPPs will induce cardiomyocyte death. AOPP-modified mouse serum albumin (AOPP-MSA) induced significant death of neonatal mouse cardiomyocytes that was attenuated by knockdown of the receptor for advanced glycation end products, but not CD36. Notably, TRAF3-interacting protein 2 (TRAF3IP2; also known as CIKS or Act1) knockdown blunted AOPP-induced apoptosis. AOPP-MSA stimulated Nox2/Rac1-dependent superoxide generation, TRAF3IP2 expression, and TRAF3IP2-dependent JNK activation. The superoxide anion generating xanthine/xanthine oxidase system and hydrogen peroxide both induced TRAF3IP2 expression. Further, AOPP-MSA induced mitochondrial Bax translocation and release of cytochrome c into cytoplasm. Moreover, AOPP-MSA suppressed antiapoptotic Bcl-2 and Bcl-xL expression. These effects were reversed by TRAF3IP2 knockdown or forced expression of mutant JNK. Similar to its effects in neonatal cardiomyocytes, AOPP-MSA induced adult cardiomyocyte death in part via TRAF3IP2. These results demonstrate for the first time that AOPPs induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK activation in vitro and suggest that AOPPs may contribute to myocardial injury in vivo. Thus TRAF3IP2 may represent a potential therapeutic target in ischemic heart disease. (C) 2013 Elsevier Inc. All rights reserved. C1 [Valente, Anthony J.; Clark, Robert A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Valente, Anthony J.; Clark, Robert A.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Yoshida, Tadashi; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA 70161 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Delafontaine, Patrice/0000-0003-3744-3617; Yoshida, Tadashi/0000-0002-4544-1497 FU Department of Veterans Affairs Research Career Scientist Award; VA Office of Research and Development Biomedical Laboratory Research and Development Service Award [11O1BX000246]; NHLBI/NIH [HL-86787]; NHLBI [HL-70241, HL-80682] FX B.C. is a recipient of the Department of Veterans Affairs Research Career Scientist Award and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award 11O1BX000246 and NHLBI/NIH Grant HL-86787. The contents of this report do not represent the views of the Department of Veterans Affairs or the U.S. government. PD is supported by NHLBI Grants HL-70241 and HL-80682. NR 49 TC 23 Z9 25 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 125 EP 135 DI 10.1016/j.freeradbiomed.2013.02.012 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500016 PM 23453926 ER PT J AU Abdelmegeed, MA Jang, S Banerjee, A Hardwick, JP Song, BJ AF Abdelmegeed, Mohamed A. Jang, Sehwan Banerjee, Atrayee Hardwick, James P. Song, Byoung-Joon TI Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Acute liver injury; Acetaminophen; CYP2E1; 3-Nitrotyrosine; Protein nitration; N-acetylcysteine; Mitochondrial dysfunction; Free radicals ID NITRIC-OXIDE SYNTHASE; INDUCED HEPATOTOXICITY; COVALENT BINDING; IMMUNOHISTOCHEMICAL LOCALIZATION; SUPEROXIDE-DISMUTASE; N-ACETYLCYSTEINE; OXIDATIVE STRESS; TERMINAL KINASE; KNOCKOUT MICE; MOUSE-LIVER AB Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2 h in mice exposed to a single APAP dose (350 mg/kg ip), which caused severe liver necrosis at 24 h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity. Published by Elsevier Inc. C1 [Abdelmegeed, Mohamed A.; Jang, Sehwan; Banerjee, Atrayee; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Hardwick, James P.] NE Ohio Med Univ, Coll Med, Dept Integrat Med Sci, Rootstown, OH 44272 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism. We are thankful to Dr. Klaus Gawrisch for supporting this study. We are grateful to ProtTech, Inc and Protea Biosciences, Inc. for determining the protein sequences by mass-spectral analyses. NR 69 TC 30 Z9 31 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 211 EP 222 DI 10.1016/j.freeradbiomed.2013.02.018 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500025 PM 23454065 ER PT J AU Ehrenshaft, M Roberts, JE Mason, RP AF Ehrenshaft, Marilyn Roberts, Joan E. Mason, Ronald P. TI Hypericin-mediated photooxidative damage of alpha-crystallin in human lens epithelial cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Singlet oxygen; Hypericin; alpha-Crystallin; Actin; Human lens epithelial cells; N-formylkynurenine; Free radicals ID ST-JOHNS-WORT; N-FORMYLKYNURENINE; IMMUNOLOGICAL DETECTION; FLUORESCENCE; PROTEINS; PHOTOTOXICITY; PERFORATUM; DEPRESSION; CULTURE; DRUGS AB St. John's wort (Hypericum perforatum), a perennial herb native to Europe, is widely used for and seems to be effective in treatment of mild to moderate depression. Hypericin, a singlet oxygen-generating photosensitizer that absorbs in both the visible and the UVA range, is considered to be one of the bioactive ingredients of St John's wort, and commercial preparations are frequently calibrated to contain a standard concentration. Hypericin can accumulate in ocular tissues, including lenses, and can bind in vitro to alpha-crystallin, a major lens protein. alpha-crystallin is required for lens transparency and also acts as a chaperone to ensure its own integrity and the integrity of all lens proteins. Because there is no crystallin turnover, damage to alpha-crystallin is cumulative over the lifetime of the lens and can lead to cataracts, the principal cause of blindness worldwide. In this work we study hypericin photosensitization of alpha-crystallin and detect extensive polymerization of bovine cc-crystallin exposed in vitro to hypericin and UVA. We use fluorescence confocal microscopy to visualize binding between hypericin and alpha-crystallin in a human lens epithelial (HLE) cell line. Further, we show that UVA irradiation of hypericin-treated HLE cells results in a dramatic decrease in alpha-crystallin detection concurrent with a dramatic accumulation of the tryptophan oxidation product N-formylkynurenine (NFK). Examination of actin in HLE cells indicates that this cytoskeleton protein accumulates NFK resulting from hypericin-mediated photosensitization. This work also shows that filtration of wavelengths <400 nm provides incomplete protection against cc-crystallin modification and NFK accumulation, suggesting that even by wearing UV-blocking sunglasses, routine users of St. John's wort cannot adequately shield their lenses from hypericin-mediated photosensitized damage. Published by Elsevier Inc. C1 [Ehrenshaft, Marilyn; Roberts, Joan E.; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Ehrenshaft, M (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM ehrensh1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX The authors thank B. Jean Corbett and Mary Mason for their valuable help in the preparation of the manuscript. We are grateful to Jeff Tucker and Dr. Agnes Janoshazi for their expert help with confocal microscopy. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 36 TC 4 Z9 5 U1 1 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2013 VL 60 BP 347 EP 354 DI 10.1016/j.freeradbiomed.2013.02.023 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 151UU UT WOS:000319486500038 PM 23453985 ER PT J AU Muller, HK Wegener, G Liebenberg, N Zarate, CA Popoli, M Elfving, B AF Muller, Heidi Kaastrup Wegener, Gregers Liebenberg, Nico Zarate, Carlos A., Jr. Popoli, Maurizio Elfving, Betina TI Ketamine regulates the presynaptic release machinery in the hippocampus SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Ketamine; SNARE; Synapsin; Synaptotagmin; CaMKII; Antidepressant ID RAT PREFRONTAL CORTEX; SYNAPTIC VESICLE PROTEINS; EVOKED GLUTAMATE RELEASE; NMDA RECEPTOR BLOCKADE; METHYL-D-ASPARTATE; MOOD DISORDERS; SNARE COMPLEX; KINASE-II; NEUROTRANSMITTER RELEASE; DIFFERENTIAL EXPRESSION AB In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at I, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after I, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated alpha CaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Muller, Heidi Kaastrup; Wegener, Gregers; Liebenberg, Nico; Elfving, Betina] Aarhus Univ Hosp, Ctr Psychiat Res, DK-8240 Risskov, Denmark. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Popoli, Maurizio] Univ Milan, Ctr Excellence Neurodegenerat Dis, Lab Neuropsychopharmacol & Funct Neurogen, Dept Pharmacol & Biomol Sci, Milan, Italy. RP Muller, HK (reprint author), Aarhus Univ Hosp, Ctr Psychiat Res, Skovagervej 2, DK-8240 Risskov, Denmark. EM heidmull@rm.dk OI Elfving, Betina/0000-0001-6939-5088; Wegener, Gregers/0000-0002-0081-0068 FU AU Ideas; Lundbeck Foundation; Augustinus Foundation; Aase and Ejnar Danielsens Foundation; Gangsted Foundation; Overlaege Dr. Med. Einar Geert-Jorgensen and Hustru Ellen Geert-Jorgensens Foundation; Direktor Kurt Bonnelycke and Hustru Fru Grethe Bonnelyckes Foundation; Dagmar Marshalls Foundation; Else and Mogens Wedell-Wedellsborgs Foundation; Direktor Jacob Madsen and Hustru Olga Madsens Foundation; Torben and Alice Frimodts Foundation; Kong Christian den Tiendes Foundation FX This study was supported by Grants from AU Ideas, the Lundbeck Foundation, Augustinus Foundation, Aase and Ejnar Danielsens Foundation, Gangsted Foundation, Overlaege Dr. Med. Einar Geert-Jorgensen and Hustru Ellen Geert-Jorgensens Foundation, Direktor Kurt Bonnelycke and Hustru Fru Grethe Bonnelyckes Foundation, Dagmar Marshalls Foundation, Else and Mogens Wedell-Wedellsborgs Foundation, Direktor Jacob Madsen and Hustru Olga Madsens Foundation, Torben and Alice Frimodts Foundation, and Kong Christian den Tiendes Foundation. The authors thank Laura Musazzi for technical advices and Pia Hogh Plougmann for her technical assistance. NR 55 TC 19 Z9 19 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2013 VL 47 IS 7 BP 892 EP 899 DI 10.1016/j.jpsychires.2013.03.008 PG 8 WC Psychiatry SC Psychiatry GA 152RR UT WOS:000319549300006 PM 23548331 ER PT J AU Enoch, MA Hodgkinson, CA Gorodetsky, E Goldman, D Roy, A AF Enoch, Mary-Anne Hodgkinson, Colin A. Gorodetsky, Elena Goldman, David Roy, Alec TI Independent effects of 5 ' and 3 ' functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE SLC6A4; 5-HTTLPR; Substance dependence; rs3813034; rs1042173; Suicide attempt ID 5-HTT GENE; POLYMORPHISM; AMYGDALA; STRESS; POPULATION; EXPRESSION; DEPRESSION; GENOTYPE; REGION; ABUSE AB The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT). DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers. There were independent G x E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034 -rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034 rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant. Our findings suggest that the 5' and 3' SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals. Published by Elsevier Ltd. C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Gorodetsky, Elena; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Roy, Alec] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [RO1 DA 10336-02] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH. NR 28 TC 7 Z9 7 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2013 VL 47 IS 7 BP 900 EP 907 DI 10.1016/j.jpsychires.2013.03.007 PG 8 WC Psychiatry SC Psychiatry GA 152RR UT WOS:000319549300007 PM 23558235 ER PT J AU Goldwyn, EE Rohani, P AF Goldwyn, Eli E. Rohani, Pejman TI Bias in Pertussis Incidence Data and Its Implications for Public Health Epidemiology SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material ID UNITED-STATES; ADULT VACCINATION; DYNAMICS; POPULATION; STRATEGIES; SIMULATIONS; INFECTIONS; ENGLAND; IMPACT; WALES C1 [Goldwyn, Eli E.] Univ Calif Davis, Dept Math, Davis, CA 95616 USA. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Goldwyn, EE (reprint author), Univ Calif Davis, Dept Math, 1 Shields Ave, Davis, CA 95616 USA. EM eegoldwyn@ucdavis.edu FU NIAID NIH HHS [R01AI101155] NR 36 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD JUL-AUG PY 2013 VL 19 IS 4 BP 379 EP 382 DI 10.1097/PHH.0b013e31826d7f95 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 154FQ UT WOS:000319657800018 PM 23128362 ER PT J AU Pandya, AA Yakel, JL AF Pandya, Anshul A. Yakel, Jerrel L. TI Activation of the alpha 7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist SO NEUROPHARMACOLOGY LA English DT Article DE 5-HT1a receptor (5-HT1a R); Alpha7 (alpha 7) receptor agonist; Anxiety; Memory and learning; Nicotinic acetylcholine receptors (nAChRs); Positive allosteric modulators (PAMs) ID POSITIVE ALLOSTERIC MODULATOR; SOCIAL-INTERACTION TEST; ELEVATED PLUS-MAZE; ACETYLCHOLINE-RECEPTOR; HIPPOCAMPAL INTERNEURONS; SYNAPTIC-TRANSMISSION; DORSAL HIPPOCAMPUS; PARTIAL AGONISTS; ANIMAL-MODELS; IN-VIVO AB The alpha 7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the alpha 7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both alpha 7 and non-alpha 7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the alpha 7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamineinduced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT1a receptor antagonist WAY-100135. However the alpha 7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that alpha 7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the alpha 7 receptors. Published by Elsevier Ltd. C1 [Pandya, Anshul A.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, MD F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM pandyaaa@niehs.nih.gov; yakel@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX We would like to thank the NIEHS animal facility and specifically Hanna Harris for taking care of the rats and for performing injections for this study. We would also like to thank Pattie Lamb for her involvement in the process of writing the animal safety protocols for behavior tests described here. We extend our appreciation to C. Erxleben and R. Saha for advice in preparing the manuscript. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH. NR 70 TC 23 Z9 23 U1 0 U2 16 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 JUL PY 2013 VL 70 BP 35 EP 42 DI 10.1016/j.neuropharm.2013.01.004 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 153YB UT WOS:000319637600005 PM 23321689 ER PT J AU Li, JM Xue, ZQ Deng, SH Luo, XG Patrylo, PR Rose, GW Cai, HB Cai, Y Yan, XX AF Li, Jian-Ming Xue, Zhi-Qin Deng, Si-Hao Luo, Xue-Gang Patrylo, Peter R. Rose, Gregory W. Cai, Huaibin Cai, Yan Yan, Xiao-Xin TI Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury SO NEUROTOXICITY RESEARCH LA English DT Article DE Alzheimer's disease; Amyloidogenesis; BACE1; Neuritic dystrophy; Synaptoplasticity ID A-BETA PEPTIDES; ALZHEIMERS-DISEASE; BETA-SECRETASE-1 ELEVATION; PERMANENT AXOTOMY; MEMORY DEFICITS; TRANSGENIC MICE; NEURON LOSS; ADULT CAT; IN-VIVO; MOTONEURONS AB The spinal cord is composed of distinct neuronal groups with well-defined anatomic connections. In some transgenic (Tg) models of Alzheimer's disease (AD), amyloid plaques develop in this structure, although the underlying cellular mechanism remains elusive. We attempted to explore the origin, evolution, and modulation of spinal beta-amyloid (A beta) deposition using Tg mice harboring five familiar AD-related mutations (5XFAD) as an experiential model. Dystrophic neuritic elements with enhanced beta-secretase-1 (BACE1) immunoreactivity (IR) appeared as early as 2 months of age, and increased with age up to 12 months examined in this study, mostly over the ventral horn (VH). Extracellular A beta IR emerged and developed during this same period, site-specifically co-existing with BACE1-labeled neurites often in the vicinity of large VH neurons that expressed the mutant human APP. The BACE1-labeled neurites almost invariably colocalized with beta-amyloid precursor protein (APP) and synaptophysin, and frequently with the vesicular glutamate transporter-1 (VGLUT). Reduced IR for the neuronal-specific nuclear antigen (NeuN) occurred in the VH by 12 months of age. In 8-month-old animals surviving 6 months after a unilateral sciatic nerve transection, there were significant increases of A beta, BACE1, and VGLUT IR in the VN of the ipsilateral relative to contralateral lumbar spinal segments. These results suggest that extracellular A beta deposition in 5XFAD mouse spinal cord relates to a progressive and amyloidogenic synaptic pathology largely involving presynaptic axon terminals from projection neurons in the brain. Spinal neuritic plaque formation is enhanced after peripheral axotomy, suggesting a retrograde transneuronal modulation on pathogenesis. C1 [Li, Jian-Ming] Changsha Med Univ, Neurosci Res Ctr, Changsha 410219, Hunan, Peoples R China. [Li, Jian-Ming; Xue, Zhi-Qin; Deng, Si-Hao; Luo, Xue-Gang; Cai, Yan; Yan, Xiao-Xin] Cent South Univ Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. [Xue, Zhi-Qin] Xinjiang Med Univ, Dept Anat, Urumqi 830011, Xinjiang, Peoples R China. [Patrylo, Peter R.; Rose, Gregory W.; Yan, Xiao-Xin] Southern Illinois Univ Sch Med, Ctr Integrated Res Cognit & Neural Sci, Carbondale, IL 62901 USA. [Cai, Huaibin] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Yan, XX (reprint author), Cent South Univ Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU Illinois Department of Public Health; National Natural Science Foundation of China [81171091, 81171160]; Hunan Natural Science Foundation [11jj5072]; National Institute on Aging, NIH [Z01-IAAG000944-04] FX This study was supported by the Illinois Department of Public Health (X.X.Y.), the National Natural Science Foundation of China (#81171091 to X.X.Y. and #81171160 to X.G.L), Hunan Natural Science Foundation (11jj5072 to J.M.L) and the intramural research program of National Institute on Aging, NIH (Z01-IAAG000944-04 to H.C.). We thank Elan Pharmaceuticals for providing the 3D6 antibody. NR 60 TC 4 Z9 5 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD JUL PY 2013 VL 24 IS 1 BP 1 EP 14 DI 10.1007/s12640-012-9355-2 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 154NK UT WOS:000319682500001 PM 23055086 ER PT J AU Vandenberg, LN Colborn, T Hayes, TB Heindel, JJ Jacobs, DR Lee, DH Myers, JP Shioda, T Soto, AM vom Saal, FS Welshons, WV Zoeller, RT AF Vandenberg, Laura N. Colborn, Theo Hayes, Tyrone B. Heindel, Jerrold J. Jacobs, David R., Jr. Lee, Duk-Hee Myers, John Peterson Shioda, Toshi Soto, Ana M. vom Saal, Frederick S. Welshons, Wade V. Zoeller, R. Thomas TI Regulatory decisions on endocrine disrupting chemicals should be based on the principles of endocrinology SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE Weight of evidence; Organizational; Adaptive effect; Hormesis; Human exposure; Epidemiology; Flare ID ORGANIZATIONAL-ACTIVATIONAL HYPOTHESIS; PRENATAL PHTHALATE EXPOSURE; NUCLEAR RECEPTOR SUPERFAMILY; NONMONOTONIC DOSE-RESPONSES; GOOD LABORATORY PRACTICES; BISPHENOL-A EXPOSURE; OF-EVIDENCE ANALYSIS; BREAST-CANCER CELLS; ANOGENITAL DISTANCE; RISK-ASSESSMENT AB For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialog on their impact on risk assessment. (c) 2013 Elsevier Inc. All rights reserved. C1 [Vandenberg, Laura N.] Tufts Univ, Ctr Regenerat & Dev Biol, Medford, MA 02155 USA. [Vandenberg, Laura N.] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Colborn, Theo] Endocrine Disrupt Exchange, Paonia, CO USA. [Hayes, Tyrone B.] Univ Calif Berkeley, Museum Vertebrate Zool, Energy & Resources Grp, Grp Endocrinol,Lab Integrat Studies Amphibian Bio, Berkeley, CA 94720 USA. [Hayes, Tyrone B.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, NIH DHHS, Res Triangle Pk, NC 27709 USA. [Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Lee, Duk-Hee] Kyungpook Natl Univ, Sch Med, Dept Prevent Med, Taegu, South Korea. [Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc Res, Mol Profiling Lab, Charlestown, MA USA. [Soto, Ana M.] Tufts Univ, Sch Med, Dept Anat & Cell Biol, Medford, MA 02155 USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Welshons, Wade V.] Univ Missouri, Dept Biomed Sci, Columbia, MO USA. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP Vandenberg, LN (reprint author), Tufts Univ, Ctr Regenerat & Dev Biol, 200 Boston Ave,Suite 4600, Medford, MA 02155 USA. EM laura.vandenberg@tufts.edu FU NIH [GM 087107, ES 08314, ES 010026, ES 018764, HL 53560, UMC MO-VMFC0018]; Susan G. Komen for Cure grant [FAS0703860]; Mitchell Kapor Foundation; Cornell-Douglas Foundation; Wallace Global Fund; Kendeda Foundation FX The authors gratefully acknowledge the following funding sources: NIH grants GM 087107 (to LNV), ES 08314 (to AMS), ES 010026 (to RTZ), ES 018764 (to FSvS), HL 53560 (to DRJ), UMC MO-VMFC0018 (to WVW), a Susan G. Komen for Cure grant FAS0703860 (to TS), grants from the Mitchell Kapor Foundation, the Cornell-Douglas Foundation, and the Wallace Global Fund (to TBH) and a grant from the Kendeda Foundation (to JPM). The funders had no role in the preparation of this manuscript. NR 216 TC 54 Z9 58 U1 10 U2 108 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2013 VL 38 BP 1 EP 15 DI 10.1016/j.reprotox.2013.02.002 PG 15 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 152MG UT WOS:000319535200001 PM 23411111 ER PT J AU Okpechi, I Swanepoel, C Rayner, B Gcelu, A Hodkinson, B Kalla, A Ramesar, R Vorster, A Adeyemo, A Heering, P Tiffin, N AF Okpechi, I Swanepoel, C. Rayner, B. Gcelu, A. Hodkinson, B. Kalla, A. Ramesar, R. Vorster, A. Adeyemo, A. Heering, P. Tiffin, N. TI Systemic lupus erythematosus (SLE) in Cape Town: A precursory report of the ALUGEN registry SO CLINICAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Okpechi, I; Swanepoel, C.; Rayner, B.] Univ Cape Town, Div Nephrol & Hypertens, ZA-7700 Rondebosch, South Africa. [Gcelu, A.; Hodkinson, B.; Kalla, A.] Univ Cape Town, Div Rheumatol, ZA-7700 Rondebosch, South Africa. [Ramesar, R.; Vorster, A.] Univ Cape Town, Dept Human Genet, ZA-7700 Rondebosch, South Africa. [Adeyemo, A.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Heering, P.] Univ Dusseldorf Germany, Dept Nephrol, Dusseldorf, Germany. [Tiffin, N.] Univ Western Cape, MRC Unit Bioinformat Capac Dev, South African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. RI Ramesar, Raj/I-6941-2015 OI Ramesar, Raj/0000-0001-5688-1634 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD JUL PY 2013 VL 32 SU 2 MA P4 BP S140 EP S141 PG 2 WC Rheumatology SC Rheumatology GA AU4HN UT WOS:000345571500064 ER PT J AU Merikangas, K AF Merikangas, Kathleen TI Breaking Down the Boundaries : Comorbidity of Mental and Physical Disorders SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Meeting Abstract DE comorbidity; epidemiology; medical disorders; mood disorders; anxiety disorders; behavior disorders; ADHD C1 [Merikangas, Kathleen] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUL PY 2013 VL 22 SU 2 MA W2-01 BP S212 EP S212 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA V41LO UT WOS:000209547900338 ER PT J AU Anderson, BL Pearlman, M Griffin, J Schulkin, J AF Anderson, Britta L. Pearlman, Mark Griffin, Jennifer Schulkin, Jay TI Conflicting and Changing Breast Cancer Screening Recommendations: Survey Study of a National Sample of ob-gyns after the Release of the 2009 USPSTF Guidelines SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE breast cancer; evidence-based practice/guidelines; health promotion and screening; research quantitative AB Objective: To assess obstetrician-gynecologists' (obgyns') use of multiple conflicting guidelines assess after the release of the 2009 U.S. Preventive Services Task Force (USPSTF) breast cancer screening recommendations. Study Design: A nationally representative sample of American College of Obstetricians and Gynecologists (ACOG) Fellows were invited to complete a survey. Results: A total of 235 of 399 ob-gyns responded (59% response rate). Twenty percent and 89% indicated that USPSTF and ACOG guidelines influence their practice, respectively, 84% are influenced by more than one guideline. The plurality of respondents was able to correctly identify ACOG and USPSTF guidelines on 10 of 12 questions. One-third agreed with both ACOG's and USPSTF's recommendations regarding mammography screening for women 40-49 years old. A total of 42% of the sample made at least one change in their practice after the release of the 2009 USPSTF breast cancer screening guidelines. Conclusion: Some ob-gyns made changes to their practices after the release of the USPSTF guidelines. When multiple guidelines exist, as in the case with breast cancer screening, physicians utilize multiple, and at times conflicting, guidelines. More research will be needed to better understand the impact (negative or positive) of multiple guidelines on the quality of healthcare. C1 [Anderson, Britta L.; Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, New York, NY 10029 USA. [Pearlman, Mark] Univ Michigan Hosp & Hlth Ctr, Dept Obstet & Gynecol, Ann Arbor, MI USA. [Pearlman, Mark] Univ Michigan Hosp & Hlth Ctr, Dept Surg, Ann Arbor, MI USA. [Pearlman, Mark] Univ Michigan, Ann Arbor, MI 48109 USA. [Griffin, Jennifer] Univ Nebraska Med Ctr, Dept Obstet & Gynecol, Omaha, NE USA. [Schulkin, Jay] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Schulkin, Jay] NIMH, Behav Endocrinol Branch, Bethesda, MD USA. RP Anderson, BL (reprint author), Amer Coll Obstetricians & Gynecologists, New York, NY 10029 USA. EM banderson@acog.org FU U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program [UA6MC19010] FX This study is funded by grant, UA6MC19010, through the U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program. NR 20 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD JUL-AUG PY 2013 VL 35 IS 4 BP 25 EP 35 DI 10.1111/jhq.12009 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OU UT WOS:000209221800003 PM 23590634 ER PT J AU Komarow, HD Young, M Nelson, C Metcalfe, DD AF Komarow, Hirsh D. Young, Michael Nelson, Celeste Metcalfe, Dean D. TI Vocal Cord Dysfunction as Demonstrated by Impulse Oscillometry SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Vocal cord dysfunction; impulse oscillometry; asthma; laryngoscopy; spirometry AB BACKGROUND: Vocal cord dysfunction (VCD) is a respiratory disorder characterized by inappropriate vocal cord adduction during inspiration. The diagnosis of VCD is challenging, because expected flow volume loop abnormalities are uncommonly noted, and laryngoscopy must be timed to coincide with symptoms. OBJECTIVE: We wanted to determine the potential role of impulse oscillometry (IOS) in the diagnosis of VCD. METHODS: We conducted an analysis of six patients in which the diagnosis of VCD was being considered as well as seven healthy subjects and five subjects with asthma. All were evaluated with IOS and spirometry, and patients underwent laryngoscopy. Two patients with suspected VCD who did not exhibit symptoms or abnormal pulmonary function at baseline underwent exercise challenge and repeat studies. One patient with suspected VCD underwent an additional irritant challenge. RESULTS: VCD was diagnosed by laryngoscopy in three of the six patients in whom the diagnosis of VCD was entertained. These three patients as a group all exhibited higher amplitude (mean, 9.3 cm H(2)0/L/second) and more variable spikes (SD, 4.8 cm H(2)0/L/second) on IOS impedance during inspiration, whereas the three patients in whom the diagnosis was not confirmed by endoscopy did not show these findings (mean, 2.0 cm H(2)0/L/second; P < .0002; SD, 0.8 cm H(2)0/L/second; P < .0001). This pattern was also not observed in the healthy volunteers (mean +/- SD, 1.8 +/- 0.7 cm H(2)0/L/second) and patients with asthma at baseline (mean, 4.2 +/- 1.2 cm H(2)0/L/second) or after exercise challenge (mean, 1.5 +/- 0.5 cm H(2)0/L/second). CONCLUSIONS: These findings support the conclusion that IOS displays a characteristic pattern in patients with VCD and thus may offer a rapid and noninvasive adjunct to the assessment and diagnosis of patients suspected to have this disorder. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Komarow, Hirsh D.; Nelson, Celeste; Metcalfe, Dean D.] NIAID, NIH, LAD, Bethesda, MD 20892 USA. [Young, Michael] SAIC Frederick Inc, Frederick Natl Lab Clin Res, Clin Monitoring Res Program, Clin Res Directorate, Frederick, MD USA. RP Komarow, HD (reprint author), NIAID, NIH, LAD, Bldg 10,Rm 1C129A1,10 Ctr Dr, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in whole or in part by the National Cancer Institute, National Institutes of Health, contract no. HHSN261200800001E (M.Y.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 32 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JUL-AUG PY 2013 VL 1 IS 4 BP 387 EP + DI 10.1016/j.jaip.2013.05.005 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA V38WW UT WOS:000209374500010 PM 24565544 ER PT J AU Spencer, RG Pleshko, N AF Spencer, Richard G. Pleshko, Nancy TI How Do Statistical Differences in Matrix-sensitive Magnetic Resonance Outcomes Translate Into Clinical Assignment Rules? SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Editorial Material C1 [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Tissue Imaging & Spect Lab, Philadelphia, PA 19122 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. FU Intramural NIH HHS [ZIA AG000922-05] NR 5 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD JUL PY 2013 VL 21 IS 7 BP 438 EP 439 DI 10.5435/JAAOS-21-07-438 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA V37MX UT WOS:000209281000009 PM 23818031 ER PT J AU Bulea, TC Kilicarslan, A Ozdemir, R Paloski, WH Contreras-Vidal, JL AF Bulea, Thomas C. Kilicarslan, Atilla Ozdemir, Recep Paloski, William H. Contreras-Vidal, Jose L. TI Simultaneous Scalp Electroencephalography (EEG), Electromyography (EMG), and Whole-body Segmental Inertial Recording for Multi-modal Neural Decoding SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 77; Neuroscience; Neurobiology; Medicine; Anatomy; Physiology; Biomedical Engineering; Molecular Biology; Electroencephalography; EEG; Electromyography; EMG; electroencephalograph; gait; brain-computer interface; brain machine interface; neural decoding; over-ground walking; robotic gait; brain; imaging; clinical techniques AB Recent studies support the involvement of supraspinal networks in control of bipedal human walking. Part of this evidence encompasses studies, including our previous work, demonstrating that gait kinematics and limb coordination during treadmill walking can be inferred from the scalp electroencephalogram (EEG) with reasonably high decoding accuracies. These results provide impetus for development of non-invasive brain-machine-interface (BMI) systems for use in restoration and/or augmentation of gait-a primary goal of rehabilitation research. To date, studies examining EEG decoding of activity during gait have been limited to treadmill walking in a controlled environment. However, to be practically viable a BMI system must be applicable for use in everyday locomotor tasks such as over ground walking and turning. Here, we present a novel protocol for non-invasive collection of brain activity (EEG), muscle activity (electromyography (EMG)), and whole-body kinematic data (head, torso, and limb trajectories) during both treadmill and over ground walking tasks. By collecting these data in the uncontrolled environment insight can be gained regarding the feasibility of decoding unconstrained gait and surface EMG from scalp EEG. C1 [Bulea, Thomas C.] NIH, Bethesda, MD 20892 USA. [Bulea, Thomas C.; Kilicarslan, Atilla; Ozdemir, Recep; Contreras-Vidal, Jose L.] Univ Houston, Dept Elect & Comp Engn, Lab Noninvas Brain Machine Interface Syst, Houston, TX 77004 USA. [Ozdemir, Recep; Paloski, William H.] Univ Houston, Dept Hlth & Human Performance, Houston, TX 77004 USA. [Ozdemir, Recep; Paloski, William H.; Contreras-Vidal, Jose L.] Univ Houston, Ctr Neuromotor & Biomech Res, Houston, TX 77004 USA. [Contreras-Vidal, Jose L.] Univ Houston, Dept Biomed Engn, Houston, TX 77004 USA. RP Bulea, TC (reprint author), NIH, Bethesda, MD 20892 USA. EM thomas.bulea@nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS) [R01NS075889-01]; Intramural Research Program of the NIH, Clinical Center; APDM, Inc. (Portland, OR) FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant # R01NS075889-01. This research was supported in part by the Intramural Research Program of the NIH, Clinical Center. The authors also thank Shahriar Iqbal and Yongtian He for assistance with data collection. The cost of open-access publication of this article was sponsored by APDM, Inc. (Portland, OR; http://apdm.com). NR 22 TC 3 Z9 3 U1 1 U2 9 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2013 IS 77 AR UNSP e50602 DI 10.3791/50602 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RG UT WOS:000209227900053 ER PT J AU Swamydas, M Lionakis, MS AF Swamydas, Muthulekha Lionakis, Michail S. TI Isolation, Purification and Labeling of Mouse Bone Marrow Neutrophils for Functional Studies and Adoptive Transfer Experiments SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 77; Cellular Biology; Infection; Infectious Diseases; Molecular Biology; Medicine; Biomedical Engineering; Bioengineering; Neutrophils; Adoptive Transfer; immunology; Neutrophils; mouse; bone marrow; adoptive transfer; density gradient; labeling; CellTracker; cell; isolation; flow cytometry; animal model AB Neutrophils are critical effector cells of the innate immune system. They are rapidly recruited at sites of acute inflammation and exert protective or pathogenic effects depending on the inflammatory milieu. Nonetheless, despite the indispensable role of neutrophils in immunity, detailed understanding of the molecular factors that mediate neutrophils' effector and immunopathogenic effects in different infectious diseases and inflammatory conditions is still lacking, partly because of their short half life, the difficulties with handling of these cells and the lack of reliable experimental protocols for obtaining sufficient numbers of neutrophils for downstream functional studies and adoptive transfer experiments. Therefore, simple, fast, economical and reliable methods are highly desirable for harvesting sufficient numbers of mouse neutrophils for assessing functions such as phagocytosis, killing, cytokine production, degranulation and trafficking. To that end, we present a reproducible density gradient centrifugation-based protocol, which can be adapted in any laboratory to isolate large numbers of neutrophils from the bone marrow of mice with high purity and viability. Moreover, we present a simple protocol that uses CellTracker dyes to label the isolated neutrophils, which can then be adoptively transferred into recipient mice and tracked in several tissues for at least 4 hr post-transfer using flow cytometry. Using this approach, differential labeling of neutrophils from wild-type and gene-deficient mice with different CellTracker dyes can be successfully employed to perform competitive repopulation studies for evaluating the direct role of specific genes in trafficking of neutrophils from the blood into target tissues in vivo. C1 [Swamydas, Muthulekha; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), USA; Animal Care and Use Committee of the NIAID FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), USA.; All mice were maintained at an American Association for the Accreditation of Laboratory Animal Care-accredited animal facility at the National Institute of Allergy and Infectious Diseases (NIAID) and housed in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals under the auspices of a protocol approved by the Animal Care and Use Committee of the NIAID. NR 22 TC 13 Z9 13 U1 3 U2 14 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2013 IS 77 AR UNSP e50586 DI 10.3791/50586 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RG UT WOS:000209227900050 PM 23892876 ER PT J AU Horkay, F AF Horkay, Ferenc TI Ion Polymer Interactions in DNA Solutions and Gels SO MACROMOLECULAR SYMPOSIA LA English DT Proceedings Paper CT Polymer Networks Conference (PNG) CY AUG 12-16, 2012 CL WY DE calcium ion; DNA; osmotic pressure; polyelectrolyte; small angle neutron scattering; swelling ID POLYELECTROLYTE SOLUTIONS; CONDENSATION; TRANSITION; NETWORKS; CATIONS AB Systematic investigations using small angle neutron scattering (SANS) were made to reveal the effect of calcium ions on the structure of DNA gels and solutions in near-physiological salt solutions. To describe the neutron scattering response two characteristic distances are required. The shorter length scale, R (approximate to 10 angstrom), was found to be governed by the geometry of the DNA chain and is close to the cross-sectional radius of the double helix. The longer length scale L corresponds to the mesh size of the network of overlapping polymer chains. L decreases with increasing DNA concentration as L proportional to C-DNA(-0.73). With increasing CaCl2 concentration both L and the scattering intensity increase. The increase in the scattering intensity reflects the reduction of the osmotic modulus as the calcium ion concentration increases. The values of the osmotic modulus derived from osmotic swelling pressure measurements are in reasonable agreement with those obtained from SANS. C1 NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Horkay, F (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, 13 South Dr, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 42 TC 0 Z9 0 U1 2 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1022-1360 EI 1521-3900 J9 MACROMOL SYMP JI Macromol. Symp. PD JUL PY 2013 VL 329 IS 1 BP 19 EP 26 DI 10.1002/masy.201300028 PG 8 WC Polymer Science SC Polymer Science GA AG5BR UT WOS:000335434600003 ER PT J AU Betz, JM AF Betz, J. M. TI Nature Exposed to Our Method of Questioning: Reliability of Natural Product Measurements SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Betz, J. M.] US NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA AL1 BP 819 EP 819 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100048 ER PT J AU Downey, T Bosserman, M Noinaj, N Buchanan, SK Rohr, J AF Downey, T. Bosserman, M. Noinaj, N. Buchanan, S. K. Rohr, J. TI Investigating and Re-Engineering Baeyer-Villiger Monooxygenase MtmOIV for Combinatorial Biosynthesis of Novel Aureolic Acid Anticancer Drug Analogues SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Downey, T.; Bosserman, M.; Rohr, J.] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY 40536 USA. [Noinaj, N.; Buchanan, S. K.] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PA5 BP 826 EP 826 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100076 ER PT J AU Divlianska, DB Wright, AE Francis, S Walters, MA Salomon, CE Diaz, PW Hassig, CA O'Keefe, BR Reed, JC Roth, GP AF Divlianska, D. B. Wright, A. E. Francis, S. Walters, M. A. Salomon, C. E. Diaz, P. W. Hassig, C. A. O'Keefe, B. R. Reed, J. C. Roth, G. P. TI In Search of Novel Cancer Therapeutics: Assessing the NCI Natural Product Library against Ten Anti-Apoptotic Protein Targets SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Divlianska, D. B.; Diaz, P. W.; Hassig, C. A.; Roth, G. P.] Sanford Burnham Med Res Inst, Orlando, FL 32827 USA. [Wright, A. E.] Florida Atlantic Univ, Oceanog Inst, Harbor Branch, Ft Pierce, FL 34946 USA. [Francis, S.; Walters, M. A.] Univ Minnesota, Inst Therapeut Discovery & Dev, Minneapolis, MN 55414 USA. [Salomon, C. E.] Univ Minnesota, Ctr Drug Design, Minneapolis, MN 55455 USA. [O'Keefe, B. R.] NCI, Mol Targets Lab, CCR, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Reed, J. C.] F Hoffmann La Roche Ltd, PRED, CH-4070 Basel, Switzerland. RI Divlianska, Daniela/I-3567-2016 OI Divlianska, Daniela/0000-0002-6871-2122 NR 0 TC 0 Z9 0 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PF4 BP 834 EP 834 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100110 ER PT J AU Castro, A Smith, EA Krumpe, LRH O'Keefe, BR Staudt, LM McMahon, JB Gustafson, KR AF Castro, A. Smith, E. A. Krumpe, Haugh L. R. O'Keefe, B. R. Staudt, L. M. McMahon, J. B. Gustafson, K. R. TI Natural Product Inhibitors of the Arginine-Specific Protease Activity of MALT1 SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Castro, A.; Smith, E. A.; Krumpe, Haugh L. R.; O'Keefe, B. R.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Krumpe, Haugh L. R.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Staudt, L. M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PK9 BP 845 EP 845 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100156 ER PT J AU Sunassee, SN Ransom, T Heinrich, CJ McMahon, JB Gustafson, KR AF Sunassee, S. N. Ransom, T. Heinrich, C. J. McMahon, J. B. Gustafson, K. R. TI New Steroidal Alkaloids from the Marine Sponge Corticium niger that Inhibit Growth of Human Colon Carcinoma Cells SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Sunassee, S. N.; Ransom, T.; Heinrich, C. J.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PK11 BP 845 EP 845 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100158 ER PT J AU Zuck, KM Rosario, M Widmer, TL Newman, DJ AF Zuck, K. M. Rosario, M. Widmer, T. L. Newman, D. J. TI New Analogs Produced by the Co-Culture of the Endophyte Xylaria sp and Phytophthora SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Zuck, K. M.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nat Prod Support Grp, Frederick, MD 21702 USA. [Rosario, M.; Newman, D. J.] NCI, Frederick Natl Lab Canc Res, DTP, Nat Prod Branch, Frederick, MD 21702 USA. [Widmer, T. L.] ARS, USDA, FDWSRU, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PL24 BP 852 EP 852 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100188 ER PT J AU Chan, STS Popplewell, W Henrich, CJ Linehan, WM Bottaro, DP McMahon, JB McKee, TC Gustafson, KR AF Chan, S. T. S. Popplewell, W. Henrich, C. J. Linehan, W. M. Bottaro, D. P. McMahon, J. B. McKee, T. C. Gustafson, K. R. TI Isolation and Identification of Natural Products from Artocarpus communis SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy on Natural Products at a Crossroad - Current and Future Directions CY JUL 14-17, 2013 CL St Louis, MO SP Amer Soc Pharmacognosy C1 [Chan, S. T. S.; Popplewell, W.; McMahon, J. B.; McKee, T. C.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, C. J.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Linehan, W. M.; Bottaro, D. P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2013 VL 79 IS 10 MA PN58 BP 870 EP 870 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AK8RG UT WOS:000338695100262 ER PT J AU Deal, C AF Deal, C. TI CHALLENGES AND OPPORTUNITIES: POTENTIALS IN RESEARCH ON AMR GONOCOCCI SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Deal, C.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA S05.2 BP A11 EP A11 DI 10.1136/sextrans-2013-051184.0032 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400028 ER PT J AU Grabowski, MK Gray, RH Serwadda, D Kigozi, G Gravitt, PE Nalugoda, F Renyolds, SJ Wawer, M Quinn, TC Tobian, AAR AF Grabowski, M. K. Gray, R. H. Serwadda, D. Kigozi, G. Gravitt, P. E. Nalugoda, F. Renyolds, S. J. Wawer, M. Quinn, T. C. Tobian, A. A. R. TI HIGH RISK HUMAN PAPILLOMAVIRUS VIRAL LOAD AND PERSISTENCE AMONG HIV-NEGATIVE AND HIV-POSITIVE MEN SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Grabowski, M. K.; Gray, R. H.; Gravitt, P. E.; Renyolds, S. J.; Wawer, M.; Quinn, T. C.; Tobian, A. A. R.] Johns Hopkins, Baltimore, MD USA. [Gray, R. H.; Serwadda, D.; Nalugoda, F.; Renyolds, S. J.; Wawer, M.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, D.] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kigozi, G.] Rakai Hlth Sci Program, En, Uganda. [Gravitt, P. E.] Perdana Univ, Grad Sch Med, Serdang, Malaysia. [Renyolds, S. J.; Quinn, T. C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, A. A. R.] Rakai Hlth Sci Program, Entebbe, Austria. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P3.222 BP A217 EP A218 DI 10.1136/sextrans-2013-051184.0679 PG 3 WC Infectious Diseases SC Infectious Diseases GA V40VR UT WOS:000209506600071 ER PT J AU Grabowski, MK Lessler, J Redd, A Kagaayi, J Laeyendecker, O Nalugoda, F Serwadda, D Wawer, M Quinn, TC Gray, RH AF Grabowski, M. K. Lessler, J. Redd, A. Kagaayi, J. Laeyendecker, O. Nalugoda, F. Serwadda, D. Wawer, M. Quinn, T. C. Gray, R. H. TI FREQUENT VIRAL INTRODUCTIONS SUSTAIN LOCAL HIV EPIDEMICS IN RURAL AFRICA SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Grabowski, M. K.; Lessler, J.; Laeyendecker, O.; Wawer, M.; Quinn, T. C.; Gray, R. H.] Johns Hopkins, Baltimore, MD USA. [Redd, A.; Laeyendecker, O.; Quinn, T. C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kagaayi, J.; Nalugoda, F.; Serwadda, D.; Wawer, M.; Gray, R. H.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, D.] Makerere Univ, Sch Med, Kampala, Uganda. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA S15.1 BP A22 EP A22 DI 10.1136/sextrans-2013-051184.0070 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400066 ER PT J AU Kenney, J Derby, N Aravantinou, M Rana, S Lifson, JD Piatak, M Gettie, A Blanchard, J Robbiani, M AF Kenney, J. Derby, N. Aravantinou, M. Rana, S. Lifson, J. D. Piatak, M., Jr. Gettie, A. Blanchard, J. Robbiani, M. TI A REPEATED LOW DOSE CO-CHALLENGE MODEL OF SHIV-RT AND HSV-2 IN RHESUS MACAQUES SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Kenney, J.; Derby, N.; Aravantinou, M.; Rana, S.; Robbiani, M.] Populat Council, New York, NY 10021 USA. [Lifson, J. D.; Piatak, M., Jr.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Gettie, A.] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Blanchard, J.] Tulane Natl Primate Res Ctr, Covington, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P2.091 BP A116 EP A116 DI 10.1136/sextrans-2013-051184.0355 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400351 ER PT J AU Marrazzo, J Rabe, L Kelly, C Livant, T Chirenje, M Richardson, B Deal, C Piper, J Hillier, S AF Marrazzo, J. Rabe, L. Kelly, C. Livant, T. Chirenje, M. Richardson, B. Deal, C. Piper, J. Hillier, S. TI HERPES SIMPLEX VIRUS (HSV) INFECTION IN THE VOICE (MTN 003) STUDY: PRE-EXPOSURE PROPHYLAXIS (PREP) FOR HIV WITH DAILY USE OF ORAL TENOFOVIR, ORAL TENOFOVIR-EMTRICITABINE, OR VAGINAL TENOFOVIR GEL SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Marrazzo, J.] Univ Washington, Seattle, WA 98195 USA. [Rabe, L.; Livant, T.; Hillier, S.] Magee Womens Res Inst, Pittsburgh, PA USA. [Kelly, C.; Richardson, B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Chirenje, M.] Univ Harare, Harare, Zimbabwe. [Deal, C.; Piper, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA O11.1 BP A46 EP A46 DI 10.1136/sextrans-2013-051184.0143 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400139 ER PT J AU Plankey, MW Hoffman, HJ Springer, G Cox, C Young, MA Margolick, JB Torre, P AF Plankey, M. W. Hoffman, H. J. Springer, G. Cox, C. Young, M. A. Margolick, J. B. Torre, P. TI THE PREVALENCE OF HEARING SENSITIVITY AMONG HIV-SEROPOSITIVE AND HIV-SERONEGATIVE MEN AND WOMEN SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Plankey, M. W.; Young, M. A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Hoffman, H. J.] NIDCD, Bethesda, MD USA. [Springer, G.; Cox, C.; Margolick, J. B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Torre, P.] San Diego State Univ, San Diego, CA 92182 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA P2.119 BP A124 EP A124 DI 10.1136/sextrans-2013-051184.0383 PG 1 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400379 ER PT J AU Quinn, TC AF Quinn, T. C. TI HIV TRANSMISSION DYNAMICS; CAN WE TRANSLATE KNOWLEDGE INTO ACTION SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Quinn, T. C.] NIAID, Baltimore, MD USA. [Quinn, T. C.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2013 VL 89 SU 1 MA PL02.3 BP A2 EP A3 DI 10.1136/sextrans-2013-051184.0005 PG 3 WC Infectious Diseases SC Infectious Diseases GA V40SD UT WOS:000209497400005 ER PT J AU Jiraporn, P Chintrakarn, P AF Jiraporn, P. Chintrakarn, P. TI Corporate social responsibility (CSR) and CEO luck: are lucky CEOs socially responsible? SO APPLIED ECONOMICS LETTERS LA English DT Article DE corporate social responsibility; lucky CEOs; option backdating; agency theory; G30; G34 AB Lucky' CEOs are given stock option grants on days when the stock price is the lowest in the month of the grant, implying opportunistic timing, severe agency problems and poor corporate governance. We find that lucky (opportunistic) CEOs invest significantly less in CSR. The evidence thus does not support the notion that CSR is primarily used to enhance managers' private benefits at the expense of shareholders. Rather, lucky CEOs appear to view CSR investments as depriving them of the free cash flow they could otherwise exploit. C1 [Jiraporn, P.] Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA. [Jiraporn, P.] Thammasat Univ, Bangkok, Thailand. [Jiraporn, P.] Mahidol Univ, Coll Management, Bangkok 10700, Thailand. [Jiraporn, P.] NIDA, Fac Business Adm, Bangkok, Thailand. [Chintrakarn, P.] MUIC, Nakhon Pathom, Thailand. RP Jiraporn, P (reprint author), Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA. EM pjiraporn@gmail.com NR 6 TC 4 Z9 4 U1 0 U2 34 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1350-4851 J9 APPL ECON LETT JI Appl. Econ. Lett. PD JUL 1 PY 2013 VL 20 IS 11 BP 1036 EP 1039 DI 10.1080/13504851.2013.772291 PG 4 WC Economics SC Business & Economics GA 150HB UT WOS:000319379700003 ER PT J AU Forrest, D Visser, TJ AF Forrest, Douglas Visser, Theo J. TI Thyroid hormone signaling Preface SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Editorial Material C1 [Forrest, Douglas] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. [Visser, Theo J.] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands. RP Forrest, D (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. EM forrestd@niddk.nih.gov FU Intramural NIH HHS NR 0 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3859 EP 3859 DI 10.1016/j.bbagen.2013.03.001 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200001 PM 23651664 ER PT J AU Grimaldi, A Buisine, N Miller, T Shi, YB Sachs, LM AF Grimaldi, Alexis Buisine, Nicolas Miller, Thomas Shi, Yun-Bo Sachs, Laurent M. TI Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Thyroid hormone; Transcriptional regulation; Histone modification; Chromatin remodeling; Coregulator; Amphibian metamorphosis ID RETINOIC ACID RECEPTORS; CHROMATIN REMODELING COMPLEXES; XENOPUS-LAEVIS METAMORPHOSIS; GENE-EXPRESSION CHANGES; INTESTINAL STEM-CELLS; HISTONE DEACETYLASE; TRANSCRIPTIONAL REPRESSION; N-COR; NUCLEAR RECEPTORS; POSTEMBRYONIC DEVELOPMENT AB Background: Thyroid hormone (TH) receptor (TR) plays critical roles in vertebrate development. However, the in vivo mechanism of TR action remains poorly explored. Scope of review: Frog metamorphosis is controlled by TH and mimics the postembryonic period in mammals when high levels of TH are also required. We review here some of the findings on the developmental functions of TH and TR and the associated mechanisms obtained from this model system. Major conclusion: A dual function model for TR in Anuran development was proposed over a decade ago. That is, unliganded TR recruits corepressors to TH response genes in premetamorphic tadpoles to repress these genes and prevent premature metamorphic changes. Subsequently, when TH becomes available, liganded TR recruits coactivators to activate these same genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model. Specifically, it has been shown that unliganded TR recruits histone deacetylase containing corepressor complexes during larval stages to control metamorphic timing, while liganded TR recruits multiple histone modifying and chromatin remodeling coactivator complexes during metamorphosis. These complexes can alter chromatin structure via nucleosome position alterations or eviction and histone modifications to contribute to the recruitment of transcriptional machinery and gene activation. General significance: The molecular mechanisms of TR action in vivo as revealed from studies on amphibian metamorphosis are very likely applicable to mammalian development as well. These findings provide a new perspective for understanding the diverse effects of TH in normal physiology and diseases caused by TH dysfunction. This article is part of a Special Issue entitled Thyroid hormone signalling. (C) 2012 Elsevier B.V. All rights reserved. C1 [Grimaldi, Alexis; Buisine, Nicolas; Sachs, Laurent M.] Museum Natl Hist Nat, Dept Regulat Dev & Diversite Mol, CNRS UMR7221, Sect Thyroid Hormone Receptor Funct & Mech Act, F-75231 Paris, France. [Miller, Thomas; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Sachs, LM (reprint author), MNHN, CNRS, UMR7221, CP 32,7 Rue Cuvier, F-75231 Paris 05, France. EM sachs@mnhn.fr FU Centre National de la Recherche Scientifique; Museum National d'Histoire Naturelle; CRESCENDO; IDEAL [259679]; TRIGGER [ANR-08-JCIC-0100-01]; National Institute of Child Health and Human Development, NIH; [LSHM-CT-2005-018652] FX This work was supported by the "Centre National de la Recherche Scientifique", the "Museum National d'Histoire Naturelle", "CRESCENDO", a European Integrated Project funding from FP6 (contract no. LSHM-CT-2005-018652), "IDEAL", a European Large Integrated Project funding from FP7 (no. 259679) and "TRIGGER" (ANR-08-JCIC-0100-01), and the Intramural Research Program of the National Institute of Child Health and Human Development, NIH. NR 120 TC 18 Z9 18 U1 3 U2 58 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3882 EP 3892 DI 10.1016/j.bbagen.2012.04.020 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200005 PM 22565053 ER PT J AU Kim, WG Cheng, SY AF Kim, Won Gu Cheng, Sheue-yann TI Thyroid hormone receptors and cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Thyroid hormone receptor mutant; Thyroid cancer; Phosphatidylinositol 3 kinase; Src kinase; beta-Catenin; Mouse model ID FOCAL ADHESION KINASE; C-ERBA-BETA; TRANSFORMING GENE PTTG; CLEAR-CELL CARCINOMA; MOUSE MODEL; PITUITARY-TUMOR; TR-BETA; V-ERBA; PHOSPHATIDYLINOSITOL 3-KINASE; NUCLEAR RECEPTOR AB Background: Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TR.s in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation. Scope of review: In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1(-/-)Thrb(-/-) mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; Thrb(PV/PV) mice) spontaneously develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer. Major conclusions: Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis. General significance: Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities. This article is part of a Special Issue entitled Thyroid hormone signalling. Published by Elsevier B.V. C1 [Kim, Won Gu; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Bldg 37,Rm 5128,37 Convent Dr MSC 4264, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Kim, Won Gu/0000-0002-8404-7759 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We regret any reference omissions due to length limitation. We wish to thank all colleagues and collaborators who have contributed to the work described in this review. The research described in this review by the authors and their colleagues at National Cancer Institute was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 97 TC 24 Z9 25 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2013 VL 1830 IS 7 SI SI BP 3928 EP 3936 DI 10.1016/j.bbagen.2012.04.002 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148KJ UT WOS:000319243200010 PM 22507269 ER PT J AU Galindo-Fraga, A Ortiz-Hernandez, AA Ramirez-Venegas, A Vazquez, RV Moreno-Espinosa, S Llamosas-Gallardo, B Perez-Patrigeon, S Salinger, M Freimanis, L Huang, CY Gu, WJ Guerrero, ML Beigel, J Ruiz-Palacios, GM AF Galindo-Fraga, Arturo Ortiz-Hernandez, Ana A. Ramirez-Venegas, Alejandra Valdez Vazquez, Rafael Moreno-Espinosa, Sarbelio Llamosas-Gallardo, Beatriz Perez-Patrigeon, Santiago Salinger, Maggie Freimanis, Laura Huang, Chiung-yu Gu, Wenjuan Lourdes Guerrero, M. Beigel, John Ruiz-Palacios, Guillermo M. CA La Red ILI 002 Study Grp TI Clinical characteristics and outcomes of influenza and other influenza-like illnesses in Mexico City SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Respiratory viral pathogens; Epidemiology; Hospital burden of disease; Influenza; Respiratory syncytial virus; Rhinovirus; Coronavirus ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY VIRAL-INFECTIONS; CRITICALLY-ILL PATIENTS; HOSPITALIZED CHILDREN; A H1N1; ETIOLOGY; VIRUSES; ADULTS; EPIDEMIOLOGY; SURVEILLANCE AB Background: Influenza-like illnesses (ILI) are estimated to cause millions of deaths annually. Despite this disease burden, the etiologic causes of ILI are poorly described for many geographical regions. Methods: Beginning in April 2010, we conducted an observational cohort study at five hospitals in Mexico City, enrolling subjects who met the criteria for ILI. Evaluations were conducted at enrollment and on day 28, with the collection of clinical data and a nasopharyngeal swab (or nasal aspirate in children). Swabs were tested by multiplex PCR for 15 viral pathogens and real-time PCR for influenza. Results: During the first year, 1065 subjects were enrolled in this study, 55% of whom were hospitalized; 24% of all subjects were children. One or more pathogens were detected by PCR in 64% of subjects, most commonly rhinovirus (25% of all isolates) and influenza (24% of isolates). Six percent of subjects died, and of those, 54% had no pathogen identified. Rhinovirus was the most common pathogen among those who died, although it did not have the highest case fatality rate. Conclusions: Multiple respiratory viruses beyond influenza are associated with significant morbidity and mortality among adults and children in Mexico City. Detection of these agents could be useful for the adjustment of antibiotic treatment in severe cases. (C) 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. C1 [Galindo-Fraga, Arturo; Perez-Patrigeon, Santiago; Lourdes Guerrero, M.; Ruiz-Palacios, Guillermo M.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. [Ortiz-Hernandez, Ana A.; Llamosas-Gallardo, Beatriz] Inst Nacl Pediat, Mexico City, DF, Mexico. [Ramirez-Venegas, Alejandra] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Valdez Vazquez, Rafael] Hosp Gen Dr Manuel Gea Gonzalez, Mexico City, DF, Mexico. [Moreno-Espinosa, Sarbelio] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [Salinger, Maggie; Huang, Chiung-yu] NIAID, Bethesda, MD 20892 USA. [Freimanis, Laura] WESTAT Corp, Rockville, MD 20850 USA. [Gu, Wenjuan; Beigel, John] NIAID, SAIC Frederick, Bethesda, MD 20892 USA. RP Galindo-Fraga, A (reprint author), Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Vasco de Quiroga 15,Col Secc 16, Mexico City 14000, DF, Mexico. EM galindofraga@yahoo.com FU Mexico Ministry of Health; U.S. National Institute of Allergy and Infectious Diseases; CONACYT through FONSEC SSA/IMSS/ISSSTE [71260, 127088]; Westat, Inc. [HHSN2722009000031]; National Cancer Institute, National Institutes of Health, 318 [HHSN261200800001E] FX La Red is funded by the Mexico Ministry of Health and the U.S. National Institute of Allergy and Infectious Diseases. This project has been funded in part by funding provided by: CONACYT through FONSEC SSA/IMSS/ISSSTE No. 71260 and No. 127088. Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) through a contract with Westat, Inc., Contract Number: HHSN2722009000031, Task Order Number: HHSN27200002. And through the National Cancer Institute, National Institutes of Health, 318 under Contract No. HHSN261200800001E. NR 36 TC 9 Z9 9 U1 0 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JUL PY 2013 VL 17 IS 7 BP E510 EP E517 DI 10.1016/j.ijid.2013.01.006 PG 8 WC Infectious Diseases SC Infectious Diseases GA 144XT UT WOS:000318976300008 PM 23416208 ER PT J AU Lin, CL Peng, GCY Karniadakis, G AF Lin, Ching-Long Peng, Grace C. Y. Karniadakis, George TI Multi-Scale modeling and simulation of biological systems Preface SO JOURNAL OF COMPUTATIONAL PHYSICS LA English DT Editorial Material C1 [Lin, Ching-Long] Univ Iowa, Iowa City, IA 52242 USA. [Peng, Grace C. Y.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Karniadakis, George] Brown Univ, Providence, RI 02912 USA. RP Lin, CL (reprint author), Univ Iowa, Iowa City, IA 52242 USA. EM ching-long-lin@uiowa.edu NR 1 TC 1 Z9 1 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9991 J9 J COMPUT PHYS JI J. Comput. Phys. PD JUL 1 PY 2013 VL 244 BP 1 EP 3 DI 10.1016/j.jcp.2013.02.004 PG 3 WC Computer Science, Interdisciplinary Applications; Physics, Mathematical SC Computer Science; Physics GA 151JO UT WOS:000319456900001 ER PT J AU Cheung, CSF Lui, JC Baron, J AF Cheung, Crystal S. F. Lui, Julian C. Baron, Jeffrey TI Identification of chondrocyte-binding peptides by phage display SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE phage display; peptide; cartilage; chondrocytes; targeted therapy ID MURINE HYPOPHOSPHATASIA; ENZYME REPLACEMENT; HOMING PEPTIDES; CELLS; VASCULATURE; CARTILAGE; BONE; OLIGOPEPTIDE; SELECTION; DELIVERY AB As an initial step toward targeting cartilage tissue for potential therapeutic applications, we sought cartilage-binding peptides using phage display, a powerful technology for selection of peptides that bind to molecules of interest. A library of phage displaying random 12-amino acid peptides was iteratively incubated with cultured chondrocytes to select phage that bind cartilage. The resulting phage clones demonstrated increased affinity to chondrocytes by ELISA, when compared to a wild-type, insertless phage. Furthermore, the selected phage showed little preferential binding to other cell types, including primary skin fibroblast, myocyte and hepatocyte cultures, suggesting a tissue-specific interaction. Immunohistochemical staining revealed that the selected phage bound chondrocytes themselves and the surrounding extracellular matrix. FITC-tagged peptides were synthesized based on the sequence of cartilage-binding phage clones. These peptides, but not a random peptide, bound cultured chondrocytes, and extracelluar matrix. In conclusion, using phage display, we identified peptide sequences that specifically target chondrocytes. We anticipate that such peptides may be coupled to therapeutic molecules to provide targeted treatment for cartilage disorders. (c) 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:10531058, 2013 C1 [Cheung, Crystal S. F.; Lui, Julian C.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Baron, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM jeffrey.baron@nih.gov RI Lui, Chun Kin Julian/E-2253-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural Research Program). NR 23 TC 5 Z9 5 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2013 VL 31 IS 7 BP 1053 EP 1058 DI 10.1002/jor.22325 PG 6 WC Orthopedics SC Orthopedics GA 149VW UT WOS:000319350500009 PM 23440926 ER PT J AU Huppmann, AR Xi, LQ Raffeld, M Pittaluga, S Jaffe, ES AF Huppmann, Alison R. Xi, Liqiang Raffeld, Mark Pittaluga, Stefania Jaffe, Elaine S. TI Subcutaneous panniculitis-like T-cell lymphoma in the pediatric age group: A lymphoma of low malignant potential SO PEDIATRIC BLOOD & CANCER LA English DT Article DE lupus panniculitis; pediatric; subcutaneous panniculitis-like T-cell lymphoma ID HIGH-DOSE CHEMOTHERAPY; CLASSIFICATION AB Background Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare neoplasm of mature cytotoxic T-cells. Most commonly occurring in young adults, few reports are described in children. A separate analysis of a significant cohort of pediatric patients has not previously been performed. Procedure We analyzed the pathology including molecular results as well as available clinical data from 16 pediatric patients (age 5 months to 21 years) who had a total of 19 biopsies submitted to the National Cancer Institute from 1999 to 2011. This included 6 males and 10 females. Results Most patients (10/16, 62.5%) had multiple skin lesions at the time of biopsy. Histologic features included rimming of adipocytes by atypical lymphocytes, fat necrosis, and karyorrhectic debris. Four biopsies showed only partial involvement by lymphoma; and plasma cells were identified in 14/19 (74%) cases, including three in which they were focally prominent. The neoplastic cells in general were positive for CD3, CD8, TIA-1, and F1 and were negative for CD4 and CD56. CD5 expression was weak to negative in 5/8 cases (63%). A clonal T-cell receptor gene rearrangement was demonstrated in 11/17 (65%). Patients were treated with a variety of agents. While 5/9 (56%) patients had evidence of recurrent skin lesions, no deaths were attributed to disease for the seven patients with follow-up information. Conclusions Pediatric SPTCL shares many clinical and pathologic features with adult SPTCL. The presence of partial involvement or admixed plasma cells makes the differential diagnosis with reactive conditions challenging in some cases. Pediatr Blood Cancer 2013; 60: 11651170. (c) 2013 Wiley Periodicals, Inc. C1 [Huppmann, Alison R.; Xi, Liqiang; Raffeld, Mark; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, NIH, 10 Ctr Dr Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 9 TC 17 Z9 18 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2013 VL 60 IS 7 BP 1165 EP 1170 DI 10.1002/pbc.24462 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 149ZZ UT WOS:000319361300026 PM 23382035 ER PT J AU Lock, RB Carol, H Maris, JM Kang, MH Reynolds, CP Kolb, EA Gorlick, R Keir, ST Billups, CA Kurmasheva, RT Houghton, PJ Smith, MA AF Lock, Richard B. Carol, Hernan Maris, John M. Kang, Min H. Reynolds, C. Patrick Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Billups, Catherine A. Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; Hsp90 inhibitors; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-PROGENITOR; ALK; MUTATION; MODELS; CRLF2; REARRANGEMENT; RESISTANCE; IKZF1; JAK AB Ganetespib, an Hsp90 inhibitor, was tested against the PPTP in vitro cell line panel and selected xenografts in vivo, including JAK2- and BRAF-mutated models. Ganetespib demonstrated potent in vitro cytotoxic activity (median rIC50 8.8nM, range 4.427.1nM). In vivo, ganetespib induced significant differences in EFS distribution for 4 of 11 xenografts. Intermediate activity (EFS T/C>2) was noted only for the MV4;11 xenograft, and there were no objective responses. Administered as single agents, Hsp90 inhibitors examined by the PPTP have shown limited evidence for a therapeutic window against both solid tumor and leukemia pediatric preclinical models. Pediatr Blood Cancer 2013; 60: E42E45. (c) 2013 Wiley Periodicals, Inc. C1 [Lock, Richard B.; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW 2, Australia. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Australia Lowy Canc Res Ctr, Leukemia Biol Program, Childrens Canc Inst, High St, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Carol, Hernan/F-5750-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 23 TC 5 Z9 5 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2013 VL 60 IS 7 BP E42 EP E45 DI 10.1002/pbc.24451 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 149ZZ UT WOS:000319361300007 PM 23303741 ER PT J AU Borthwick, LA Wynn, TA Fisher, AJ AF Borthwick, Lee A. Wynn, Thomas A. Fisher, Andrew J. TI Cytokine mediated tissue fibrosis SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Fibrosis; Cytokine; Macrophage; Fibroblast; Myoflbroblast; Inflammation ID TUMOR-NECROSIS-FACTOR; BRONCHIOLITIS OBLITERANS SYNDROME; EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; IDIOPATHIC PULMONARY-FIBROSIS; PERIPHERAL-BLOOD FIBROCYTES; LUNG-TRANSPLANT RECIPIENTS; HEPATIC STELLATE CELLS; HETEROTOPIC TRACHEAL TRANSPLANTATION; EGG-INDUCED IMMUNOPATHOLOGY AB Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. (C) 2012 Elsevier B.V. All rights reserved. C1 [Borthwick, Lee A.; Fisher, Andrew J.] Newcastle Univ, Sch Med, Inst Cellular Med, Tissue Fibrosis & Repair Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Borthwick, Lee A.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fisher, Andrew J.] Freeman Rd Hosp, Inst Transplantat, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England. RP Borthwick, LA (reprint author), Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM Lee.Borthwick@Newcastle.ac.uk OI Borthwick, Lee/0000-0003-2885-3382 FU European Union; Intramural Research Program of the NIH/NIAID FX We would like to express our sincere appreciation and thanks to all of our colleagues, both past and present, for their guidance and support. We also thank Aaron Gardner for assistance with figure preparation. LAB is supported by a Marie Curie international outgoing fellowship from the European Union Framework Programme 7. TAW is supported by the Intramural Research Program of the NIH/NIAID. NR 267 TC 49 Z9 53 U1 1 U2 50 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL PY 2013 VL 1832 IS 7 SI SI BP 1049 EP 1060 DI 10.1016/j.bbadis.2012.09.014 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 143SC UT WOS:000318887500023 PM 23046809 ER PT J AU Gao, B Radaeva, S AF Gao, Bin Radaeva, Svetlana TI Natural killer and natural killer T cells in liver fibrosis SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Viral hepatitis; Alcoholic liver disease; NKG2D; NAFLD; IFN-gamma ID CHRONIC HEPATITIS-C; ACTIVATED STELLATE CELLS; INNATE IMMUNE-SYSTEM; PHASE I/II TRIAL; NKT CELLS; ALPHA-GALACTOSYLCERAMIDE; INTERFERON-ALPHA; VIRUS-INFECTION; HCV INFECTION; PIT CELLS AB The liver lymphocyte population is enriched with natural killer (NK) cells, which plays key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the-anti-fibrotic cytokine IFN-gamma. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-alpha treatment enhances, while other factors (e.g., alcohol, TGF-beta) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-gamma. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Published by Elsevier B.V. C1 [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Radaeva, Svetlana] NIAAA, Div Metab & Hlth Effect, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. EM bgao@mail.nih.gov FU Intramural NIH HHS [ZIA AA000368-10, Z99 AA999999, ZIA AA000369-10] NR 94 TC 37 Z9 42 U1 0 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL PY 2013 VL 1832 IS 7 SI SI BP 1061 EP 1069 DI 10.1016/j.bbadis.2012.09.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 143SC UT WOS:000318887500024 PM 23022478 ER PT J AU Tanofsky-Kraff, M Engel, S Yanovski, JA Pine, DS Nelson, EE AF Tanofsky-Kraff, Marian Engel, Scott Yanovski, Jack A. Pine, Daniel S. Nelson, Eric E. TI Pediatric disinhibited eating: Toward a research domain criteria framework SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article ID DISORDERS C1 [Tanofsky-Kraff, Marian] USUHS, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD USA. [Engel, Scott] Neuropsychiat Res Inst, Fargo, ND USA. [Pine, Daniel S.; Nelson, Eric E.] NIMH, Sect Dev & Affect Neurosci, NIH, DHHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), USUHS, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637; Nelson, Eric/0000-0002-3376-2453 FU Intramural NIH HHS [Z99 HD999999, Z99 MH999999, ZIA HD000641-17, ZIA MH002781-11]; NCRR NIH HHS [L30 RR033197]; NIDDK NIH HHS [R01 DK080906]; NIMH NIH HHS [L30 MH078171] NR 7 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2013 VL 46 IS 5 SI SI BP 451 EP 455 DI 10.1002/eat.22101 PG 5 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 142EJ UT WOS:000318779000016 PM 23658090 ER PT J AU Sykora, P Yang, JL Ferrarelli, LK Tian, JY Tadokoro, T Kulkarni, A Weissman, L Keijzers, G Wilson, DM Mattson, MP Bohr, VA AF Sykora, Peter Yang, Jenq-Lin Ferrarelli, Leslie K. Tian, Jingyan Tadokoro, Takashi Kulkarni, Avanti Weissman, Lior Keijzers, Guido Wilson, David M., III Mattson, Mark P. Bohr, Vilhelm A. TI Modulation of DNA base excision repair during neuronal differentiation SO NEUROBIOLOGY OF AGING LA English DT Article DE BER; Differentiation; DNA repair; Postmitotic; Aging; Neuron; DNA damage ID OXIDATIVELY DAMAGED DNA; ALZHEIMERS-DISEASE; STRAND BREAKS; CELL-DEATH; GLYCOSYLASE; NUCLEAR; BRAIN; REPLICATION; EXPRESSION; PATHWAYS AB Neurons are terminally differentiated cells with a high rate of metabolism and multiple biological properties distinct from their undifferentiated precursors. Previous studies showed that nucleotide excision DNA repair is downregulated in postmitotic muscle cells and neurons. Here, we characterize DNA damage susceptibility and base excision DNA repair (BER) capacity in undifferentiated and differentiated human neural cells. The results show that undifferentiated human SH-SY5Y neuroblastoma cells are less sensitive to oxidative damage than their differentiated counterparts, in part because they have robust BER capacity, which is heavily attenuated in postmitotic neurons. The reduction in BER activity in differentiated cells correlates with diminished protein levels of key long patch BER components, flap endonuclease-1, proliferating cell nuclear antigen, and ligase I. Thus, because of their higher BER capacity, proliferative neural progenitor cells are more efficient at repairing DNA damage compared with their neuronally differentiated progeny. Published by Elsevier Inc. C1 [Sykora, Peter; Yang, Jenq-Lin; Ferrarelli, Leslie K.; Tian, Jingyan; Tadokoro, Takashi; Weissman, Lior; Keijzers, Guido; Wilson, David M., III; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Yang, Jenq-Lin; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Kulkarni, Avanti] Roche Palo Alto LLC, Palo Alto, CA USA. [Keijzers, Guido] Univ Copenhagen, Ctr Hlth Aging, Fac Hlth Sci, DK-1168 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Ste 100,Room 6B133, Baltimore, MD 21224 USA. EM bohrv@grc.nia.nih.gov OI Yang, Jenq-Lin/0000-0002-9897-8087 FU National Institute on Aging, National Institutes of Health FX The authors thank Dr Robert Bambara for reagents provided, and Dr Misiak and Dr Illuzzi for critical reading of the manuscript. This research is supported by intramural research program of National Institute on Aging, National Institutes of Health. NR 38 TC 20 Z9 20 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 BP 1717 EP 1727 DI 10.1016/j.neurobiolaging.2012.12.016 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900001 PM 23375654 ER PT J AU Baxter, MG Roberts, MT Gee, NA Lasley, BL Morrison, JH Rapp, PR AF Baxter, Mark G. Roberts, Mary T. Gee, Nancy A. Lasley, Bill L. Morrison, John H. Rapp, Peter R. TI Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys SO NEUROBIOLOGY OF AGING LA English DT Article DE Ovarian hormones; Aging; Macaque; Learning; Memory; Prefrontal; Temporal ID HEALTH INITIATIVE MEMORY; CONJUGATED EQUINE ESTROGENS; SURGICALLY MENOPAUSAL MONKEYS; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; PREFRONTAL CORTEX; MACACA-FASCICULARIS; RECOGNITION MEMORY; ALZHEIMERS-DISEASE; PLUS PROGESTIN AB Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex. (C) 2013 Elsevier Inc. All rights reserved. C1 [Baxter, Mark G.; Morrison, John H.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Baxter, Mark G.; Morrison, John H.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Roberts, Mary T.; Gee, Nancy A.; Lasley, Bill L.] Calif Natl Primate Res Ctr, Davis, CA USA. [Gee, Nancy A.; Lasley, Bill L.] Univ Calif, Sch Vet Med, Ctr Hlth & Environm, Dept Populat Hlth & Reprod, Davis, CA USA. [Rapp, Peter R.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Baxter, MG (reprint author), Mt Sinai Sch Med, Dept Neurosci, 1 Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. FU NIA [P01-AG016765]; NCRR [P51-RR000169] FX We thank Carmel Stanko, Tracy Ojakangas, and Lisa Novik for technical assistance, and Dr Kari Christe for veterinary advice and support. This research was supported by NIA grant P01-AG016765, in part by the Intramural Research Program of the NIA, and was carried out at the California National Primate Research Center, supported by NCRR grant P51-RR000169. NR 43 TC 14 Z9 14 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 BP 1882 EP 1890 DI 10.1016/j.neurobiolaging.2012.12.017 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900018 PM 23369546 ER PT J AU Majounie, E Cross, W Newsway, V Dillman, A Vandrovcova, J Morris, CM Nalls, MA Ferrucci, L Owen, MJ O'Donovan, MC Cookson, MR Singleton, AB de Silva, R Morris, HR AF Majounie, Elisa Cross, William Newsway, Victoria Dillman, Allissa Vandrovcova, Jana Morris, Christopher M. Nalls, Michael A. Ferrucci, Luigi Owen, Michael J. O'Donovan, Michael C. Cookson, Mark R. Singleton, Andrew B. de Silva, Rohan Morris, Huw R. TI Variation in tau isoform expression in different brain regions and disease states SO NEUROBIOLOGY OF AGING LA English DT Article DE Progressive supranuclear palsy; Tauopathies; MAPT ID PROGRESSIVE SUPRANUCLEAR PALSY; MESSENGER-RNA ISOFORMS; ALZHEIMERS-DISEASE; CORTICOBASAL DEGENERATION; PARKINSONS-DISEASE; GENE-EXPRESSION; MAPT LOCUS; HAPLOTYPE; ASSOCIATION; IDENTIFICATION AB Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat (4R) tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating the mechanisms involved in PSP and other tauopathies. We used a tau isoform-specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy control samples. We identified a marked difference in 4R-tau relative expression, across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus compared with pons, cerebellum, and frontal cortex. 4R-tau expression levels were related to the MAPT H1 and H1c haplotypes. Similar regional variation was seen in PSP case and in control samples. (C) 2013 Elsevier Inc. All rights reserved. C1 [Majounie, Elisa; Cross, William; Newsway, Victoria; Owen, Michael J.; O'Donovan, Michael C.; Morris, Huw R.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Majounie, Elisa; Dillman, Allissa; Nalls, Michael A.; Cookson, Mark R.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Vandrovcova, Jana; de Silva, Rohan] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Morris, Christopher M.] Newcastle Univ, Inst Neurosci, Med Toxicol Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morris, Christopher M.] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. RP Morris, HR (reprint author), Univ Wales Hosp, Cardiff CF14 4XN, S Glam, Wales. EM morrishr@cf.ac.uk RI Morris, Huw/B-8527-2008; Singleton, Andrew/C-3010-2009; Cross, William/G-1299-2015; OI Morris, Huw/0000-0002-5473-3774; O'Donovan, Michael/0000-0001-7073-2379 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000932-03]; PSP (Europe) Association; UK Medical Research Council [G0501560, G0400074]; Alzheimer's Society; Alzheimer's Research Trust, Brains for Dementia Research Project; National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust; Newcastle University FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000932-03. This study was funded by the PSP (Europe) Association and UK Medical Research Council research grant G0501560 to RdS.; Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project, and by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. NR 22 TC 8 Z9 8 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2013 VL 34 IS 7 AR 1922.e7 DI 10.1016/j.neurobiolaging.2013.01.017 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 140TS UT WOS:000318678900026 PM 23428180 ER PT J AU Agster, KL Mejias-Aponte, CA Clark, BD Waterhouse, BD AF Agster, Kara L. Mejias-Aponte, Carlos A. Clark, Brian D. Waterhouse, Barry D. TI Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE norepinephrine; prefrontal; somatosensory; motor; locus coeruleus; stereology ID MEDIAL PREFRONTAL CORTEX; CENTRAL-NERVOUS-SYSTEM; LOCUS-COERULEUS; CEREBRAL-CORTEX; VOLUME TRANSMISSION; AXON TERMINALS; LAMINAR DISTRIBUTION; AWAKE RAT; NOREPINEPHRINE; INNERVATION AB The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine -hydroxylase (DH)-immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region-specific, impact of LC output on different cortical areas. J. Comp. Neurol. 521:21952207, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Agster, Kara L.; Clark, Brian D.; Waterhouse, Barry D.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Mejias-Aponte, Carlos A.] NIDA, Baltimore, MD 21224 USA. RP Waterhouse, BD (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. EM waterhouse@drexelmed.edu FU National Institute of Drug Abuse [DA017960]; Pennsylvania Department of Health; National Institute of Neurological Disorders and Stroke fellowship [T32 NINDS NS 007440] FX Grant sponsor: National Institute of Drug Abuse; Grant number: DA017960 (to B. D. W.); Grant sponsor: the Pennsylvania Department of Health (to B. D. W.); Grant sponsor: National Institute of Neurological Disorders and Stroke fellowship; Grant number: T32 NINDS NS 007440 (to K.L.A.). NR 50 TC 10 Z9 10 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2013 VL 521 IS 10 BP 2195 EP 2207 DI 10.1002/cne.23270 PG 13 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 133SO UT WOS:000318160400002 PM 23184811 ER PT J AU Dimitrov, EL Yanagawa, Y Usdin, TB AF Dimitrov, Eugene L. Yanagawa, Yuchio Usdin, Ted B. TI Forebrain GABAergic projections to locus coeruleus in mouse SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE noradrenergic; forebrain; brainstem; GAD67-GFP knockin; anatomical tract tracing ID CORTICOTROPIN-RELEASING-FACTOR; IN-SITU HYBRIDIZATION; VENTROLATERAL PREOPTIC NUCLEUS; LOWER BRAIN-STEM; AFFERENT-PROJECTIONS; HYPOTHALAMIC PROJECTIONS; NORADRENERGIC SYSTEM; EFFERENT CONNECTIONS; GALANINERGIC NEURONS; PROTEIN EXPRESSION AB The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in -aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity. J. Comp. Neurol. 521:23732397, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Dimitrov, Eugene L.; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Yanagawa, Yuchio] Gunma Univ, Grad Sch Med, Dept Genet & Behav Neurosci, Maebashi, Gumma 3718511, Japan. [Yanagawa, Yuchio] JST, CREST, Maebashi, Gumma 3718511, Japan. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, 35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU National Institute of Mental Health [ZIA MH002685-16] FX Grant sponsor: the Intramural Program of the National Institute of Mental Health; Grant number: ZIA MH002685-16. NR 74 TC 9 Z9 10 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2013 VL 521 IS 10 BP 2373 EP 2397 DI 10.1002/cne.23291 PG 25 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 133SO UT WOS:000318160400011 PM 23296594 ER PT J AU Pearce, S Nezich, CL Spinazzola, A AF Pearce, Sarah Nezich, Catherine Laura Spinazzola, Antonella TI Mitochondrial diseases: Translation matters SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE Mitochondrial encephalopathies; Translation; Ribosome; Assembly factors ID HEREDITARY OPTIC NEUROPATHY; SIDEROBLASTIC ANEMIA-MLASA; KEARNS-SAYRE SYNDROME; 12S RIBOSOMAL-RNA; NADH-QUINONE OXIDOREDUCTASE; NON-SYNDROMIC DEAFNESS; C-OXIDASE DEFICIENCY; STROKE-LIKE EPISODES; M-AAA PROTEASE; DIABETES-MELLITUS AB Mitochondrial diseases comprise a heterogeneous group of disorders characterized by compromised energy production. Since the early days of mitochondrial medical genetics, it has been known that these can be caused by defects in mitochondrial protein synthesis. However, only in recent years have we begun to develop a broader picture of the array of proteins required for mitochondrial translation. With this new knowledge has come the realization that there are many more neurological and other, diseases attributable to impaired mitochondrial translation than previously thought. Perturbation of any part of this intricate machinery, from the primary sequence of transfer or ribosomal RNAs, to the proteolytic processing of ribosomal proteins, can cause mitochondrial dysfunction and disease. In this review we discuss the current understanding of the mechanisms and factors involved in mammalian mitochondrial translation, and the diverse pathologies resulting when it malfunctions. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. (C) 2012 Published by Elsevier Inc. C1 [Pearce, Sarah; Nezich, Catherine Laura; Spinazzola, Antonella] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Nezich, Catherine Laura] NINDS, NIH, Bethesda, MD 20892 USA. RP Spinazzola, A (reprint author), MRC, Mitochondrial Biol Unit, Wellcome Trust MRC Bldg,Hills Rd, Cambridge CB2 0XY, England. EM as1@mrc-mbu.cam.ac.uk FU Medical Research Council, UK; European Union; National Institutes of Health, Bethesda, USA FX The authors are supported by the Medical Research Council, UK. A.S. is in receipt of a European Union Marie Curie Fellowship. C.L.N is supported by the National Institutes of Health, Bethesda, USA. NR 132 TC 15 Z9 15 U1 0 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUL PY 2013 VL 55 SI SI BP 1 EP 12 DI 10.1016/j.mcn.2012.08.013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 131MZ UT WOS:000317999100001 PM 22986124 ER PT J AU Maris, E Womelsdorf, T Desimone, R Fries, P AF Maris, Eric Womelsdorf, Thilo Desimone, Robert Fries, Pascal TI Rhythmic neuronal synchronization in visual cortex entails spatial phase relation diversity that is modulated by stimulation and attention SO NEUROIMAGE LA English DT Article DE Phase; Synchronization; Oscillation; Gamma; Alpha; Theta; Attention; Selection; Monkey; Visual ID FALSE DISCOVERY RATE; BAND SYNCHRONIZATION; OLFACTORY-BULB; GAMMA CYCLE; OSCILLATIONS; WAVES; DYNAMICS; V1; SEQUENCES; SELECTION AB Groups of neurons tend to synchronize in distinct frequency bands. Within a given frequency band, synchronization is defined as the consistency of phase relations between site pairs, over time. This synchronization has been investigated in numerous studies and has been found to be modulated by sensory stimulation or cognitive conditions. Here, we investigate local field potentials (LFPs) and multi-unit activity (MUA) recorded from area V4 of two monkeys performing a selective visual attention task. We show that phase relations, that are consistent over time, are typically diverse across site pairs. That is, across site pairs, mean phase relations differ substantially and this across-site-pair phase-relation diversity (SPHARED, for Spatial PHAse RElation Diversity) is highly reliable. Furthermore, we show that visual stimulation and selective attention can shift the pattern of phase relations across site pairs. These shifts are again diverse and this across-site-pair phase-relation-shift diversity (SPHARESD) is again highly reliable. We find SPHARED for LFP-LFP, LFP-MUA and MUA-MUA pairs, stimulus-induced SPHARESD for LFP-LFP and LFP-MUA pairs, and attention-induced SPHARESD for LFP-LFP pairs. SPHARESD is a highly interesting signal from the perspective of impact on downstream neuronal activity. We provide several pieces of evidence for such a role. (C) 2013 Elsevier Inc. All rights reserved. C1 [Maris, Eric; Womelsdorf, Thilo; Fries, Pascal] Radboud Univ Nijmegen, Donders Ctr Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. [Womelsdorf, Thilo] York Univ, Dept Biol, Fac Sci & Engn, N York, ON M3J 1P3, Canada. [Desimone, Robert] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Fries, Pascal] Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci, D-60528 Frankfurt, Germany. RP Maris, E (reprint author), Radboud Univ Nijmegen, Donders Ctr Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. EM e.maris@donders.ru.nl RI Fries, Pascal/E-3196-2010; Maris, Eric/E-4876-2012; OI Fries, Pascal/0000-0002-4270-1468; Maris, Eric/0000-0001-5166-1800; Womelsdorf, Thilo/0000-0001-6921-4187 FU BrainGain Smart Mix Programme of the Ministry of Economic Affairs; Ministry of Education, Culture and Science of the Netherlands; Human Frontier Science Program Organization [RGP0070/2003]; Volkswagen Foundation [I/79876]; European Science Foundation European Young Investigator Award Program; European Union [HEALTH-F2-2008-200728]; Netherlands Organization for Scientific Research [452-03-344, 016-071-079]; National Institute of Mental Health Intramural Research Program; National Institutes of Health [R01-EY017292] FX The authors gratefully acknowledge the support of the BrainGain Smart Mix Programme of the Ministry of Economic Affairs and the Ministry of Education, Culture and Science of the Netherlands. This work was supported by Human Frontier Science Program Organization grant RGP0070/2003 (P.F.), the Volkswagen Foundation grant I/79876 (P.F.), the European Science Foundation European Young Investigator Award Program (P.F.), the European Union (HEALTH-F2-2008-200728 to P.F.), the Netherlands Organization for Scientific Research grants 452-03-344 (P.F.) and 016-071-079 (T.W.), the National Institute of Mental Health Intramural Research Program (R.D.), and National Institutes of Health grant R01-EY017292 (R.D.). We thank J. H. Reynolds, A E. Rorie, A. F. Rossi, and R C. Saunders for help during the experiments. NR 40 TC 14 Z9 14 U1 1 U2 29 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 JUL 1 PY 2013 VL 74 BP 99 EP 116 DI 10.1016/j.neuroimage.2013.02.007 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 124CL UT WOS:000317441300012 PM 23416733 ER PT J AU Edwards, D Cortes, M Datta, A Minhas, P Wassermann, EM Bikson, M AF Edwards, Dylan Cortes, Mar Datta, Abhishek Minhas, Preet Wassermann, Eric M. Bikson, Marom TI Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: A basis for high-definition tDCS SO NEUROIMAGE LA English DT Article DE tDCS; TES; TMS; Targeted stimulation; Human head model; Electric fields ID HUMAN MOTOR CORTEX; RANDOM NOISE STIMULATION; MAGNETIC STIMULATION; CHRONIC STROKE; COIL DESIGN; CORTICAL STIMULATION; DC STIMULATION; EXCITABILITY; ACTIVATION; ELECTRODES AB Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 x 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 x 1 montage (4x cathode, surrounding a single central anode; montage radius similar to 3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 x 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 x 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 x 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 x 1-Ring montage for cortically targeted neuromodulation. (c) 2013 Published by Elsevier Inc. C1 [Edwards, Dylan; Cortes, Mar] Cornell Univ, Coll Med, Burke Med Res Inst, White Plains, NY 10605 USA. [Edwards, Dylan; Cortes, Mar] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA. [Edwards, Dylan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Edwards, Dylan] Univ Western Australia, Australian Neuromuscular Res Inst, Nedlands, WA 6009, Australia. [Edwards, Dylan] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia. [Datta, Abhishek; Minhas, Preet; Bikson, Marom] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Behav Neurol Unit, Bethesda, MD USA. RP Edwards, D (reprint author), Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA. EM dedwards@burke.org FU NICHD NIH HHS [R01 HD069776] NR 55 TC 83 Z9 83 U1 2 U2 39 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 JUL 1 PY 2013 VL 74 BP 266 EP 275 DI 10.1016/j.neuroimage.2013.01.042 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 124CL UT WOS:000317441300026 PM 23370061 ER PT J AU Lam, KH Ji, HF Zheng, F Ren, W Zhou, QF Shung, KK AF Lam, Kwok Ho Ji, Hong Fen Zheng, Fan Ren, Wei Zhou, Qifa Shung, K. Kirk TI Development of lead-free single-element ultrahigh frequency (170-320 MHz) ultrasonic transducers SO ULTRASONICS LA English DT Article DE UHF ultrasonic transducer; Lead-free; Composite sol-gel; Thick film ID MEDICAL IMAGING APPLICATIONS; FREE PIEZOELECTRIC CERAMICS; FERROELECTRIC THICK-FILMS; INTRAVASCULAR ULTRASOUND; 0-3 COMPOSITE; PZT; FABRICATION; DESIGN; SYSTEM; BIOMICROSCOPY AB This paper presents the design, fabrication and characterization of single-element ultrahigh frequency (UHF) ultrasonic transducers in which the center frequency ranged from 170 to 320 MHz. The center frequency of > 300 MHz is the highest value of lead-free ceramic ultrasonic transducers ever reported. With concern in the environmental pollution of lead-based materials, the transducer elements presented in this work were lead-free K0.5Na0.5NbO3/Bi0.5Na0.5TiO3 (KNN/BNT) composite thick films. All transducers were evaluated in a pulse-echo arrangement. The measured -6 dB bandwidth of the transducers ranged from 35% to 64%. With the optimized piezoelectric properties of the composite film, the insertion loss of the UHF transducers was measured and determined to range from -50 to -60 dB. In addition to the pulse-echo measurement, a 6 mu m tungsten wire phantom was also imaged with a 205 MHz transducer to demonstrate the imaging capability. The measured -6 dB axial and lateral resolutions were found to be 12 mu m and 50 mu m, respectively. The transducer performance presented in this work is shown to be better or comparable to previously reported results even though the frequency is much higher. (C) 2013 Elsevier B. V. All rights reserved. C1 [Lam, Kwok Ho; Zheng, Fan; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lam, Kwok Ho; Zheng, Fan; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Ji, Hong Fen; Ren, Wei] Xi An Jiao Tong Univ, Minist Educ, Key Lab, Elect Mat Res Lab, Xian 710049, Peoples R China. [Ji, Hong Fen; Ren, Wei] Xi An Jiao Tong Univ, Int Ctr Dielect Res, Xian 710049, Peoples R China. RP Lam, KH (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM kokokhlam@gmail.com RI Lam, K.H./B-7765-2014 OI Lam, K.H./0000-0003-1456-9049 FU NIH [P41-EB2182] FX This work was financially supported by NIH Grant P41-EB2182. NR 39 TC 10 Z9 10 U1 4 U2 76 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X J9 ULTRASONICS JI Ultrasonics PD JUL PY 2013 VL 53 IS 5 BP 1033 EP 1038 DI 10.1016/j.ultras.2013.01.012 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 120PW UT WOS:000317184400014 PM 23485349 ER PT J AU Camalier, CE Yi, M Yu, LR Hood, BL Conrads, KA Lee, YJ Lin, YM Garneys, LM Bouloux, GF Young, MR Veenstra, TD Stephens, RM Colburn, NH Conrads, TP Beck, GR AF Camalier, Corinne E. Yi, Ming Yu, Li-Rong Hood, Brian L. Conrads, Kelly A. Lee, Young Jae Lin, Yiming Garneys, Laura M. Bouloux, Gary F. Young, Matthew R. Veenstra, Timothy D. Stephens, Robert M. Colburn, Nancy H. Conrads, Thomas P. Beck, George R., Jr. TI An integrated understanding of the physiological response to elevated extracellular phosphate SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; INHIBITED 3T3 CELLS; FACTOR-I RECEPTOR; PROTEIN-KINASE PATHWAY; OSTEOBLAST-LIKE CELLS; INORGANIC-PHOSPHATE; C-FOS; BONE MINERALIZATION; DIETARY PHOSPHATE; VITAMIN-D AB Recent studies have suggested that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. We have used an integrated quantitative biology approach, combining transcriptomics and proteomics to define a multi-phase, extracellular phosphate-induced, signaling network in pre-osteoblasts as well as primary human and mouse mesenchymal stromal cells. We identified a rapid mitogenic response stimulated by elevated phosphate that results in the induction of immediate early genes including c-fos. The mechanism of activation requires FGF receptor signaling followed by stimulation of N-Ras and activation of AP-1 and serum response elements. A distinct long-term response also requires FGF receptor signaling and results in N-Ras activation and expression of genes and secretion of proteins involved in matrix regulation, calcification, and angiogenesis. The late response is synergistically enhanced by addition of FGF23 peptide. The intermediate phase results in increased oxidative phosphorylation and ATP production and is necessary for the late response providing a functional link between the phases. Collectively, the results define elevated phosphate, as a mitogen and define specific mechanisms by which phosphate stimulates proliferation and matrix regulation. Our approach provides a comprehensive understanding of the cellular response to elevated extracellular phosphate, functionally connecting temporally coordinated signaling, transcriptional, and metabolic events with changes in long-term cell behavior. J. Cell. Physiol. 228: 15361550, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Camalier, Corinne E.; Lee, Young Jae; Lin, Yiming; Garneys, Laura M.; Beck, George R., Jr.] Emory Univ, Div Endocrinol, Dept Med, Atlanta, GA 30322 USA. [Yi, Ming; Stephens, Robert M.] SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD USA. [Yu, Li-Rong; Veenstra, Timothy D.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD USA. [Hood, Brian L.; Conrads, Thomas P.] Inova Hlth Syst, Gynecol Canc Ctr Excellence, Womens Hlth Integrated Res Ctr, Annandale, VA USA. [Conrads, Kelly A.; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Lee, Young Jae] Jeju Natl Univ, Coll Vet Med, Cheju, South Korea. [Bouloux, Gary F.] Emory Univ, Dept Surg, Div Oral & Maxillofacial Surg, Atlanta, GA 30322 USA. RP Beck, GR (reprint author), Emory Univ, Div Endocrinol Metab & Lipids, Dept Med, 101 Woodruff Circle,Room 1026, Atlanta, GA 30322 USA. EM george.beck@emory.edu FU National Cancer Institute [CA84573, CA136059, CA136716]; Emory University-URC1433; Jeju National University, Korea; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This project has been funded by grants from the National Cancer Institute CA84573, CA136059, CA136716, and Emory University-URC1433 (CEC, KAC, YJL, YL, LMG, and GRB Jr.). YJL is also supported by a research grant from Jeju National University, Korea (2010). 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 NO1-CO-12400. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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 United States Government. NR 118 TC 23 Z9 23 U1 1 U2 60 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 2013 VL 228 IS 7 BP 1536 EP 1550 DI 10.1002/jcp.24312 PG 15 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 113PX UT WOS:000316681100020 PM 23280476 ER PT J AU Rasmussen, B Allen, S Rasmussen, ZA Bajwa, R AF Rasmussen, Bruce Allen, Sheldon Rasmussen, Zeba A. Bajwa, Rashid TI Learning from disasters to save lives every day in Pakistan SO LANCET LA English DT Editorial Material ID FUTURE IMPLICATIONS; NEWBORN SURVIVAL; DECADE; FLOODS C1 [Rasmussen, Zeba A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bajwa, Rashid] Natl Rural Support Programme, Islamabad, Pakistan. EM rasmussenbruce@hotmail.com NR 16 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUN 29 PY 2013 VL 381 IS 9885 BP 2232 EP 2234 DI 10.1016/S0140-6736(13)60652-2 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 173SU UT WOS:000321100300008 PM 23684253 ER PT J AU Berezhkovskii, AM Shvartsman, SY AF Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI Kinetics of receptor occupancy during morphogen gradient formation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NERVOUS-SYSTEM; DIFFUSION AB During embryogenesis, sheets of cells are patterned by concentration profiles of morphogens, molecules that act as dose-dependent regulators of gene expression and cell differentiation. Concentration profiles of morphogens can be formed by a source-sink mechanism, whereby an extracellular protein is secreted from a localized source, diffuses through the tissue and binds to cell surface receptors. A morphogen molecule bound to its receptor can either dissociate or be internalized by the cell. The effects of morphogens on cells depend on the occupancy of surface receptors, which in turn depends on morphogen concentration. In the simplest case, the local concentrations of the morphogen and morphogen-receptor complexes monotonically increase with time from zero to their steady-state values. Here, we derive analytical expressions for the time scales which characterize the formation of the steady-state concentrations of both the diffusible morphogen molecules and orphogen-receptor complexes at a given point in the patterned tissue. (C) 2013 AIP Publishing LLC. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Lewis Singler Inst Integrat Genom, Princeton, NJ 08544 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU NIH, Center for Information Technology; National Science Foundation [DMS-1119714, DMS-0718604] FX A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. S.Y.S. acknowledges partial support by the National Science Foundation [grants DMS-1119714 and DMS-0718604]. The authors thank Bomyi Lim (Princeton) for preparing the figure used in this paper. NR 28 TC 4 Z9 4 U1 1 U2 10 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 28 PY 2013 VL 138 IS 24 AR 244105 DI 10.1063/1.4811654 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 174IF UT WOS:000321148200006 ER PT J AU Mizurini, DM Francischetti, IMB Monteiro, RQ AF Mizurini, Daniella M. Francischetti, Ivo M. B. Monteiro, Robson Q. TI Aegyptin inhibits collagen-induced coagulation activation in vitro and thromboembolism in vivo SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Aegyptin; Mosquito saliva; Collagen; Platelets; Blood coagulation; Pulmonary thromboembolism ID PLATELET GLYCOPROTEIN-VI; VON-WILLEBRAND-FACTOR; THROMBUS FORMATION; SALIVARY-GLAND; FACTOR-XII; HEMOSTASIS; ANTICOAGULANTS; TARGETS; BINDING; MODEL AB Aegyptin is a mosquito salivary gland protein and potent inhibitor of platelet aggregation. Aegyptin binds to the von Willebrand factor-binding site on collagen and prevents its interaction with platelets. Because collagen also induces plasma clotting by activation of factor XII, we evaluated the effects of aegyptin on collagen-induced coagulation activation and how it interferes with thrombosis in three different in vivo models. Our results demonstrate that aegyptin abolishes collagen-induced clot formation and thrombin generation in platelet-free plasma. Aegyptin has no antithrombotic activity in the arteriovenous shunt model (collagen-independent) but it prevents laser-induced collagen-mediated thrombus formation in rats. Furthermore, aegyptin protects mice from collagen and epinephrine-induced thromboembolism. Therefore, aegyptin has a dual antithrombotic mechanism: inhibition of platelet-collagen interaction and collagen's pro-coagulant activity. This is the first description of a collagen-binding protein that also inhibits collagen-mediated coagulant activity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mizurini, Daniella M.; Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Med Biochem, BR-21941 Rio De Janeiro, RJ, Brazil. [Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Monteiro, RQ (reprint author), Inst Bioquim Med CCS UFRJ, Ave Carlos Chagas Filho 373,Cidade Univ, BR-21941590 Rio De Janeiro, Brazil. EM robsonqm@bioqmed.ufrj.br RI Monteiro, Robson/B-8007-2014 FU Brazilian agency: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Brazilian agency: Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This research was supported by the following Brazilian agencies: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 24 TC 7 Z9 8 U1 1 U2 13 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 JUN 28 PY 2013 VL 436 IS 2 BP 235 EP 239 DI 10.1016/j.bbrc.2013.05.082 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 180NG UT WOS:000321601300022 PM 23726920 ER PT J AU Wyatt, MK Tsai, JY Mishra, S Campos, M Jaworski, C Fariss, RN Bernstein, SL Wistow, G AF Wyatt, M. Keith Tsai, Jen-Yue Mishra, Sanghamitra Campos, Maria Jaworski, Cynthia Fariss, Robert N. Bernstein, Steven L. Wistow, Graeme TI Interaction of Complement Factor H and Fibulin3 in Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; MALATTIA LEVENTINESE; OXIDATIVE STRESS; TISSUE INHIBITOR; VARIANT; DRUSEN; RISK; POLYMORPHISM; GENE; SUSCEPTIBILITY AB Age-related macular degeneration (AMD) is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen) in Bruch's membrane basal to the retinal pigment epithelium (RPE). A sequence variant (Y402H) in short consensus repeat domain 7 (SCR7) of complement factor H (CFH) is associated with risk for "dry'' AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H) screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3), which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H). This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD. C1 [Wyatt, M. Keith; Mishra, Sanghamitra; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. [Tsai, Jen-Yue; Campos, Maria; Fariss, Robert N.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Jaworski, Cynthia] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Bernstein, Steven L.] Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. [Bernstein, Steven L.] Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU NEI Intramural Research Program FX This work was supported by the NEI Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 15 Z9 15 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 28 PY 2013 VL 8 IS 6 AR e68088 DI 10.1371/journal.pone.0068088 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IH UT WOS:000321148400162 PM 23840815 ER PT J AU Koulaouzidis, A Rondonotti, E Karargyris, A AF Koulaouzidis, Anastasios Rondonotti, Emanuele Karargyris, Alexandros TI Small-bowel capsule endoscopy: A ten-point contemporary review SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Capsule endoscopy; Calprotectin; Meta-analysis; Review; Preparation; Reading software; Complication; Indications ID DOUBLE-BALLOON ENTEROSCOPY; SUSPECTED BLOOD INDICATOR; COMPUTED VIRTUAL CHROMOENDOSCOPY; FAMILIAL ADENOMATOUS POLYPOSIS; DIAGNOSTIC YIELD; CROHNS-DISEASE; TRACHEAL ASPIRATION; FECAL CALPROTECTIN; COLOR ENHANCEMENT; PILLCAM SB AB The introduction of capsule endoscopy (CE) in clinical practice increased the interest for the study of the small-bowel. Consequently, in about 10 years, an impressive quantity of literature on indications, diagnostic yield (DY), safety profile and technical evolution of CE has been published as well as several reviews. At present time, there are 5 small-bowel capsule enteroscopy (SBCE) models in the worldwide market. Head-to-head trials have showed in the great majority of studies comparable results in terms of DY, image quality and completion rate. CE meta-analyses formed the basis of national/international guidelines; these guidelines place CE in a prime position for the diagnostic workup of patients with obscure gastrointestinal bleeding, known and/or suspected Crohn's disease and possible small-bowel neoplasia. A 2-L polyethylene glycol-based purge, administered the day before the procedure, is the most widely practiced preparation regimen. Whether this regimen can be further improved (i.e., by further decreasing its volume, changing the timing of administration, coupling it with prokinetics and/or other factors) or if it can really affect the DY, is still under discussion. Faecal calprotectin has been used in SBCE studies in two settings: in patients taking nonsteroidal anti-inflammatory drugs, to evaluate the type and extent of mucosal damage and, more importantly from a clinical point of view, in patients with known or suspected Crohn's disease for assessment of inflammation activity. Although there is still a lot of debate around the exact reasons of SBCE poor performance in various small-bowel segments, it is worth to remember that the capsule progress is non-steerable, hence more rapid in the proximal than in lower segments of the small-bowel. Capsule aspiration, a relatively unexpected complication, has been reported with increasing frequency. This is probably related with the increase in the mean age of patients undergoing CE. CE video review is a time-consuming procedure. Therefore, several attempts have been made to develop technical software features, in order to make CE video analysis easier and shorter (without jeopardizing its accuracy). Suspected Blood Indicator, QuickView and Fujinon Intelligent Chromo Endoscopy are some of the software tools that have been checked in various clinical studies to date. (C) 2013 Baishideng. All rights reserved. C1 [Koulaouzidis, Anastasios] Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Edinburgh EH16 4SA, Midlothian, Scotland. [Rondonotti, Emanuele] Osped Valduce, Gastroenterol Unit, I-22100 Como, Italy. [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20814 USA. RP Koulaouzidis, A (reprint author), Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Endoscopy Unit, 51 Little France Crescent,Old Dalkeith Rd, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com NR 144 TC 58 Z9 60 U1 3 U2 14 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUN 28 PY 2013 VL 19 IS 24 BP 3726 EP 3746 DI 10.3748/wjg.v19.i24.3726 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 173XG UT WOS:000321115100003 PM 23840112 ER PT J AU Friis, S Sales, KU Godiksen, S Peters, DE Lin, CY Vogel, LK Bugge, TH AF Friis, Stine Sales, Katiuchia Uzzun Godiksen, Sine Peters, Diane E. Lin, Chen-Yong Vogel, Lotte K. Bugge, Thomas H. TI A Matriptase-Prostasin Reciprocal Zymogen Activation Complex with Unique Features PROSTASIN AS A NON-ENZYMATIC CO-FACTOR FOR MATRIPTASE ACTIVATION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL SODIUM-CHANNEL; EPIDERMAL BARRIER FUNCTION; SERINE-PROTEASE INHIBITOR; HAIR FOLLICLE DEVELOPMENT; NEURAL-TUBE CLOSURE; PLASMINOGEN ACTIVATION; CELL-SURFACE; PLACENTAL DEVELOPMENT; MONOCLONAL-ANTIBODY; PROTEOLYTIC CASCADE AB Matriptase and prostasin are part of a cell surface proteolytic pathway critical for epithelial development and homeostasis. Here we have used a reconstituted cell-based system and transgenic mice to investigate the mechanistic interrelationship between the two proteases. We show that matriptase and prostasin form a reciprocal zymogen activation complex with unique features. Prostasin serves as a critical co-factor for matriptase activation. Unexpectedly, however, prostasin-induced matriptase activation requires neither prostasin zymogen conversion nor prostasin catalytic activity. Prostasin zymogen conversion to active prostasin is dependent on matriptase but does not require matriptase zymogen conversion. Consistent with these findings, wild type prostasin, activation cleavage site-mutated prostasin, and catalytically inactive prostasin all were biologically active in vivo when overexpressed in the epidermis of transgenic mice, giving rise to a severe skin phenotype. Our finding of non-enzymatic stimulation of matriptase activation by prostasin and activation of prostasin by the matriptase zymogen provides a tentative mechanistic explanation for several hitherto unaccounted for genetic and biochemical observations regarding these two membrane-anchored serine proteases and their downstream targets. C1 [Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Sales, Katiuchia Uzzun] NIDCR, Clin Res Core, NIH, Bethesda, MD 20892 USA. [Friis, Stine; Godiksen, Sine; Vogel, Lotte K.] Univ Copenhagen, Fac Hlth Sci, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Godiksen, Sine] Univ Copenhagen, Fac Sci, Dept Biol, DK-2200 Copenhagen, Denmark. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Bugge, TH (reprint author), NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU National Institutes of Health, NIDCR, Intramural Research Program; Harboe Foundation; Lundbeck Foundation; Foundation of 17.12.1981; Augustinus Foundation; Kobmand Kristian Kjaer og Hustrus Foundation; Kjaer-Foundation; Dagmar Marshalls Foundation; Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation; Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation; Fabrikant Einar Willumsens Mindelegat FX This work was supported, in whole or in part, by the National Institutes of Health, NIDCR, Intramural Research Program (to T. H. B). This work was also supported by the Harboe Foundation, the Lundbeck Foundation, and the Foundation of 17.12.1981 (to S. F.) and the Augustinus Foundation, the Kobmand Kristian Kjaer og Hustrus Foundation, the Kjaer-Foundation, the Dagmar Marshalls Foundation, the Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation, the Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation, and Fabrikant Einar Willumsens Mindelegat (to S.G.). NR 51 TC 28 Z9 28 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 JUN 28 PY 2013 VL 288 IS 26 BP 19028 EP 19039 DI 10.1074/jbc.M113.469932 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 176WB UT WOS:000321335800038 PM 23673661 ER PT J AU He, XM Chatterjee, R John, S Bravo, H Sathyanarayana, BK Biddie, SC FitzGerald, PC Stamatoyannopoulos, JA Hager, GL Vinson, C AF He, Ximiao Chatterjee, Raghunath John, Sam Bravo, Hector Sathyanarayana, B. K. Biddie, Simon C. FitzGerald, Peter C. Stamatoyannopoulos, John A. Hager, Gordon L. Vinson, Charles TI Contribution of nucleosome binding preferences and co-occurring DNA sequences to transcription factor binding SO BMC GENOMICS LA English DT Article DE TFBS; Nucleosome; GR; c-Jun ID GLUCOCORTICOID-RECEPTOR-BINDING; UCSC GENOME BROWSER; CHIP-SEQ; CHROMATIN ACCESSIBILITY; GENE-REGULATION; DROSOPHILA; OCCUPANCY; PROMOTERS; SITES; ORGANIZATION AB Background: Chromatin plays a critical role in regulating transcription factors (TFs) binding to their canonical transcription factor binding sites (TFBS). Recent studies in vertebrates show that many TFs preferentially bind to genomic regions that are well bound by nucleosomes in vitro. Co-occurring secondary motifs sometimes correlated with functional TFBS. Results: We used a logistic regression to evaluate how well the propensity for nucleosome binding and co-occurrence of a secondary motif identify which canonical motifs are bound in vivo. We used ChIP-seq data for three transcription factors binding to their canonical motifs: c-Jun binding the AP-1 motif (TGA(C)/(G)TCA), GR (glucocorticoid receptor) binding the GR motif (G-ACA-(T)/(C)GT-C), and Hoxa2 (homeobox a2) binding the Pbx (Pre-B-cell leukemia homeobox) motif (TGATTGAT). For all canonical TFBS in the mouse genome, we calculated intrinsic nucleosome occupancy scores (INOS) for its surrounding 150-bps DNA and examined the relationship with in vivo TF binding. In mouse mammary 3134 cells, c-Jun and GR proteins preferentially bound regions calculated to be well-bound by nucleosomes in vitro with the canonical AP-1 and GR motifs themselves contributing to the high INOS. Functional GR motifs are enriched for AP-1 motifs if they are within a nucleosome-sized 150-bps region. GR and Hoxa2 also bind motifs with low INOS, perhaps indicating a different mechanism of action. Conclusion: Our analysis quantified the contribution of INOS and co-occurring sequence to the identification of functional canonical motifs in the genome. This analysis revealed an inherent competition between some TFs and nucleosomes for binding canonical TFBS. GR and c-Jun cooperate if they are within 150-bps. Binding of Hoxa2 and a fraction of GR to motifs with low INOS values suggesting they are not in competition with nucleosomes and may function using different mechanisms. C1 [He, Ximiao; Chatterjee, Raghunath; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [John, Sam; Biddie, Simon C.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Sathyanarayana, B. K.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, Genet Branch, NIH, Bethesda, MD 20892 USA. [Bravo, Hector] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [John, Sam; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Room 3128,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM Vinsonc@mail.nih.gov OI Biddie, Simon/0000-0002-8253-0253; Corrada Bravo, Hector/0000-0002-1255-4444 NR 50 TC 9 Z9 9 U1 0 U2 6 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 JUN 28 PY 2013 VL 14 AR 428 DI 10.1186/1471-2164-14-428 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 177QV UT WOS:000321391200001 PM 23805837 ER PT J AU Jones, JC Freeman, GJ AF Jones, Jennifer C. Freeman, Gordon J. TI Costimulatory Genes: Hotspots of Conflict between Host Defense and Autoimmunity SO IMMUNITY LA English DT Editorial Material C1 [Jones, Jennifer C.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM Gordon_Freeman@dfci.harvard.edu RI Jones, Jennifer/C-8691-2015 OI Jones, Jennifer/0000-0002-9488-7719 FU NIAID NIH HHS [R01 AI089955, P01 AI056299, P01 AI080192, U19 AI082630] NR 10 TC 2 Z9 2 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 27 PY 2013 VL 38 IS 6 BP 1083 EP 1085 DI 10.1016/j.immuni.2013.06.008 PG 4 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500002 PM 23809156 ER PT J AU Tai, X Erman, B Alag, A Mu, J Kimura, M Katz, G Guinter, T McCaughtry, T Etzensperger, R Feigenbaum, L Singer, DS Singer, A AF Tai, Xuguang Erman, Batu Alag, Amala Mu, Jie Kimura, Motoko Katz, Gil Guinter, Terry McCaughtry, Tom Etzensperger, Ruth Feigenbaum, Lionel Singer, Dinah S. Singer, Alfred TI Foxp3 Transcription Factor Is Proapoptotic and Lethal to Developing Regulatory T Cells unless Counterbalanced by Cytokine Survival Signals SO IMMUNITY LA English DT Article ID NEGATIVE SELECTION; LINEAGE FATE; GENE; SPECIFICITY; APOPTOSIS; THYMUS; SELF; BIM; DIFFERENTIATION; AUTOIMMUNITY AB Immune tolerance requires regulatory T (Treg) cells to prevent autoimmune disease, with the transcription factor Foxp3 functioning as the critical regulator of Treg cell development and function. We report here that Foxp3 was lethal to developing Treg cells in the thymus because it induced a unique proapoptotic protein signature (Puma(++) p-Bim(++) p-JNK(++) DUSP6(-)) and repressed expression of prosurvival Bcl-2 molecules. However, Foxp3 lethality was prevented by common gamma chain (gc)-dependent cytokine signals that were present in the thymus in limiting amounts sufficient to support only similar to 1 million Treg cells. Consequently, most newly arising Treg cells in the thymus were deprived of this signal and underwent Foxp3-induced death, with Foxp3(+)CD25(-) Treg precursor cells being the most susceptible. Thus, we identify Foxp3 as a proapoptotic protein that requires developing Treg cells to compete with one another for limiting amounts of gamma c-dependent survival signals in the thymus. C1 [Tai, Xuguang; Alag, Amala; Mu, Jie; Kimura, Motoko; Katz, Gil; Guinter, Terry; McCaughtry, Tom; Etzensperger, Ruth; Singer, Dinah S.; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Erman, Batu] Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. [Feigenbaum, Lionel] SAIC Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are grateful to P. Henkart for editorial assistance; J. Bluestone, V. Kuchroo, A. Strasser, and M. A. Farrar for mice; and R. Hodes, J.-H. Park, and N. Taylor for reading the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 44 TC 55 Z9 57 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 27 PY 2013 VL 38 IS 6 BP 1116 EP 1128 DI 10.1016/j.immuni.2013.02.022 PG 13 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500008 PM 23746651 ER PT J AU Chappert, P Bouladoux, N Naik, S Schwartz, RH AF Chappert, Pascal Bouladoux, Nicolas Naik, Shruti Schwartz, Ronald H. TI Specific Gut Commensal Flora Locally Alters T Cell Tuning to Endogenous Ligands SO IMMUNITY LA English DT Article ID SEGMENTED FILAMENTOUS BACTERIA; ADAPTIVE TOLERANCE; IMMUNE-SYSTEM; INTESTINAL MICROBIOTA; ACTIVATION THRESHOLD; VIRAL-INFECTION; IN-VIVO; RESPONSES; INDUCTION; CD4(+) AB Differences in gut commensal flora can dramatically influence autoimmune responses, but the mechanisms behind this are still unclear. We report, in a Th1-cell-driven murine model of autoimmune arthritis, that specific gut commensals, such as segmented filamentous bacteria, have the ability to modulate the activation threshold of self-reactive T cells. In the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhanced the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen. Together with subtle differences in early lineage differentiation, this ultimately led to an enhanced recruitment of pathogenic Th1 cells and the development of a more severe form of autoimmune arthritis. These findings define a key role for the gut commensal flora in sustaining ongoing autoimmune responses through the local fine tuning of T-cell-receptor-proximal activation events in autoreactive T cells. C1 [Chappert, Pascal; Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Naik, Shruti] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Chappert, P (reprint author), Univ Paris 05, Sorbonne Paris Cite, INSERM U1013, F-75743 Paris 15, France. EM pascal.chappert@inserm.fr OI chappert, pascal/0000-0002-9799-4608 FU Intramural Research Program of the NIAID at the National Institutes of Health, Bethesda, MD, USA FX We thank N.J. Singh for helpful discussions and comments on the design of the experiments; N.J. Singh, Y. Belkaid, J. Davoust, and D.A. Gross for helpful comments on the manuscript; N. Shulzhenko and A. Morgun for help on the design of the antibiotic-treatment experiments and the analysis of SFB colonization; E.J. Chuang for technical assistance; and D. Trageser-celser, C. Acevedo, and the National Institutes of Allergy and Infectious Diseases (NIAID) germ-free facility for maintaining the mice used in these experiments and technical assistance. This work was supported by the Intramural Research Program of the NIAID at the National Institutes of Health, Bethesda, MD, USA. NR 47 TC 19 Z9 20 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 27 PY 2013 VL 38 IS 6 BP 1198 EP 1210 DI 10.1016/j.immuni.2013.06.005 PG 13 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500015 PM 23809163 ER PT J AU Sonda, N Simonato, F Peranzoni, E Cali, B Bortoluzzi, S Bisognin, A Wang, E Marincola, FM Naldini, L Gentner, B Trautwein, C Sackett, SD Zanovello, P Molon, B Bronte, V AF Sonda, Nada Simonato, Francesca Peranzoni, Elisa Cali, Bianca Bortoluzzi, Stefania Bisognin, Andrea Wang, Ena Marincola, Francesco M. Naldini, Luigi Gentner, Bernhard Trautwein, Christian Sackett, Sara Dutton Zanovello, Paola Molon, Barbara Bronte, Vincenzo TI miR-142-3p Prevents Macrophage Differentiation during Cancer-Induced Myelopoiesis SO IMMUNITY LA English DT Article ID COLONY-STIMULATING FACTOR; DENDRITIC CELL-DIFFERENTIATION; SUPPRESSOR-CELLS; PANCREATIC-CANCER; T-CELLS; GM-CSF; MYELOID CELLS; MICRORNAS; BETA; PROGRESSION AB Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumorreleased cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP* isoform of C/EBP beta transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBP beta LAP* by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor-specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy. C1 [Sonda, Nada; Simonato, Francesca; Cali, Bianca; Zanovello, Paola] Univ Padua, Dept Surg Oncol & Gastroenterol, Oncol & Immunol Sect, I-35128 Padua, Italy. [Sonda, Nada; Peranzoni, Elisa; Zanovello, Paola; Molon, Barbara] IRCCS, Ist Oncol Veneto, I-35128 Padua, Italy. [Molon, Barbara] Venetian Inst Mol Med, I-35129 Padua, Italy. [Bortoluzzi, Stefania; Bisognin, Andrea] Univ Padua, Dept Biol, I-35121 Padua, Italy. [Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Naldini, Luigi; Gentner, Bernhard] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Naldini, Luigi; Gentner, Bernhard] Ist Sci San Raffaele, Div Regenerat Med Gene Therapy & Stem Cells, I-20132 Milan, Italy. [Naldini, Luigi; Gentner, Bernhard] Univ Vita Salute San Raffaele, Sch Med, I-20132 Milan, Italy. [Trautwein, Christian; Sackett, Sara Dutton] RWTH Univ Hosp, Dept Med 3, D-52074 Aachen, Germany. [Bronte, Vincenzo] Univ Verona, Verona Univ Hosp, I-37134 Verona, Italy. [Bronte, Vincenzo] Univ Verona, Dept Pathol, Immunol Sect, I-37134 Verona, Italy. RP Bronte, V (reprint author), Univ Verona, Verona Univ Hosp, I-37134 Verona, Italy. EM vincenzo.bronte@univr.it RI Bronte, Vincenzo/K-7902-2016; Bisognin, Andrea/J-3619-2013; OI Bronte, Vincenzo/0000-0002-3741-5141; Bisognin, Andrea/0000-0002-9114-1508; Bortoluzzi, Stefania/0000-0001-8240-3070; Gentner, Bernhard/0000-0001-6024-4718 FU Italian Ministry of Education, University and Research [RBAP11T3WB_003, 2009NREAT2_003]; Italian Association for Cancer Research (AIRC) [IG10400, 12182, AGIMM 100005, 6599]; AIRC-Cariparo; BMBF [01KU1214B]; OBIHEP [360365]; Fondazione Telethon FX We thank Maurizio Buggio, Serena Zilio, and Stefano Ugel for help with the in vivo experiments and Andrea Predonzani for the generation of plasmids. This work was supported by grants from the Italian Ministry of Education, University and Research (FIRB project RBAP11T3WB_003 and MIUR project 2009NREAT2_003), Italian Association for Cancer Research (AIRC, Grants IG10400, 12182, AGIMM 100005, and 6599), and AIRC-Cariparo, Regional Grant 2008. The work of C.T. was supported by the BMBF 01KU1214B (OBIHEP 360365). NR 56 TC 39 Z9 40 U1 3 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 27 PY 2013 VL 38 IS 6 BP 1236 EP 1249 DI 10.1016/j.immuni.2013.06.004 PG 14 WC Immunology SC Immunology GA AA2TR UT WOS:000330947500018 PM 23809164 ER PT J AU Nee, R Jindal, RM Little, D Ramsey-Goldman, R Agodoa, L Hurst, FP Abbott, KC AF Nee, Robert Jindal, Rahul M. Little, Dustin Ramsey-Goldman, Rosalind Agodoa, Lawrence Hurst, Frank P. Abbott, Kevin C. TI Racial Differences and Income Disparities Are Associated With Poor Outcomes in Kidney Transplant Recipients With Lupus Nephritis SO TRANSPLANTATION LA English DT Article DE USRDS; Lupus nephritis; Median household income ID 3 ETHNIC-GROUPS; RENAL-TRANSPLANTATION; SOCIOECONOMIC-FACTORS; ERYTHEMATOSUS; SURVIVAL; RACE/ETHNICITY; FEATURES; RACE AB Background. An analysis of income and racial/ethnic disparities on renal transplant outcomes in recipients with lupus nephritis (LN) has not been reported. We analyzed the United States Renal Data System database to assess the impact of these disparities on graft loss and death in the LN and non-LN cohorts. Methods. We identified 4214 patients with LN as the cause of end-stage renal disease in a retrospective cohort of 150,118 patients first transplanted from January 1, 1995 to July 1, 2006. We merged data on median household income from the United States Census based on the ZIP code. Results. In multivariate Cox regression analyses, African-Americans (AF) recipients with LN (vs. non-AF) had an increased risk of graft loss (adjusted hazard ratio [AHR], 1.39; 95% confidence interval [CI], 1.21-1.60) and death (AHR, 1.33; 95% CI, 1.09-1.63). Furthermore, there were significant associations of lower-income quintiles with higher risk for graft loss and death among AF with LN. In comparison, among non-AF recipients with LN, income levels did not predict risk for transplant outcomes. The racial disparity for both graft loss and death outcomes among AF with LN was greater than among AF without LN (AHR, 1.32; 95% CI, 1.29-1.36 for graft loss and AHR, 1.02; 95% CI, 0.99-1.05 for death). Conclusions. AF kidney transplant recipients with LN were at increased risk for graft loss and death compared with non-AF. Income levels were associated with the risk of graft loss and death in AF but not in non-AF recipients with LN. C1 [Nee, Robert; Little, Dustin; Hurst, Frank P.; Abbott, Kevin C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Jindal, Rahul M.] Walter Reed Natl Mil Med Ctr, Dept Surg, Bethesda, MD 20889 USA. [Jindal, Rahul M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD 20892 USA. RP Jindal, RM (reprint author), Walter Reed Natl Mil Med Ctr, Dept Transplantat, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM jindalr@msn.com OI Abbott, Kevin/0000-0003-2111-7112 NR 30 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2013 VL 95 IS 12 BP 1471 EP 1478 DI 10.1097/TP.0b013e318292520e PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299EF UT WOS:000330377600012 PM 23680929 ER PT J AU Gea-Banacloche, JC AF Gea-Banacloche, Juan C. TI Antiviral cell therapy: is this the future? SO BLOOD LA English DT Editorial Material ID T-LYMPHOCYTES; DISEASE C1 NCI, Bethesda, MD 20892 USA. RP Gea-Banacloche, JC (reprint author), NCI, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 3 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 27 PY 2013 VL 121 IS 26 BP 5108 EP 5109 DI 10.1182/blood-2013-05-500082 PG 4 WC Hematology SC Hematology GA 184OJ UT WOS:000321900700002 PM 23813935 ER PT J AU Morellato-Castillo, L Acharya, P Combes, O Michiels, J Descours, A Ramos, OHP Yang, YP Vanham, G Alien, KK Kwong, PD Martin, L Kessler, P AF Morellato-Castillo, Laurence Acharya, Priyamvada Combes, Olivier Michiels, Johan Descours, Anne Ramos, Oscar H. P. Yang, Yongping Vanham, Guido Alien, Kevin K. Kwong, Peter D. Martin, Loic Kessler, Pascal TI Interfacial Cavity Filling To Optimize CD4-Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; CD4-BOUND CONFORMATION; ENTRY INHIBITORS; CD4 RECEPTOR; ANTIBODY; BINDING; DESIGN; CORE; PROTEINS AB Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 nonnatural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure. with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity. C1 [Morellato-Castillo, Laurence; Combes, Olivier; Descours, Anne; Ramos, Oscar H. P.; Martin, Loic; Kessler, Pascal] CEA, IBiTecS, Serv Ingn Mol Prot, F-91191 Gif Sur Yvette, France. [Acharya, Priyamvada; Yang, Yongping; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Michiels, Johan; Vanham, Guido; Alien, Kevin K.] Inst Trop Med, Dept Biomed Sci, Virol Unit, B-2000 Antwerp, Belgium. RP Martin, L (reprint author), CEA, IBiTecS, Serv Ingn Mol Prot, F-91191 Gif Sur Yvette, France. EM loic.martin@cea.fr; pascal.kessler@cea.fr FU sixth European Union Framework Program Microbicide Project (EMPRO); Intramural AIDS Targeted Anti-Retroviral Program (IATAP), NIH; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Seventh Framework Program (FP7) [242135]; EU program EVA/MRC [QLKZ-CT-1999-00609, GP828102]; UK Medical Research Council; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This work was supported by the sixth European Union Framework Program Microbicide Project (EMPRO), by the Intramural AIDS Targeted Anti-Retroviral Program (IATAP), NIH, by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Seventh Framework Program (FP7/2007-2013) under grant agreement no. 242135 (CHAARM). L120.3 Ab was provided by the Centralised Facility for AIDS Reagents supported by EU program EVA/MRC (contract QLKZ-CT-1999-00609 and GP828102) and the UK Medical Research Council. We also thank Novartis Vaccine for providing gp120SF162. Synchrotron: Use of sector 22 (South-east Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract W-31-109-Eng-38. NR 47 TC 10 Z9 10 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 27 PY 2013 VL 56 IS 12 BP 5033 EP 5047 DI 10.1021/jm4002988 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 175NJ UT WOS:000321237100017 PM 23710622 ER PT J AU Chen, JW Feng, G Song, Y Wardenburg, JB Lin, S Inoshima, I Otto, M Wunderink, RG AF Chen, Jiwang Feng, Gang Song, Yang Wardenburg, Juliane B. Lin, Simon Inoshima, Ichiro Otto, Michael Wunderink, Richard G. TI Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model SO PLOS ONE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; ILLUMINA MICROARRAY; DISEASE-ONTOLOGY; ANTIBIOTICS; INFECTION; SEPSIS; PATHOGENESIS; MANAGEMENT; CELLS AB Background: Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown. Methods: A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNF alpha, IL1 beta, Interferon-gamma and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses. Results: LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1 beta, Interferon-gamma and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy. Conclusion: LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level. C1 [Chen, Jiwang; Wunderink, Richard G.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Chen, Jiwang] Univ Illinois, Sect Pulm Crit Care Med Allergy & Sleep, Chicago, IL USA. [Feng, Gang; Lin, Simon] Northwestern Univ, Biomed Informat Ctr, Chicago, IL 60611 USA. [Song, Yang] Illinois State Univ, Microbiol Grp, Sch Biol Sci, Normal, IL 61761 USA. [Wardenburg, Juliane B.; Inoshima, Ichiro] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Lin, Simon] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Otto, Michael] NIAID, Bethesda, MD 20892 USA. RP Chen, JW (reprint author), Northwestern Univ, Dept Med, Chicago, IL 60611 USA. EM chenjw@uic.edu RI song, yang/P-1033-2015; OI Otto, Michael/0000-0002-2222-4115; Wunderink, Richard/0000-0002-8527-4195 FU Pfizer [WS1826185]; National Center for Advancing Translational Sciences Grant [8UL1TR000150]; NCI Cancer Center Support Grant [NCI CA060553]; Intramural Research Program of the NIAID FX This study was supported by Pfizer ASPIRE Award, Pfizer Investigator-Initiated Grant (WS1826185, to JC), the National Center for Advancing Translational Sciences Grant (8UL1TR000150) and the NCI Cancer Center Support Grant (NCI CA060553 to GF and SL) and the Intramural Research Program of the NIAID (to MO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 1 Z9 1 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e67994 DI 10.1371/journal.pone.0067994 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000107 PM 23826353 ER PT J AU Famooto, A Almujtaba, M Dareng, E Akarolo-Anthony, S Ogbonna, C Offiong, R Olaniyan, O Wheeler, CM Doumatey, A Rotimi, CN Adeyemo, A Adebamowo, CA AF Famooto, Ayo Almujtaba, Maryam Dareng, Eileen Akarolo-Anthony, Sally Ogbonna, Celestine Offiong, Richard Olaniyan, Olayinka Wheeler, Cosette M. Doumatey, Ayo Rotimi, Charles N. Adeyemo, Adebowale Adebamowo, Clement A. TI RPS19 and TYMS SNPs and Prevalent High Risk Human Papilloma Virus Infection in Nigerian Women SO PLOS ONE LA English DT Article ID DIAMOND-BLACKFAN-ANEMIA; CERVICAL-CANCER; REGISTRY; ASSOCIATION; TUMORS; TOOL AB High risk HPV (hrHPV) infection is a necessary cause of cervical cancer but the host genetic determinants of infection are poorly understood. We enrolled 267 women who presented to our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. We collected information on demographic characteristics, risk factors of cervical cancer and obtained samples of blood and cervical exfoliated cells from all participants. We used Roche Linear Array HPV Genotyping Test(R) to characterize the prevalent HPV according to manufacturer's instruction; Sequenom Mass Array to test 21 SNPs in genes/regions previously associated with hrHPV and regression models to examine independent factors associated with HPV infection. We considered a p<0.05 as significant because this is a replication study. There were 65 women with and 202 women without hrHPV infection. Under the allelic model, we found significant association between two SNPs, rs2305809 on RPS19 and rs2342700 on TYMS, and prevalent hrHPV infection. Multivariate analysis of hrHPV risk adjusted for age, body mass index, smoking, age of menarche, age at sexual debut, lifetime total number of sexual partners and the total number of pregnancies as covariates, yielded a p-value of 0.071 and 0.010 for rs2305809 and rs2342700, respectively. Our findings in this unique population suggest that a number of genetic risk variants for hrHPV are shared with other population groups. Definitive studies with larger sample sizes and using genome wide approaches are needed to understand the genetic architecture of hrHPV risk in multiple populations. C1 [Famooto, Ayo; Almujtaba, Maryam; Dareng, Eileen; Akarolo-Anthony, Sally; Ogbonna, Celestine; Adebamowo, Clement A.] Inst Human Virol, Dept Res & Training, Abuja, FCT, Nigeria. [Akarolo-Anthony, Sally; Adebamowo, Clement A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Offiong, Richard] Univ Abuja, Teaching Hosp, Gwagwalada, FCT, Nigeria. [Olaniyan, Olayinka] Natl Hosp, Abuja, FCT, Nigeria. [Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Doumatey, Ayo; Rotimi, Charles N.; Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Inst Human Virol, Baltimore, MD 21201 USA. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Adebamowo, CA (reprint author), Inst Human Virol, Dept Res & Training, Abuja, FCT, Nigeria. EM cadebamowo@som.umaryland.edu OI Adebamowo, Sally/0000-0003-4713-2433; Adeyemo, Adebowale/0000-0002-3105-3231 FU National Cancer Institute [D43CA153792] FX The project described was supported by Award Number D43CA153792 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 2 Z9 2 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e66930 DI 10.1371/journal.pone.0066930 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000018 PM 23826176 ER PT J AU Gandolfi, B Alhaddad, H Affolter, VK Brockman, J Haggstrom, J Joslin, SEK Koehne, AL Mullikin, JC Outerbridge, CA Warren, WC Lyons, LA AF Gandolfi, Barbara Alhaddad, Hasan Affolter, Verena K. Brockman, Jeffrey Haggstrom, Jens Joslin, Shannon E. K. Koehne, Amanda L. Mullikin, James C. Outerbridge, Catherine A. Warren, Wesley C. Lyons, Leslie A. TI To the Root of the Curl: A Signature of a Recent Selective Sweep Identifies a Mutation That Defines the Cornish Rex Cat Breed SO PLOS ONE LA English DT Article ID AUTOSOMAL RECESSIVE HYPOTRICHOSIS; PROTEIN-COUPLED RECEPTOR; HYPOHIDROTIC ECTODERMAL DYSPLASIA; HAIR FOLLICLE DEVELOPMENT; WOOLLY HAIR; DOMESTIC CAT; COAT MUTANT; P2RY5 GENE; LYSOPHOSPHATIDIC ACID; PHOSPHATIDIC-ACID AB The cat (Felis silvestris catus) shows significant variation in pelage, morphological, and behavioral phenotypes amongst its over 40 domesticated breeds. The majority of the breed specific phenotypic presentations originated through artificial selection, especially on desired novel phenotypic characteristics that arose only a few hundred years ago. Variations in coat texture and color of hair often delineate breeds amongst domestic animals. Although the genetic basis of several feline coat colors and hair lengths are characterized, less is known about the genes influencing variation in coat growth and texture, especially rexoid - curly coated types. Cornish Rex is a cat breed defined by a fixed recessive curly coat trait. Genome-wide analyses for selection (d(i), Tajima's D and nucleotide diversity) were performed in the Cornish Rex breed and in 11 phenotypically diverse breeds and two random bred populations. Approximately 63K SNPs were used in the analysis that aimed to localize the locus controlling the rexoid hair texture. A region with a strong signature of recent selective sweep was identified in the Cornish Rex breed on chromosome A1, as well as a consensus block of homozygosity that spans approximately 3 Mb. Inspection of the region for candidate genes led to the identification of the lysophosphatidic acid receptor 6 (LPAR6). A 4 bp deletion in exon 5, c.250_253_delTTTG, which induces a premature stop codon in the receptor, was identified via Sanger sequencing. The mutation is fixed in Cornish Rex, absent in all straight haired cats analyzed, and is also segregating in the German Rex breed. LPAR6 encodes a G protein-coupled receptor essential for maintaining the structural integrity of the hair shaft; and has mutations resulting in a wooly hair phenotype in humans. C1 [Gandolfi, Barbara; Alhaddad, Hasan; Joslin, Shannon E. K.; Lyons, Leslie A.] Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Affolter, Verena K.; Koehne, Amanda L.] Univ Calif Davis, Sch Vet Med, Dept Pathol, Davis, CA 95616 USA. [Brockman, Jeffrey] Hills Pet Nutr Ctr, Topeka, KS USA. [Haggstrom, Jens] Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden. [Mullikin, James C.] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Outerbridge, Catherine A.] Univ Calif Davis, Sch Vet Med, Dept Vet Med & Epidemiol, Davis, CA 95616 USA. [Warren, Wesley C.] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. RP Gandolfi, B (reprint author), Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM bgandolfi@ucdavis.edu OI Alhaddad, Hasan/0000-0001-7904-2913 FU National Center for Research Resources; Office of Research Infrastructure Programs of the National Institute of Health [R24 RR016094]; Winn Feline Foundation [W10-14, W11-041]; Center for Companion Animal Health at University of California Davis [2010-09-F]; George and Phyllis Miller Feline Health Fund of the San Francisco Foundation [2008-36-F] FX This project was supported by the National Center for Research Resources and the Office of Research Infrastructure Programs of the National Institute of Health through Grant Number R24 RR016094, the Winn Feline Foundation (W10-14, W11-041), the Center for Companion Animal Health at University of California Davis (2010-09-F) (http://www.vetmed.ucdavis.edu/ccah/index.cfm), and the George and Phyllis Miller Feline Health Fund of the San Francisco Foundation (2008-36-F). Support for the development of the Illumina Infinium Feline 63K iSelect DNA array was provided by the Morris Animal Foundation (http://www.morrisanimalfoundation.org)via a donation from Hill's Pet Food, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 11 Z9 11 U1 1 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e67105 DI 10.1371/journal.pone.0067105 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000027 PM 23826204 ER PT J AU Lee, SY Chen, SL Chang, YH Chen, PS Huang, SY Tzeng, NS Wang, YS Wang, LJ Lee, IH Wang, TY Yeh, TL Yang, YK Hong, JS Lu, RB AF Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Chen, Po See Huang, San-Yuan Tzeng, Nian-Sheng Wang, Yu-Shan Wang, Liang-Jen Lee, I. Hui Wang, Tzu-Yun Yeh, Tzung Lieh Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naive Patients with Bipolar II Disorder SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; GROWTH-FACTOR-BETA; INSULIN-RESISTANCE; MAJOR DEPRESSION; ADIPOSE-TISSUE; FACTOR-ALPHA; LITHIUM TREATMENT; RATING-SCALE; DOUBLE-BLIND AB Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP) and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naive patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naive patients (n = 117) diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI) and plasma cytokines (TNF-alpha, CRP, IL-6, and TGF-beta) were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7) and triglyceride (P = 0.005) levels. Changes in plasma TGF-beta 1 were significantly associated with changes in BMI (P = 8.2E-6), cholesterol (P = 0.004), and triglyceride (P = 0.006) levels. However, changes in plasma TNF-alpha and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003) levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006) and TNF-alpha (P = 0.039) levels. Plasma CRP and TGF-beta 1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology of clinical symptoms and metabolic disturbance in BP-II. C1 [Lee, Sheng-Yu; Chen, Shiou-Lan; Chen, Po See; Lee, I. Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Tainan 70101, Taiwan. [Chen, Shiou-Lan; Wang, Yu-Shan; Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med, Tainan 70101, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med & Hosp, Inst Allied Hlth Sci, Tainan 70101, Taiwan. [Huang, San-Yuan; Tzeng, Nian-Sheng] Triserv Gen Hosp, Natl Def Med Ctr, Dept Psychiat, Taipei, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Wang, Tzu-Yun] Tainan Hosp, Dept Hlth, Dept Psychiat, Tainan, Taiwan. [Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Dept Psychiat, Tainan 70101, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers FX This work was supported in part by grant NSC98-2314-B-006-022-MY3 (to RBL) and NSC98-2314-B-006-022-MY3 (to SYL) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute, and the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 17 Z9 17 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e66847 DI 10.1371/journal.pone.0066847 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000016 PM 23826157 ER PT J AU Masaoka, A Gassman, NR Horton, JK Kedar, PS Witt, KL Hobbs, CA Kissling, GE Tano, K Asagoshi, K Wilson, SH AF Masaoka, Aya Gassman, Natalie R. Horton, Julie K. Kedar, Padmini S. Witt, Kristine L. Hobbs, Cheryl A. Kissling, Grace E. Tano, Keizo Asagoshi, Kenjiro Wilson, Samuel H. TI Interaction between DNA Polymerase beta and BRCA1 SO PLOS ONE LA English DT Article ID BASE EXCISION-REPAIR; CELL NUCLEAR ANTIGEN; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; MOUSE FIBROBLASTS; OXIDATIVE STRESS; COMET ASSAY; DAMAGE; CANCER; RADIATION AB The breast cancer 1 (BRCA1) protein is a tumor suppressor playing roles in DNA repair and cell cycle regulation. Studies of DNA repair functions of BRCA1 have focused on double-strand break (DSB) repair pathways and have recently included base excision repair (BER). However, the function of BRCA1 in BER is not well defined. Here, we examined a BRCA1 role in BER, first in relation to alkylating agent (MMS) treatment of cells and the BER enzyme DNA polymerase beta (pol beta). MMS treatment of BRCA1 negative human ovarian and chicken DT40 cells revealed hypersensitivity, and the combined gene deletion of BRCA1 and pol beta in DT40 cells was consistent with these factors acting in the same repair pathway, possibly BER. Using cell extracts and purified proteins, BRCA1 and pol beta were found to interact in immunoprecipitation assays, yet in vivo and in vitro assays for a BER role of BRCA1 were negative. An alternate approach with the human cells of immunofluorescence imaging and laser-induced DNA damage revealed negligible BRCA1 recruitment during the first 60 s after irradiation, the period typical of recruitment of pol beta and other BER factors. Instead, 15 min after irradiation, BRCA1 recruitment was strong and there was gamma-H2AX co-localization, consistent with DSBs and repair. The rapid recruitment of pol beta was similar in BRCA1 positive and negative cells. However, a fraction of pol beta initially recruited remained associated with damage sites much longer in BRCA1 positive than negative cells. Interestingly, pol beta expression was required for BRCA1 recruitment, suggesting a partnership between these repair factors in DSB repair. C1 [Masaoka, Aya; Gassman, Natalie R.; Horton, Julie K.; Kedar, Padmini S.; Asagoshi, Kenjiro; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Witt, Kristine L.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Kissling, Grace E.] NIEHS, Biostatist Branch, NIH, Res Triangle Pk, NC USA. [Hobbs, Cheryl A.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Tano, Keizo] Kyoto Univ, Inst Res Reactor, Dept Radiat Life Sci & Radiat Med Sci, Kumatori, Osaka 59004, Japan. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159]; Ministry of Education, Culture, Sports, Science and Technology of Japan [20510051, 24510072] FX This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050159 from the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences(to SHW), and by Grants-in-Aid (20510051, 24510072) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to KT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e66801 DI 10.1371/journal.pone.0066801 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000010 PM 23826138 ER PT J AU Monfredi, O Maltseva, LA Spurgeon, HA Boyett, MR Lakatta, EG Maltsev, VA AF Monfredi, Oliver Maltseva, Larissa A. Spurgeon, Harold A. Boyett, Mark R. Lakatta, Edward G. Maltsev, Victor A. TI Beat-to-Beat Variation in Periodicity of Local Calcium Releases Contributes to Intrinsic Variations of Spontaneous Cycle Length in Isolated Single Sinoatrial Node Cells SO PLOS ONE LA English DT Article ID PACEMAKER CELLS; DIASTOLIC DEPOLARIZATION; RYANODINE RECEPTOR; CA2+ RELEASES AB Spontaneous, submembrane local Ca2+ releases LCRs) generated by the sarcoplasmic reticulum in sinoatrial nodal cells, the cells of the primary cardiac pacemaker, activate inward Na+/Ca2+-exchange current to accelerate the diastolic depolarization rate, and therefore to impact on cycle length. Since LCRs are generated by Ca2+ release channel i.e. ryanodine receptor) openings, they exhibit a degree of stochastic behavior, manifested as notable cycle-to-cycle variations in the time of their occurrence. Aim: The present study tested whether variation in LCR periodicity contributes to intrinsic beat-to-beat) cycle length variability in single sinoatrial nodal cells. Methods: We imaged single rabbit sinoatrial nodal cells using a 2D-camera to capture LCRs over the entire cell, and, in selected cells, simultaneously measured action potentials by perforated patch clamp. Results: LCRs begin to occur on the descending part of the action potential-induced whole-cell Ca2+ transient, at about the time of the maximum diastolic potential. Shortly after the maximum diastolic potential mean 54 +/- 7.7 ms, n = 14), the ensemble of waxing LCR activity converts the decay of the global Ca2+ transient into a rise, resulting in a late, whole-cell diastolic Ca2+ elevation, accompanied by a notable acceleration in diastolic depolarization rate. On average, cells n = 9) generate 13.2 +/- 3.7 LCRs per cycle mean +/- SEM), varying in size 7.1 +/- 4.2 mu m) and duration 44.2 +/- 27.1 ms), with both size and duration being greater for later-occurring LCRs. While the timing of each LCR occurrence also varies, the LCR period i.e. the time from the preceding Ca2+ transient peak to an LCR's subsequent occurrence) averaged for all LCRs in a given cycle closely predicts the time of occurrence of the next action potential, i.e. the cycle length. Conclusion: Intrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual LCRs each cycle. C1 [Monfredi, Oliver; Maltseva, Larissa A.; Spurgeon, Harold A.; Lakatta, Edward G.; Maltsev, Victor A.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Monfredi, Oliver; Boyett, Mark R.] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England. RP Maltsev, VA (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM MaltsevVi@grc.nia.nih.gov OI Boyett, Mark/0000-0003-3931-2020; Monfredi, Oliver/0000-0003-1292-2902 FU National Institutes of Health, National Institute on Aging; British Cardiovascular Society; University of Manchester; Higher Education Funding Council for England FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and by the British Cardiovascular Society (OM), the University of Manchester (OM, MRB) and the Higher Education Funding Council for England (MRB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 11 Z9 11 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2013 VL 8 IS 6 AR e67247 DI 10.1371/journal.pone.0067247 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IX UT WOS:000321150000048 PM 23826247 ER PT J AU Little, MP Zablotska, LB Lipshultz, SE AF Little, Mark P. Zablotska, Lydia B. Lipshultz, Steven E. TI Ischemic Heart Disease after Breast Cancer Radiotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CIRCULATORY DISEASE; CHILDHOOD-CANCER; RADIATION; MORTALITY; EXPOSURE C1 [Little, Mark P.] NCI, Bethesda, MD 20892 USA. [Zablotska, Lydia B.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Lipshultz, Steven E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Little, MP (reprint author), NCI, Bethesda, MD 20892 USA. EM mark.little@nih.gov NR 6 TC 4 Z9 4 U1 0 U2 5 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 JUN 27 PY 2013 VL 368 IS 26 BP 2523 EP 2524 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 171KQ UT WOS:000320926900020 PM 23802524 ER PT J AU Sharma, V Misteli, T AF Sharma, Vivek Misteli, Tom TI Non-coding RNAs in DNA damage and repair SO FEBS LETTERS LA English DT Review DE Non-coding RNA; DNA damage; Repair; miRNA; Long non-coding RNA; Genome integrity ID DOUBLE-STRAND BREAKS; CELL-CYCLE; MICRORNA BIOGENESIS; TUMOR-SUPPRESSOR; DOWN-REGULATION; CHROMATIN-STRUCTURE; IONIZING-RADIATION; END RESECTION; HOMOLOGOUS RECOMBINATION; TRANSLATIONAL REPRESSION AB Non-coding RNAs (ncRNAs) are increasingly recognized as central players in diverse biological processes. Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple ncRNA species. Recent studies indicate that DNA-damage induced ncRNAs contribute to regulation of cell cycle, apoptosis and DNA repair, and thus play a key role in maintaining genome stability. This review summarizes the emerging role of ncRNAs in DNA damage and repair. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Sharma, Vivek; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU NIH DBT Khorana-Nirenberg Fellowship; NIH, National Cancer Institute, Center for Cancer Research FX V.S. is supported by an NIH DBT Khorana-Nirenberg Fellowship. Work in the Misteli laboratory is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors would like to thank Misteli laboratory members for helpful feedback on the manuscript. NR 127 TC 27 Z9 27 U1 1 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUN 27 PY 2013 VL 587 IS 13 SI SI BP 1832 EP 1839 DI 10.1016/j.febslet.2013.05.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 171FK UT WOS:000320910300003 PM 23684639 ER PT J AU Rebello, A Smith, MG Neumeier, JJ White, BD Yu, YK AF Rebello, A. Smith, M. G. Neumeier, J. J. White, B. D. Yu, Yi-Kuo TI Transition from one-dimensional antiferromagnetism to three-dimensional antiferromagnetic order in single-crystalline CuSb2O6 SO PHYSICAL REVIEW B LA English DT Article ID SPIN-PEIERLS TRANSITION; HEISENBERG-CHAINS; COMPOUND CUGEO3; MAGNETIC ORDER; RANGE; STATE AB Measurements of magnetic susceptibility, heat capacity, and thermal expansion are reported for single-crystalline CuSb2O6 in the temperature range 5 < T < 350 K. The magnetic susceptibility exhibits a broad peak centered near 60 K that is typical of one-dimensional antiferromagnetic compounds. Long-range antiferromagnetic order at T-N = 8.7 K is accompanied by an energy gap [Delta = 17.48(6) K]. This transition represents a crossover from one- to three-dimensional antiferromagnetic behavior. Both heat capacity and the thermal expansion coefficients exhibit distinct jumps at TN, which are similar to those observed at the normal-superconducting phase transition in a superconductor. This behavior is quite unusual and is presumably associated with a spin-Peierls transition occurring as a result of three-dimensional phonons coupling with Jordan-Wigner-transformed fermions. C1 [Rebello, A.; Smith, M. G.; Neumeier, J. J.; White, B. D.] Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. [Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Rebello, A (reprint author), Montana State Univ, Dept Phys, POB 173840, Bozeman, MT 59717 USA. FU National Science Foundation [DMR-0907036] FX We thank Anton Vorontsov for valuable discussions. This material is based on the work supported by the National Science Foundation under Contract No. DMR-0907036. NR 33 TC 7 Z9 7 U1 3 U2 27 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 J9 PHYS REV B JI Phys. Rev. B PD JUN 27 PY 2013 VL 87 IS 22 AR 224427 DI 10.1103/PhysRevB.87.224427 PG 7 WC Physics, Condensed Matter SC Physics GA 172JS UT WOS:000320999800004 ER PT J AU Roychoudhuri, R Hirahara, K Mousavi, K Clever, D Klebanoff, CA Bonelli, M Sciume, G Zare, H Vahedi, G Dema, B Yu, ZY Liu, H Takahashi, H Rao, M Muranski, P Crompton, JG Punkosdy, G Bedognetti, D Wang, E Hoffmann, V Rivera, J Marincola, FM Nakamura, A Sartorelli, V Kanno, Y Gattinoni, L Muto, A Igarashi, K O'Shea, JJ Restifo, NP AF Roychoudhuri, Rahul Hirahara, Kiyoshi Mousavi, Kambiz Clever, David Klebanoff, Christopher A. Bonelli, Michael Sciume, Giuseppe Zare, Hossein Vahedi, Golnaz Dema, Barbara Yu, Zhiya Liu, Hui Takahashi, Hayato Rao, Mahadev Muranski, Pawel Crompton, Joseph G. Punkosdy, George Bedognetti, Davide Wang, Ena Hoffmann, Victoria Rivera, Juan Marincola, Francesco M. Nakamura, Atsushi Sartorelli, Vittorio Kanno, Yuka Gattinoni, Luca Muto, Akihiko Igarashi, Kazuhiko O'Shea, John J. Restifo, Nicholas P. TI BACH2 represses effector programs to stabilize T-reg-mediated immune homeostasis SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; CELL-DIFFERENTIATION; SUSCEPTIBILITY LOCI; RISK LOCI; B-CELLS; TRANSCRIPTION; DISEASE; INTERLEUKIN-4; METAANALYSIS AB Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment(1). Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma(2), Crohn's disease(3,4), coeliac disease(5), vitiligo(6), multiple sclerosis(7) and type 1 diabetes(8). Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (T-reg) cells and consequently for suppression of lethal inflammation in a manner that was T-reg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during T-reg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within T(H)1, T(H)2 and T(H)17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. C1 [Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Yu, Zhiya; Rao, Mahadev; Muranski, Pawel; Crompton, Joseph G.; Gattinoni, Luca; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hirahara, Kiyoshi; Bonelli, Michael; Sciume, Giuseppe; Vahedi, Golnaz; Takahashi, Hayato; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Mousavi, Kambiz; Zare, Hossein; Sartorelli, Vittorio] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Dema, Barbara; Rivera, Juan] NIAMS, Lab Mol Immunogenet, NIH, Bethesda, MD 20892 USA. [Liu, Hui; Bedognetti, Davide; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Punkosdy, George] NIAID, NIH, Bethesda, MD 20892 USA. [Hoffmann, Victoria] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Nakamura, Atsushi; Muto, Akihiko; Igarashi, Kazuhiko] Tohoku Univ, Grad Sch Med, Dept Biochem, Sendai, Miyagi 9808575, Japan. [Muto, Akihiko; Igarashi, Kazuhiko] Japan Sci & Technol Agcy, CREST, Sendai, Miyagi 9808575, Japan. [Restifo, Nicholas P.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Roychoudhuri, R (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM roychoudhuri@mail.nih.gov; osheajo@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Roychoudhuri, Rahul/A-7442-2010; Kanno, Yuka/B-5802-2013; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017; OI Gattinoni, Luca/0000-0003-2239-3282; Roychoudhuri, Rahul/0000-0002-5392-1853; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319; Bedognetti, Davide/0000-0002-5857-773X; Restifo, Nicholas P./0000-0003-4229-4580; Igarashi, Kazuhiko/0000-0002-2470-2475 FU Intramural Research Programs of the National Cancer Institute (NIH); National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH Center for Regenerative Medicine; JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH FX This research was supported by the Intramural Research Programs of the National Cancer Institute (NIH) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the NIH Center for Regenerative Medicine and the JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH. We thank D. N. Roychoudhuri, D. C. Macallan, G. E. Griffin, S. A. Rosenberg, M. S. Rao, Y. Ji, D. Palmer, M. Sukumar, G. Fabozzi, K. Hanada, E. Lugli, J. H. Pan and N. Van Panhuys for discussions, A. Mixon and S. Farid for cell sorting, G. McMullen for mouse handling and Y. Luo, Y. Wakabayashi, J. Zhu, G. Gutierrez-Cruz and H. W. Sun for help with sequencing and analysis. NR 35 TC 91 Z9 94 U1 4 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 27 PY 2013 VL 498 IS 7455 BP 506 EP + DI 10.1038/nature12199 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 171LH UT WOS:000320929400057 PM 23728300 ER PT J AU Chong, A Child, R Wehrly, TD Rockx-Brouwer, D Qin, AP Mann, BJ Celli, J AF Chong, Audrey Child, Robert Wehrly, Tara D. Rockx-Brouwer, Dedeke Qin, Aiping Mann, Barbara J. Celli, Jean TI Structure-Function Analysis of DipA, a Francisella tularensis Virulence Factor Required for Intracellular Replication SO PLOS ONE LA English DT Article ID OUTER-MEMBRANE PROTEIN; COILED-COIL DOMAINS; PATHOGENICITY ISLAND; ESCHERICHIA-COLI; LEGIONELLA-PNEUMOPHILA; MURINE MACROPHAGES; STREPTOCOCCUS-PNEUMONIAE; PHAGOSOMAL ESCAPE; LIVE VACCINE; VI SECRETION AB Francisella tularensis is a highly infectious bacterium whose virulence relies on its ability to rapidly reach the macrophage cytosol and extensively replicate in this compartment. We previously identified a novel Francisella virulence factor, DipA (FTT0369c), which is required for intramacrophage proliferation and survival, and virulence in mice. DipA is a 353 amino acid protein with a Sec-dependent signal peptide, four Sel1-like repeats (SLR), and a C-terminal coiled-coil (CC) domain. Here, we determined through biochemical and localization studies that DipA is a membrane-associated protein exposed on the surface of the prototypical F. tularensis subsp. tularensis strain SchuS4 during macrophage infection. Deletion and substitution mutagenesis showed that the CC domain, but not the SLR motifs, of DipA is required for surface exposure on SchuS4. Complementation of the dipA mutant with either DipA CC or SLR domain mutants did not restore intracellular growth of Francisella, indicating that proper localization and the SLR domains are required for DipA function. Co-immunoprecipitation studies revealed interactions with the Francisella outer membrane protein FopA, suggesting that DipA is part of a membrane-associated complex. Altogether, our findings indicate that DipA is positioned at the host-pathogen interface to influence the intracellular fate of this pathogen. C1 [Chong, Audrey; Child, Robert; Wehrly, Tara D.; Rockx-Brouwer, Dedeke; Celli, Jean] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Qin, Aiping; Mann, Barbara J.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Mann, Barbara J.] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. RP Chong, A (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM chonga@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI000953-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, project number AI000953-01. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 6 Z9 6 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2013 VL 8 IS 6 AR e67965 DI 10.1371/journal.pone.0067965 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400125 PM 23840797 ER PT J AU Fozzatti, L Park, JW Zhao, L Willingham, MC Cheng, SY AF Fozzatti, Laura Park, Jeong Won Zhao, Li Willingham, Mark C. Cheng, Sheue-yann TI Oncogenic Actions of the Nuclear Receptor Corepressor (NCOR1) in a Mouse Model of Thyroid Cancer SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; HORMONE-BETA-RECEPTOR; TUMOR-SUPPRESSOR P53; VALPROIC ACID; CO-REPRESSOR; IN-VIVO; TRANSCRIPTIONAL ACTIVITY; BREAST-CANCER; CELL-LINES; GENE AB Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (Thrb(PV/PV) mice) that spontaneously develops thyroid cancer. Thrb(PV/PV) mice harbor a dominantly negative thyroid hormone receptor beta (TR beta) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing Thrb(PV) mice with mice that globally express an NCOR1 mutant protein (NCOR1 Delta ID) in which the receptor interaction domains have been modified so that it cannot interact with the TR beta, or PV, in mice. Remarkably, expression of NCOR1 Delta ID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21(waf1/cip1); Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in thyroids of Thrb(PV/PV) mice. In thyroids of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice, the p53/PV complex could not recruit NCOR1 Delta ID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer. C1 [Fozzatti, Laura; Park, Jeong Won; Zhao, Li; Willingham, Mark C.; 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, Bldg 37, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank Dr. A. Hollenberg (Harvard Medical School) for providing Ncor1 Delta ID mice. The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 52 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2013 VL 8 IS 6 AR e67954 DI 10.1371/journal.pone.0067954 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400122 PM 23840792 ER PT J AU Guo, R Abdelmohsen, K Morin, PJ Gorospe, M AF Guo, Rong Abdelmohsen, Kotb Morin, Patrice J. Gorospe, Myriam TI Novel MicroRNA Reporter Uncovers Repression of Let-7 by GSK-3 beta SO PLOS ONE LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3-BETA; OVARIAN-CANCER CELLS; KINASE 3-BETA; POSTTRANSCRIPTIONAL REGULATION; COLORECTAL-CANCER; INDUCE APOPTOSIS; TUMOR-GROWTH; EXPRESSION; RNA; P53 AB Several members of the let-7 microRNA family are downregulated in ovarian and other cancers. They are thought to act as tumor suppressors by lowering growth-promoting and anti-apoptotic proteins. In order to measure cellular let-7 levels systematically, we have developed a highly sensitive let-7 reporter assay system based on the expression of a chimeric mRNA that contains the luciferase coding region and a 3'-untranslated region (UTR) bearing two let-7-binding sites. In cells expressing the reporter construct, termed pmirGLO-let7, luciferase activity was high when let-7 was absent, while luciferase activity was low when let-7 levels were elevated. The ovarian cancer cell lines BG-1 and UCI-101 were transfected with the let-7 reporter and surveyed with a library of kinase inhibitors in order to identify pathways affecting let-7 activity. Among the inhibitors causing changes in endogenous let-7 abundance, the lowering of glycogen synthase kinase 3 (GSK-3)beta function specifically increased let-7 levels and lowered luciferase activity. Similarly, silencing GSK-3 beta increased both mature and primary-let-7 levels in BG-1 cells, and decreased BG-1 cell survival. Further studies identified p53 as a downstream effector of the GSK-3 beta-mediated repression of let-7 biosynthesis. Our studies highlight GSK-3 beta as a novel therapeutic target in ovarian tumorigenesis. C1 [Guo, Rong; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Morin, Patrice J.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Morin, Patrice J.] Amer Assoc Canc Res, Philadelphia, PA USA. RP Morin, PJ (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM pat.morin@aacr.org; myriam-gorospe@nih.gov FU National Institute on Aging-Intramural Research Program of the National Institutes of Health FX The work was funded entirely by the National Institute on Aging-Intramural Research Program of the 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 61 TC 4 Z9 4 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2013 VL 8 IS 6 AR e66330 DI 10.1371/journal.pone.0066330 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DN UT WOS:000321424400023 PM 23840442 ER PT J AU Jimeno-Yepes, AJ Plaza, L Mork, JG Aronson, AR Diaz, A AF Jimeno-Yepes, Antonio J. Plaza, Laura Mork, James G. Aronson, Alan R. Diaz, Alberto TI MeSH indexing based on automatically generated summaries SO BMC BIOINFORMATICS LA English DT Article ID BIOMEDICAL TEXT; RETRIEVAL; DOCUMENTS; MEDLINE AB Background: MEDLINE citations are manually indexed at the U. S. National Library of Medicine (NLM) using as reference the Medical Subject Headings (MeSH) controlled vocabulary. For this task, the human indexers read the full text of the article. Due to the growth of MEDLINE, the NLM Indexing Initiative explores indexing methodologies that can support the task of the indexers. Medical Text Indexer (MTI) is a tool developed by the NLM Indexing Initiative to provide MeSH indexing recommendations to indexers. Currently, the input to MTI is MEDLINE citations, title and abstract only. Previous work has shown that using full text as input to MTI increases recall, but decreases precision sharply. We propose using summaries generated automatically from the full text for the input to MTI to use in the task of suggesting MeSH headings to indexers. Summaries distill the most salient information from the full text, which might increase the coverage of automatic indexing approaches based on MEDLINE. We hypothesize that if the results were good enough, manual indexers could possibly use automatic summaries instead of the full texts, along with the recommendations of MTI, to speed up the process while maintaining high quality of indexing results. Results: We have generated summaries of different lengths using two different summarizers, and evaluated the MTI indexing on the summaries using different algorithms: MTI, individual MTI components, and machine learning. The results are compared to those of full text articles and MEDLINE citations. Our results show that automatically generated summaries achieve similar recall but higher precision compared to full text articles. Compared to MEDLINE citations, summaries achieve higher recall but lower precision. Conclusions: Our results show that automatic summaries produce better indexing than full text articles. Summaries produce similar recall to full text but much better precision, which seems to indicate that automatic summaries can efficiently capture the most important contents within the original articles. The combination of MEDLINE citations and automatically generated summaries could improve the recommendations suggested by MTI. On the other hand, indexing performance might be dependent on the MeSH heading being indexed. Summarization techniques could thus be considered as a feature selection algorithm that might have to be tuned individually for each MeSH heading. C1 [Jimeno-Yepes, Antonio J.; Mork, James G.; Aronson, Alan R.] Natl Lib Med, Bethesda, MD 20894 USA. [Jimeno-Yepes, Antonio J.] Natl ICT Australia, Victoria Res Lab, Melbourne, Vic, Australia. [Plaza, Laura] UNED NLP & IR Grp, Madrid 28040, Spain. [Diaz, Alberto] UCM NIL Grp, Madrid 28040, Spain. RP Jimeno-Yepes, AJ (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM antonio.jimeno@gmail.com OI Diaz, Alberto/0000-0002-7641-8919; DIAZ ESTEBAN, ALBERTO/0000-0003-1966-3421; Jimeno Yepes, Antonio Jose/0000-0002-6581-094X FU NIH, National Library of Medicine; National Library of Medicine; Spanish Government [TIN2009-14659-C03-01]; Australian Government as by the Department of Broadband, Communications; Australian Research Council through the ICT Centre of Excellence program; Digital Economy FX This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by an appointment of A. Jimeno-Yepes to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education.; This research was also supported by the Spanish Government through the project TIN2009-14659-C03-01.; National ICT Australia (NICTA) is funded by the Australian Government as represented by the Department of Broadband, Communications and the Digital Economy and the Australian Research Council through the ICT Centre of Excellence program. NR 41 TC 9 Z9 9 U1 0 U2 12 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 JUN 26 PY 2013 VL 14 AR 208 DI 10.1186/1471-2105-14-208 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 179FM UT WOS:000321505200001 PM 23802936 ER PT J AU Tovar, A Hennessy, E Must, A Hughes, SO Gute, DM Sliwa, S Boulos, RJ Vikre, EK Kamins, CL Tofuri, K Pirie, A Economos, CD AF Tovar, Alison Hennessy, Erin Must, Aviva Hughes, Sheryl O. Gute, David M. Sliwa, Sarah Boulos, Rebecca J. Vikre, Emily Kuross Kamins, Christina Luongo Tofuri, Kerline Pirie, Alex Economos, Christina D. TI Feeding styles and evening family meals among recent immigrants SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Family meal; Feeding styles; Children; Obesity; Immigrants ID BODY-MASS INDEX; UNITED-STATES; PARENTING STYLES; WEIGHT STATUS; LONGITUDINAL ASSOCIATIONS; ADOLESCENT OVERWEIGHT; CHILDHOOD OVERWEIGHT; AMERICAN CHILDREN; PHYSICAL-ACTIVITY; RISK-FACTORS AB The protective effect of family meals on unhealthy weight gain and diet has been shown across multiple age groups; however, it is unknown whether a similar effect is present among diverse immigrant populations. In addition, little research has focused on factors associated with the frequency of evening family meals, such as feeding styles (how parents interact with their child around feeding). Therefore the goals of this paper are to explore the 1) association between the frequency of evening family meals and child weight status among new immigrant families, and 2) influence of immigrant mothers' feeding styles on the frequency of evening family meals. Baseline self-reported socio-demographic information and measured heights and weights were collected for both mother and child (age range: 3-12 years) among 387 mother-child dyads enrolled in Live Well, a community-based, participatory-research, randomized controlled lifestyle intervention to prevent excessive weight gain in recent (<10 years in the U. S.) immigrant mothers and children. For children, height and weight measurements were transformed into BMI z-scores using age-and sex-specific CDC standards and categorized as overweight (85th-94th percentile) and obese (>= 95th percentile); mothers' BMI was calculated. Frequency of evening family meals, eating dinner in front of the TV, acculturation and responses to the Caregiver's Feeding Styles Questionnaire (CFSQ) were also obtained from the mother. Children were categorized as "eating evening family meals regularly" if they had an evening family meal >= 5 times per week. Overall, 20% of children were overweight and 25% were obese. Less than half (40.9%) of families had regular evening family meals. In multivariate analyses, adjusting for covariates, children who were overweight/obese were significantly less likely to have >= 5 evening family meals/week compared with normal weight children (OR = 0.51, 95% CI 0.32-0.82). Mothers who had a low demanding/high responsive or a low demanding/low responsive feeding style, were less likely to have >= 5 evening family meals/week compared to mothers with a high demanding/high responsive feeding style (OR = 0.41, 95% CI 0.18-0.0.96, OR = 0.33, 95% CI 0.13-0.87, respectively). Future interventions and programs that seek to help parents establish healthy household routines, such as family meals, may consider tailoring to specific maternal feeding styles. C1 [Tovar, Alison] Univ Rhode Isl, Dept Nutr & Food Sci, Kingston, RI 02818 USA. [Hennessy, Erin] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Must, Aviva] Tufts Univ, Dept Publ Hlth & Community Med, Sch Med, Boston, MA 02111 USA. [Hughes, Sheryl O.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Gute, David M.] Tufts Univ, Sch Engn, Dept Civil & Environm Engn, Medford, MA 02155 USA. [Sliwa, Sarah; Boulos, Rebecca J.; Vikre, Emily Kuross; Kamins, Christina Luongo; Tofuri, Kerline; Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Pirie, Alex] Immigrant Serv Providers Grp Hlth, Somerville, MA 02143 USA. RP Tovar, A (reprint author), Univ Rhode Isl, Dept Nutr & Food Sci, 112 Ranger Hall, Kingston, RI 02818 USA. EM alison_tovar@mail.uri.edu FU National Institutes of Health (NIH), Bethesda MD [5R01HD057841]; NIH FX We would like to thank these members of the Live Well Steering Committee (Nesly Metayer, Franklin Dalembert, Raymond R. Hyatt, Warren Goldstein-Gelb, Maria Landaverde, Melissa McWhinney, Joyce Guilhermino de Padua, Helen Sinzker, Heloisa Galvao, and Ismael Vasquez). In addition, we thank the Live Well women and their children for participating in this study. Funding for this research was provided by grant 5R01HD057841 from the National Institutes of Health (NIH), Bethesda MD. Postdoctoral research funds for Alison Tovar were provided by an NIH supplement from this grant. NR 47 TC 4 Z9 4 U1 4 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD JUN 26 PY 2013 VL 10 AR 84 DI 10.1186/1479-5868-10-84 PG 8 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 181IV UT WOS:000321662100001 PM 23803223 ER PT J AU Shrestha, S Foxman, B Weinberger, DM Steiner, C Viboud, C Rohani, P AF Shrestha, Sourya Foxman, Betsy Weinberger, Daniel M. Steiner, Claudia Viboud, Cecile Rohani, Pejman TI Identifying the Interaction Between Influenza and Pneumococcal Pneumonia Using Incidence Data SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TIME-SERIES ANALYSIS; HONG KONG INFLUENZA; STREPTOCOCCUS-PNEUMONIAE; PANDEMIC INFLUENZA; BACTERIAL PNEUMONIA; RESPIRATORY VIRUSES; UNITED-STATES; A H1N1; DISEASE; ASSOCIATION AB The association between influenza virus and the bacterium Streptococcus pneumoniae (pneumococcus) has been proposed as a polymicrobial system, whereby transmission and pathogenicity of one pathogen (the bacterium) are affected by interactions with the other (the virus). However, studies focusing on different scales of resolution have painted an inconsistent picture: Individual-scale animal experiments have unequivocally demonstrated an association, whereas epidemiological support in human populations is, at best, inconclusive. We integrate weekly incidence reports and a mechanistic transmission model within a likelihood-based inference framework to characterize the nature, timing, and magnitude of this interaction. We find support for a strong but short-lived interaction, with influenza infection increasing susceptibility to pneumococcal pneumonia similar to 100-fold. We infer modest population-level impacts arising from strong processes at the level of an individual, thereby resolving the dichotomy in seemingly inconsistent observations across scales. An accurate characterization of the influenza-pneumococcal interaction can form a basis for more effective clinical care and public health measures for pneumococcal pneumonia. C1 [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Foxman, Betsy] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Weinberger, Daniel M.; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Steiner, Claudia] US Dept HHS, Healthcare Cost & Utilizat Project, Ctr Delivery Org & Markets, Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shrestha, S (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM sourya@umich.edu RI Foxman, Betsy/E-1836-2015; OI Shrestha, Sourya/0000-0002-6106-6834; Foxman, Betsy/0000-0001-6682-238X; Weinberger, Daniel/0000-0003-1178-8086 FU Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation; Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, NIH FX Funding: S.S. and P. R. were supported by the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation. P. R. also received support from the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, NIH. NR 62 TC 28 Z9 30 U1 2 U2 16 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 JUN 26 PY 2013 VL 5 IS 191 AR 191ra84 DI 10.1126/scitranslmed.3005982 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 171KX UT WOS:000320928000005 PM 23803706 ER PT J AU Yewdell, JW Spiro, DJ Golding, H Quill, H Mittelman, A Nabel, GJ AF Yewdell, Jonathan W. Spiro, David J. Golding, Hana Quill, Helen Mittelman, Abraham Nabel, Gary J. TI Getting to the Heart of Influenza SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Mittelman, Abraham; Nabel, Gary J.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Spiro, David J.] NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Quill, Helen] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM gary.nabel@sanofi.com FU Intramural NIH HHS [ZIA AI001055-05] NR 4 TC 0 Z9 0 U1 0 U2 4 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 JUN 26 PY 2013 VL 5 IS 191 AR 191ed8 DI 10.1126/scitranslmed.3006735 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 171KX UT WOS:000320928000001 PM 23803701 ER PT J AU Amin-ul Mannan, M Shadrick, WR Biener, G Shin, BS Anshu, A Raicu, V Frick, DN Dey, M AF Amin-ul Mannan, M. Shadrick, William R. Biener, Gabriel Shin, Byung-Sik Anshu, Ashish Raicu, Valerica Frick, David N. Dey, Madhusudan TI An Ire1-Phk1 Chimera Reveals a Dispensable Role of Autokinase Activity in Endoplasmic Reticulum Stress Response SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ire1; RNA splicing; RNase; protein kinase; unfolded protein response ID UNFOLDED PROTEIN RESPONSE; MESSENGER-RNA; TRANSMEMBRANE PROTEIN; TRANSCRIPTION FACTOR; FLUORESCENT PROTEIN; CATALYTIC SUBUNIT; KINASE-ACTIVITY; IRE1 KINASE; MECHANISM; INSIGHTS AB The endoplasmic reticulunn transmembrane receptor Ire1 senses over-accumulation of unfolded proteins in the endoplasnnic reticulunn and initiates the unfolded protein response (UPR). The cytoplasmic portion of Ire1 has a protein kinase domain (KD) and a kinase extension nuclease (KEN) domain that cleaves an mRNA for encoding the Had transcription factor needed to express UPR genes. During this UPR signaling, Ire1 proteins self-assemble into an oligomer of dimers, which essentially requires autophosphorylation of a constituent activation loop in the KD. However, it is not clear how dimerization, autophosphorylation, and KEN domain function are precisely coordinated. In this study, we uncoupled the KD and KEN domain functions, by removing the activation loop along with an extended region that we called the auto-inhibitory region (AIR), or by swapping the activation loop with a homologous loop from phosphorylase kinase 1 (Ire1(PHK)). Both Ire1(Delta AIR) and Ire1(PHK) activated the UPR even when either protein contained a mutation (D797A) that abolished the ability of Ire1 KD to transfer phosphates to the AIR. Neither protein functioned when containing mutations in key ATP binding residues (E746A and N749A) or in residues that disrupted Ire1 dimer interface (W426A or R697D). We interpret these results as evidence supporting the notion that the primary function of the kinase domain is to autophosphorylate the AIR in order to relieve auto-inhibition and that ADP acts as a switch to activate the KEN domain-catalyzed HAC1 mRNA cleavage. Published by Elsevier Ltd. C1 [Amin-ul Mannan, M.; Anshu, Ashish; Raicu, Valerica; Dey, Madhusudan] Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. [Shadrick, William R.; Frick, David N.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Biener, Gabriel; Raicu, Valerica] Univ Wisconsin, Dept Phys, Milwaukee, WI 53211 USA. [Shin, Byung-Sik] NIH, Bethesda, MD 20892 USA. RP Dey, M (reprint author), Univ Wisconsin, Dept Biol Sci, Room 460,Lapham Hall,3209 North Maryland Ave, Milwaukee, WI 53211 USA. EM deym@umw.edu FU RGI grants (UWM internal funds); National Science Foundation [IIP-1114305, PHY-1058470, PHY-1126386] FX We thank Dr. Thomas E. Dever (National Institute of Child Health & Human Development, National Institutes of Health) for reagents and helpful discussion throughout the project. We thank Dr. Alan G. Hinnebusch (National Institute of Child Health & Human Development, National Institutes of Health) and Prof. Colin Scanes (UW-Milwaukee) for reading the manuscript and for useful suggestions. This work was partly supported by RGI grants (UWM internal funds) awarded to M.D. and National Science Foundation grants (IIP-1114305, PHY-1058470 and PHY-1126386) awarded to V.R. NR 43 TC 0 Z9 0 U1 1 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 26 PY 2013 VL 425 IS 12 BP 2083 EP 2099 DI 10.1016/j.jmb.2013.02.036 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164MN UT WOS:000320414300001 ER PT J AU Johnson, BC Metifiot, M Ferris, A Pommier, Y Hughes, SH AF Johnson, Barry C. Metifiot, Mathieu Ferris, Andrea Pommier, Yves Hughes, Stephen H. TI A Homology Model of HIV-1 Integrase and Analysis of Mutations Designed to Test the Model SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV; integration; dimerization; infectivity; modeling ID VIRUS TYPE-1 INTEGRASE; DNA-BINDING DOMAIN; PROTEIN IN-VITRO; TERMINAL DOMAIN; RETROVIRAL INTEGRATION; MOLECULAR-MECHANISMS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; FLEXIBLE LOOP; ACTIVE-SITE AB Although there are structures of the different domains of human immunodeficiency virus type 1 (HIV-1) integrase (IN), there is no structure of the entire protein. The recently determined crystal structures of the prototype foamy virus (PFV) IN tetramer, in complexes with viral DNA, led to the generation of models of full-length HIV-1 IN. These models were generated, in part, by superimposing the structures of the domains of HIV-1 IN onto the structure of full-length PFV IN. We developed a model for HIV-1 IN-based solely on its sequence alignment with PFV IN-that differs in several ways from the previous models. Specifically, in our model, the junction between the catalytic core domain and C-terminal domain adopts a helix-loop-helix motif that is similar to the corresponding segment of PFV IN and differs from the crystal structures of these two HIV-1 IN domains. The alignment of residues in the C-terminal domain also differs from the previous models. Our model can be used to explain the phenotype of previously published HIV-1 IN mutants. We made additional mutants, and the behavior of these new mutants provides additional support for the model. (c) 2013 Published by Elsevier Ltd. C1 [Johnson, Barry C.; Ferris, Andrea; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Metifiot, Mathieu; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, POB B, Ft Detrick, MD 21702 USA. EM hughesst@mail.nih.gov FU National Institutes of Health Intramural Program; Center for Cancer Research; National Cancer Institute; National Institutes of Health grants from the AIDS Intramural AIDS Targeted Antiviral Program FX Our studies were supported by the National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute and by National Institutes of Health grants from the AIDS Intramural AIDS Targeted Antiviral Program. We thank Ferri Soheilian and Kunio Nagashima at the Electron Microscopy Laboratory at Frederick National Laboratory for electron microscopy imaging and Al Kane for assistance with figures. NR 51 TC 20 Z9 20 U1 0 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 26 PY 2013 VL 425 IS 12 BP 2133 EP 2146 DI 10.1016/j.jmb.2013.03.027 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164MN UT WOS:000320414300003 PM 23542006 ER PT J AU Lu, J Frerich, JM Turtzo, LC Li, SQ Chiang, J Yang, CZ Wang, XP Zhang, C Wu, CX Sun, ZC Niu, G Zhuang, ZP Brady, RO Chen, XY AF Lu, Jie Frerich, Jason M. Turtzo, L. Christine Li, Siqi Chiang, Jeffrey Yang, Chunzhang Wang, Xiaoping Zhang, Chao Wu, Chenxi Sun, Zhongchan Niu, Gang Zhuang, Zhengping Brady, Roscoe O. Chen, Xiaoyuan TI Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NERVE GROWTH-FACTOR; H3 ACETYLATION; UP-REGULATION; HEAD-INJURY; EXPRESSION; RATS; MICE; ASTROCYTES; ACTIVATION; MECHANISMS AB Acute traumatic brain injury (TBI) is associated with long-term cognitive and behavioral dysfunction. In vivo studies have shown histone deacetylase inhibitors (HDACis) to be neuroprotective following TBI in rodent models. HDACis are intriguing candidates because they are capable of provoking widespread genetic changes and modulation of protein function. By using known HDACis and a unique small-molecule pan-HDACi (LB-205), we investigated the effects and mechanisms associated with HDACi-induced neuroprotection following CNS injury in an astrocyte scratch assay in vitro and a rat TBI model in vivo. We demonstrate the preservation of sufficient expression of nerve growth factor (NGF) and activation of the neurotrophic tyrosine kinase receptor type 1 (TrkA) pathway following HDACi treatment to be crucial in stimulating the survival of CNS cells after TBI. HDACi treatment up-regulated the expression of NGF, phospho-TrkA, phospho-protein kinase B (p-AKT), NF-kappa B, and B-cell lymphoma 2 (Bcl-2) cell survival factors while down-regulating the expression of p75 neurotrophin receptor (NTR), phospho-JNK, and Bcl-2-associated X protein apoptosis factors. HDACi treatment also increased the expression of the stem cell biomarker nestin, and decreased the expression of reactive astrocyte biomarker GFAP within damaged tissue following TBI. These findings provide further insight into the mechanisms by which HDACi treatment after TBI is neuroprotective and support the continued study of HDACis following acute TBI. C1 [Lu, Jie; Turtzo, L. Christine; Wu, Chenxi; Sun, Zhongchan; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Frerich, Jason M.; Li, Siqi; Yang, Chunzhang; Wang, Xiaoping; Zhang, Chao; Zhuang, Zhengping; Brady, Roscoe O.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Chiang, Jeffrey] NCI, NIH, Bethesda, MD 20892 USA. [Lu, Jie; Turtzo, L. Christine; Chen, Xiaoyuan] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; bradyr@ninds.nih.gov; shawn.chen@nih.gov FU Department of Defense in the Center for Neuroscience and Regenerative Medicine; Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NINDS; Imaging Sciences Training Program (sponsored by Radiology and Imaging Sciences in the Clinical Center and Intramural Research Programs of the NIBIB); Howard Hughes Medical Institute-NIH Medical Research Scholars Program FX We thank Dr. Paul E. Gallant [National Institute of Neurological Disorders and Stroke (NINDS) Light Microscopy Facility] for assistance with confocal microscopy, Dr. Dragan Maric (NINDS Flow Cytometry Core Facility) for assistance with flow cytometry, and Lixte Biotechnology Holdings for providing LB-205. This work was supported by the Department of Defense in the Center for Neuroscience and Regenerative Medicine, Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NINDS, Imaging Sciences Training Program (sponsored by Radiology and Imaging Sciences in the Clinical Center and Intramural Research Programs of the NIBIB) (J.L.), and Howard Hughes Medical Institute-NIH Medical Research Scholars Program (J.M.F.). NR 39 TC 26 Z9 28 U1 1 U2 10 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 JUN 25 PY 2013 VL 110 IS 26 BP 10747 EP 10752 DI 10.1073/pnas.1308950110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179EY UT WOS:000321503700067 PM 23754423 ER PT J AU Chen, Y Pasapera, AM Koretsky, AP Waterman, CM AF Chen, Yun Pasapera, Ana M. Koretsky, Alan P. Waterman, Clare M. TI Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mechanosensing; integrin; tissue mechanics ID CALPAIN-MEDIATED PROTEOLYSIS; ENDOTHELIAL-CELLS; GENE-EXPRESSION; CYCLIC STRETCH; CARDIAC MYOCYTES; KINASE INHIBITOR; SKELETAL-MUSCLE; SRC; ACTIVATION; FAK AB Cells are mechanosensitive to extracellular matrix (ECM) deformation, which can be caused by muscle contraction or changes in hydrostatic pressure. Focal adhesions (FAs) mediate the linkage between the cell and the ECM and initiate mechanically stimulated signaling events. We developed a stretching apparatus in which cells grown on fibronectin-coated elastic substrates can be stretched and imaged live to study how FAs dynamically respond to ECM deformation. Human bone osteosarcoma epithelial cell line U2OS was transfected with GFP-paxillin as an FA marker and subjected to sustained uniaxial stretching. Two responses at different timescales were observed: rapid FA growth within seconds after stretching, and delayed FA disassembly and loss of cell polarity that occurred over tens of minutes. Rapid FA growth occurred in all cells; however, delayed responses to stretch occurred in an orientation-specificmanner, specifically in cells with their long axes perpendicular to the stretching direction, but not in cells with their long axes parallel to stretch. Pharmacological treatments demonstrated that FA kinase (FAK) promotes but Src inhibits rapid FA growth, whereas FAK, Src, and calpain 2 all contribute to delayed FA disassembly and loss of polarity in cells perpendicular to stretching. Immunostaining for phospho-FAK after stretching revealed that FAK activation was maximal at 5 s after stretching, specifically in FAs oriented perpendicular to stretch. We hypothesize that orientation-specific activation of strain/stress-sensitive proteins in FAs upstream to FAK and Src promote orientation-specific responses in FA growth and disassembly that mediate polarity rearrangement in response to sustained stretch. C1 [Chen, Yun; Koretsky, Alan P.] NINDS, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. [Pasapera, Ana M.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Waterman, CM (reprint author), NINDS, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Waterman, Clare/0000-0001-6142-6775; Chen, Yun/0000-0001-6917-7814 FU National Research Council Fellowship; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke FX We thank Sergey Plotinikov, Robert Fischer, and Ingo Thievessen for helpful discussions; Bill Shin for maintaining microscopes in the C.M.W. laboratory; and Ruperto Villadiego for helping build the cell stretcher. This work was supported by the National Research Council Fellowship (to Y.C.) and the intramural programs of the National Heart, Lung, and Blood Institute (A.M.P. and C.M.W.) and the National Institute of Neurological Disorders and Stroke (Y.C. and A.P.K.). NR 55 TC 15 Z9 15 U1 2 U2 19 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 JUN 25 PY 2013 VL 110 IS 26 BP E2352 EP E2361 DI 10.1073/pnas.1221637110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179EY UT WOS:000321503700007 PM 23754369 ER PT J AU Truong, QA Hayden, D Woodard, PK Kirby, R Chou, ET Nagurney, JT Wiviott, SD Fleg, JL Schoenfeld, DA Udelson, JE Hoffmann, U AF Truong, Quynh A. Hayden, Douglas Woodard, Pamela K. Kirby, Ruth Chou, Eric T. Nagurney, John T. Wiviott, Stephen D. Fleg, Jerome L. Schoenfeld, David A. Udelson, James E. Hoffmann, Udo TI Sex Differences in the Effectiveness of Early Coronary Computed Tomographic Angiography Compared With Standard Emergency Department Evaluation for Acute Chest Pain The Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II Trial SO CIRCULATION LA English DT Article DE acute coronary syndrome; chest pain; emergency service, hospital; sex; tomography; x-ray computed ID AMERICAN-HEART-ASSOCIATION; CT ANGIOGRAPHY; ARTERY-DISEASE; CARDIOVASCULAR-RADIOLOGY; DIAGNOSTIC PERFORMANCE; CLINICAL-CARDIOLOGY; DOSE REDUCTION; RADIATION; RISK; INTERVENTION AB Background We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) and standard emergency department (ED) evaluation in patients with acute chest pain. Methods and Results In the Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II multicenter, controlled trial, we randomized 1000 patients (47% women) 40 to 74 years of age with symptoms suggestive of acute coronary syndrome to an early CCTA or standard ED evaluation. In this prespecified analysis, women in the CCTA arm had a greater reduction in length of stay, lower hospital admission rates, and lesser increased cumulative radiation dose than men in a comparison of ED strategies (P for interaction 0.02). Although women had lower acute coronary syndrome rates than men (3% versus 12%; P<0.0001), sex differences in length of stay persisted after adjustment for baseline differences, including acute coronary syndrome rate (P for interaction <0.03). Length of stay was similar between sexes with normal CCTA findings (P=0.11). There was no missed acute coronary syndrome for either sex. No difference was observed in major adverse cardiac events between sexes and ED strategies (P for interaction =0.39). Women had more normal CCTA examinations than men (58% versus 37%; P<0.0001), less obstructive coronary disease by CCTA (5% versus 17%; P=0.0001), but similar normalcy rates for functional testing (P=0.65). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), whereas women had comparable low 5% rates regardless of ED strategy. Conclusions This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of acute coronary syndrome. The findings may be explained by lower CAD prevalence and severity in women than men. C1 [Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program,Div Cardiol, Boston, MA 02114 USA. [Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Emergency Dept, Boston, MA 02114 USA. [Hayden, Douglas; Schoenfeld, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Kirby, Ruth; Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Chou, Eric T.] Kaiser Permanente Fontana Med Ctr, Fontana, CA USA. [Wiviott, Stephen D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02114 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. RP Truong, QA (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, 165 Cambridge St,Ste 400, Boston, MA 02114 USA. EM qtruong@partners.org FU National Institutes of Health/National Heart, Lung, and Blood Institute [U01HL092040, U01HL092022, K23HL098370, L30HL093896]; Qi Imaging; St. Jude Medical; American College of Radiology Imaging Network; Duke Clinical Research Institute FX The study was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022). Dr Truong was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL098370 and L30HL093896).; Dr Truong receives grant support from Qi Imaging, St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute. The other authors report no conflicts. NR 22 TC 9 Z9 9 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 25 PY 2013 VL 127 IS 25 BP 2494 EP 2502 DI 10.1161/CIRCULATIONAHA.113.001736 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 171HU UT WOS:000320916900013 PM 23685743 ER PT J AU Sommers, CL Rouquette-Jazdanian, AK Robles, AI Kortum, RL Merrill, RK Li, WM Nath, N Wohlfert, E Sixt, KM Belkaid, Y Samelson, LE AF Sommers, Connie L. Rouquette-Jazdanian, Alexandre K. Robles, Ana I. Kortum, Robert L. Merrill, Robert K. Li, Wenmei Nath, Nandan Wohlfert, Elizabeth Sixt, Katherine M. Belkaid, Yasmine Samelson, Lawrence E. TI miRNA Signature of Mouse Helper T Cell Hyper-Proliferation SO PLOS ONE LA English DT Article ID LYMPHOPROLIFERATIVE DISEASE; HOMEOSTATIC PROLIFERATION; ERK ACTIVATION; MUTANT MICE; EXPRESSION; MIR-146A; CANCER; LAT; MICRORNA-21; PATHWAY AB Helper T cells from a mutant mouse model, LAT Y136F, hyper-proliferate and cause a severe lymphoproliferative disease that kills the mice by six months of age. LAT Y136F mice carry a tyrosine to phenylalanine mutation in the Linker for Activation of T cells (LAT) gene. This mutation leads to a number of changes in T cells that result in altered cytokine production including increased IL-4 production, increased proliferation, and decreased apoptosis. Hyper-proliferation of the mutant T cells contributes to lymphadenopathy, splenomegaly, and multi-organ T cell infiltration. miRNAs are short non-coding RNAs that regulate expression of cohorts of genes. This study investigates which miRNAs are expressed in LAT Y136F T cells and compares these to miRNAs expressed in wild type T cells that are undergoing proliferation in two other settings. The first setting is homeostatic proliferation, which was modeled by adoptive transfer of wild type T cells into T cell-deficient mice. The second setting is proliferation in response to infection, which was modeled by infection of wild type mice with the nematode H. polygyrus. By comparing miRNA expression in these three proliferative states (LAT Y136F hyper-proliferation, homeostatic proliferation and proliferation in response to H. polygyrus infection) to expression in wild type naive CD4(+) T cells, we found miRNAs that were highly regulated in all three proliferative states (miR-21 and miR-146a) and some that were more specific to individual settings of proliferation such as those more specific for LAT Y136F lymphoproliferative disease (miR-669f, miR-155 and miR-466a/b). Future experiments that modulate levels of the miRNAs identified in this study may reveal the roles of these miRNAs in T cell proliferation and/or lymphoproliferative disease. C1 [Sommers, Connie L.; Rouquette-Jazdanian, Alexandre K.; Kortum, Robert L.; Merrill, Robert K.; Li, Wenmei; Nath, Nandan; Sixt, Katherine M.; Samelson, Lawrence E.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Robles, Ana I.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sommers, Connie L.; Wohlfert, Elizabeth; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sommers, CL (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM sommersc@helix.nih.gov FU National Cancer Institute Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2013 VL 8 IS 6 AR e66709 DI 10.1371/journal.pone.0066709 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175IB UT WOS:000321223000023 PM 23825558 ER PT J AU Krist, AH Glenn, BA Glasgow, RE Balasubramanian, BA Chambers, DA Fernandez, ME Heurtin-Roberts, S Kessler, R Ory, MG Phillips, SM Ritzwoller, DP Roby, DH Rodriguez, HP Sabo, RT Gorin, SNS Stange, KC AF Krist, Alex H. Glenn, Beth A. Glasgow, Russell E. Balasubramanian, Bijal A. Chambers, David A. Fernandez, Maria E. Heurtin-Roberts, Suzanne Kessler, Rodger Ory, Marcia G. Phillips, Siobhan M. Ritzwoller, Debra P. Roby, Dylan H. Rodriguez, Hector P. Sabo, Roy T. Gorin, Sherri N. Sheinfeld Stange, Kurt C. CA MOHR Study Grp TI Designing a valid randomized pragmatic primary care implementation trial: the my own health report (MOHR) project SO IMPLEMENTATION SCIENCE LA English DT Article DE Patient-reported measures; Health behaviors; Mental health; Pragmatic trial; Electronic health record; Primary care ID BEHAVIORAL-COUNSELING INTERVENTIONS; DECISION-MAKING; UNDERSERVED COMMUNITY; EDUCATIONAL OUTREACH; PREVENTIVE-SERVICES; SCREENING-TEST; SCIENCE; CANCER; PHYSICIANS; CONTEXT AB Background: There is a pressing need for greater attention to patient-centered health behavior and psychosocial issues in primary care, and for practical tools, study designs and results of clinical and policy relevance. Our goal is to design a scientifically rigorous and valid pragmatic trial to test whether primary care practices can systematically implement the collection of patient-reported information and provide patients needed advice, goal setting, and counseling in response. Methods: This manuscript reports on the iterative design of the My Own Health Report (MOHR) study, a cluster randomized delayed intervention trial. Nine pairs of diverse primary care practices will be randomized to early or delayed intervention four months later. The intervention consists of fielding the MOHR assessment - addresses 10 domains of health behaviors and psychosocial issues - and subsequent provision of needed counseling and support for patients presenting for wellness or chronic care. As a pragmatic participatory trial, stakeholder groups including practice partners and patients have been engaged throughout the study design to account for local resources and characteristics. Participatory tasks include identifying MOHR assessment content, refining the study design, providing input on outcomes measures, and designing the implementation workflow. Study outcomes include the intervention reach (percent of patients offered and completing the MOHR assessment), effectiveness (patients reporting being asked about topics, setting change goals, and receiving assistance in early versus delayed intervention practices), contextual factors influencing outcomes, and intervention costs. Discussion: The MOHR study shows how a participatory design can be used to promote the consistent collection and use of patient-reported health behavior and psychosocial assessments in a broad range of primary care settings. While pragmatic in nature, the study design will allow valid comparisons to answer the posed research question, and findings will be broadly generalizable to a range of primary care settings. Per the pragmatic explanatory continuum indicator summary (PRECIS) framework, the study design is substantially more pragmatic than other published trials. The methods and findings should be of interest to researchers, practitioners, and policy makers attempting to make healthcare more patient-centered and relevant. C1 [Krist, Alex H.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Richmond, VA 23298 USA. [Glenn, Beth A.; Roby, Dylan H.; Rodriguez, Hector P.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90095 USA. [Glasgow, Russell E.; Heurtin-Roberts, Suzanne; Phillips, Siobhan M.] NCI, Implementat Sci Team, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Balasubramanian, Bijal A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Dallas, TX 75390 USA. [Chambers, David A.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Fernandez, Maria E.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Kessler, Rodger] Vermont Coll Med, Dept Family Med, Burlington, VT 05405 USA. [Ory, Marcia G.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX 77843 USA. [Ritzwoller, Debra P.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80231 USA. [Sabo, Roy T.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Gorin, Sherri N. Sheinfeld] NCI, SAIC Frederick, NIH, DCCPS, Bethesda, MD 20892 USA. [Gorin, Sherri N. Sheinfeld] NYPAC, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Krist, AH (reprint author), Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, POB 980251, Richmond, VA 23298 USA. EM ahkrist@vcu.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; Office of Behavioral and Social Sciences Research; National Center for Advancing Translational Sciences (CTSA) [ULTR00058] FX Funding for the MOHR project was provided by the National Cancer Institute, Agency for Healthcare Research and Quality, Office of Behavioral and Social Sciences Research, and National Center for Advancing Translational Sciences (CTSA Grant Number ULTR00058). Dr. Stange's time is supported in part by a Clinical Research Professorship from the American Cancer Society and by the National Cancer Society through the Intergovernmental Personnel Act. The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the funders. For their support and guidance of the MOHR project we would like to thank Janice Genervro PhD MSW, David Meyers MD, Robert M Kaplan PhD, Holly Jimison PhD, Richard Wood MHA, Kayla Fair RN MPH, Jennifer Leeman PHD MPH, Catherine L Rohweder DrPH, Alexis Moore MPH, Maria E Fernandez PhD, John Quillin PhD CGC, Melissa Hayes BS, Paul Estabrooks PhD, Christine Nelson PhD RN, and John Heintzman MD MPH. NR 71 TC 19 Z9 19 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUN 25 PY 2013 VL 8 AR 73 DI 10.1186/1748-5908-8-73 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 171NB UT WOS:000320935000001 PM 23799943 ER PT J AU Pearson, GD Kaltman, JR Lauer, MS AF Pearson, Gail D. Kaltman, Jonathan R. Lauer, Michael S. TI Evidence-Based Medicine Comes of Age in Pediatric Cardiology SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE congenital heart disease; congenital heart surgery; pediatric cardiovascular research. ID NATIONAL HEART; LUNG AB Outcomes have improved significantly in pediatric cardiovascular disease in recent decades. The challenge now is to sustain these advances through innovative clinical trials, fundamental molecular investigations, genetics and genomics, and outreach to families, emphasizing the importance of participating in research. We describe several such efforts and provide a vision of the future for pediatric cardiovascular research. (J Am Coll Cardiol 2013;61:2565-7) (C) 2013 by the American College of Cardiology Foundation C1 [Pearson, Gail D.; Kaltman, Jonathan R.; Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Pearson, GD (reprint author), NHLBI, Adult & Pediat Cardiac Res Program, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8132, Bethesda, MD 20892 USA. EM pearsong@mail.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 11 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 25 PY 2013 VL 61 IS 25 BP 2565 EP 2567 DI 10.1016/j.jacc.2013.03.054 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 167AO UT WOS:000320602700011 PM 23623909 ER PT J AU Emery, AC Eiden, MV Mustafa, T Eiden, LE AF Emery, Andrew C. Eiden, Maribeth V. Mustafa, Tomris Eiden, Lee E. TI Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in Neuronal and Endocrine Cells SO SCIENCE SIGNALING LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; NERVE GROWTH-FACTOR; DROSOPHILA PDZ-GEF; PROTEIN-KINASE; FACTOR CNRASGEF; CYCLIC-AMP; SYNAPTIC PLASTICITY; POLYPEPTIDE PACAP; PC12 CELLS AB G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR)-mediated increases in the second messenger cyclic adenosine monophosphate (cAMP) activate the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), and in neuroendocrine cells, this pathway leads to cAMP-dependent neuritogenesis mediated through Rap1 and B-Raf. We found that the Rap guanine nucleotide exchange factor Rapgef2 was enriched from primary bovine neuroendocrine cells by cAMP-agarose affinity chromatography and that it was specifically eluted by cAMP. With loss-of-function experiments in the rat neuronal cell line Neuroscreen-1 (NS-1) and gain-of-function experiments in human embryonic kidney 293T cells, we demonstrated that Rapgef2 connected GPCR-dependent activation of adenylate cyclase and increased cAMP concentration with the activation of ERK in neurons and endocrine cells. Furthermore, knockdown of Rapgef2 blocked cAMP-and ERK-dependent neuritogenesis. Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity. C1 [Emery, Andrew C.; Mustafa, Tomris; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. [Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Emery, Andrew/0000-0002-6760-2570; Eiden, Lee/0000-0001-7524-944X FU NIH [1ZIAMH002386, 1ZIAMH002592] FX This work was funded by the Intramural Research Program of the NIH Projects 1ZIAMH002386 (to L.E.E.) and 1ZIAMH002592 (to M.V.E.). NR 58 TC 14 Z9 20 U1 0 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 J9 SCI SIGNAL JI Sci. Signal. PD JUN 25 PY 2013 VL 6 IS 281 AR ra51 DI 10.1126/scisignal.2003993 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 170LU UT WOS:000320853200002 PM 23800469 ER PT J AU Harper, MT Londono, JEC Quick, K Londono, JC Flockerzi, V Philipp, SE Birnbaumer, L Freichel, M Poole, AW AF Harper, Matthew T. Londono, Juan E. Camacho Quick, Kathryn Londono, Julia Camacho Flockerzi, Veit Philipp, Stephan E. Birnbaumer, Lutz Freichel, Marc Poole, Alastair W. TI Transient Receptor Potential Channels Function as a Coincidence Signal Detector Mediating Phosphatidylserine Exposure SO SCIENCE SIGNALING LA English DT Article ID OPERATED CALCIUM-CHANNELS; SMOOTH-MUSCLE-CELLS; HUMAN-PLATELETS; NA+/CA2+ EXCHANGER; CA2+ ENTRY; TRPC3 CHANNELS; ACTIVATION; THROMBIN; MOUSE; ORAI1 AB Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates G(q)-coupled protease-activated receptors, and collagen-related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca2+ entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C(TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na+, which coupled to reverse-mode Na+/Ca2+ exchange to allow calcium influx and thereby contribute to Ca2+ signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine. C1 [Harper, Matthew T.; Poole, Alastair W.] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. [Londono, Juan E. Camacho; Freichel, Marc] Heidelberg Univ, Inst Pharmacol, D-69120 Heidelberg, Germany. [Londono, Juan E. Camacho; Londono, Julia Camacho; Flockerzi, Veit; Philipp, Stephan E.; Freichel, Marc] Univ Saarland, Fac Med, Dept Expt & Clin Pharmacol & Toxicol, D-66424 Homburg, Germany. [Quick, Kathryn] UCL, Wolfson Inst Bioned Res, Mol Nocicept Grp, London WC1E 6BT, England. [Birnbaumer, Lutz] NIH, Transmembrane Signaling Grp, Res Triangle Pk, NC 27709 USA. RP Harper, MT (reprint author), Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. EM m.harper@bris.ac.uk; a.poole@bris.ac.uk RI Harper, Matthew/G-5630-2013 OI Harper, Matthew/0000-0002-4740-637X FU British Heart Foundation [RG/10/006/28299]; Klinische Forschergruppe [196]; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); "Forschungsausschuss" and "HOMFOR" program der Universitat des Saarlandes; Deutsche Forschungsgemeinschaft [GK 1326, SFB 530]; Biotechnology and Biological Sciences Research Council [BB/F000227/1]; NIH [Z01-ES101684] FX This work was supported by the British Heart Foundation (program grant RG/10/006/28299; M.T.H. and A.W.P.), the Klinische Forschergruppe 196, DZHK (German Centre for Cardiovascular Research), the BMBF (German Ministry of Education and Research), the "Forschungsausschuss" and "HOMFOR" program der Universitat des Saarlandes (M.F.), the Deutsche Forschungsgemeinschaft (GK 1326 and SFB 530; S.E.P.), the Biotechnology and Biological Sciences Research Council (BB/F000227/1; K.Q.), and the Intramural Research Program of the NIH (project Z01-ES101684; L.B.). NR 59 TC 26 Z9 26 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 25 PY 2013 VL 6 IS 281 AR ra50 DI 10.1126/scisignal.2003701 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 170LU UT WOS:000320853200001 PM 23800468 ER PT J AU Yan, Y Kong, H Wu, EJ Newman, AH Xu, M AF Yan, Y. Kong, H. Wu, E. J. Newman, A. H. Xu, M. TI DOPAMINE D3 RECEPTORS REGULATE RECONSOLIDATION OF COCAINE MEMORY SO NEUROSCIENCE LA English DT Article DE dopamine D3 receptor; reconsolidation; reward learning; cocaine; mutant mice; antagonist PG01037 ID NUCLEUS-ACCUMBENS CORE; DRUG-SEEKING BEHAVIOR; D-3 RECEPTORS; PROTEIN-SYNTHESIS; INDUCED REINSTATEMENT; BASOLATERAL AMYGDALA; PROGRESSIVE-RATIO; BRAIN REWARD; ADDICTION; EXTINCTION AB Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates the acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-min (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least 1 week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Yan, Y.; Kong, H.; Xu, M.] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. [Wu, E. J.] Univ Colorado, Boulder, CO 80309 USA. [Newman, A. H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Xu, M (reprint author), Univ Chicago, Dept Anesthesia & Crit Care, Box 428, Chicago, IL 60637 USA. EM mxu@dacc.uchicago.edu FU NIDA [DA17323, DA025088]; NIDA Intramural Research Program FX We greatly appreciate Dr. H. Jiao's assistance for mouse genotyping, Dr. J. Katz for discussions and suggestions, and J. Cao for synthesizing PG01037. M.X. was supported by Grants from NIDA (DA17323 and DA025088). A.H.N was supported by the NIDA Intramural Research Program. NR 67 TC 7 Z9 7 U1 0 U2 19 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 JUN 25 PY 2013 VL 241 BP 32 EP 40 DI 10.1016/j.neuroscience.2013.03.005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 146MY UT WOS:000319096400004 PM 23506736 ER PT J AU Keil, MF Briassoulis, G Nesterova, M Miraftab, N Gokarn, N Wu, TJ Stratakis, CA AF Keil, M. F. Briassoulis, G. Nesterova, M. Miraftab, N. Gokarn, N. Wu, T. J. Stratakis, C. A. TI THREAT BIAS IN MICE WITH INACTIVATING MUTATIONS OF Prkar1a SO NEUROSCIENCE LA English DT Article DE protein kinase A; amygdala; orbitofrontal cortex; anxiety; Prkar1a; threat detection ID PROTEIN-KINASE-A; LONG-TERM POTENTIATION; PREFRONTAL CORTEX; MEMORY CONSOLIDATION; BASOLATERAL AMYGDALA; SIGNALING PATHWAYS; REGULATORY SUBUNIT; CARNEY COMPLEX; DEFENSIVE BEHAVIORS; ANATOMICAL LOCATION AB Anxiety disorders are associated with abnormalities in the neural processing of threat-related stimuli. However, the neurobiological mechanisms underlying threat bias in anxiety are not well understood. We recently reported that a Prkar1a heterozygote (Prkar1a(+/-)) mouse with haploinsufficiency for the main regulatory subunit (R1 alpha) of protein kinase A (PKA) exhibits an anxiety-like phenotype associated with increased cAMP signaling in the amygdala. Prkar1a(+/-) mice provide a novel model to test the direct effect of altered PKA expression and subsequent anxiety-like behavioral phenotype on the response to threat. We hypothesized that Prkar1a(+/-) mice would exhibit a bias in threat detection since increased amygdala activity during emotional stimuli is associated with a maladaptive response. We measured behavior and PKA activity in brain areas after exposure to predator or control odor exposure in male Prkar1a(+/-) and wild-type (WT) littermates. Indeed, there were significant differences in the behavioral response to threat detection; WT mice showed the expected response of decrease in exploratory behavior during predator vs. control odor exposure, while Prkar1a(+/-) mice did not alter their behavior between conditions. Basal and total PICA activity was independently associated with genotype, with an interaction between genotype and threat condition. Prkar1a(+/-) mice had higher PICA activity in amygdala and ventromedial hypothalamus in response to predator odor. In contrast, WT mice had higher PKA activity in amygdala and orbitofrontal cortex after exposure to control odor. Dysregulated PKA activity in the amygdala-prefrontal cortex circuitry in Prkar1a(+/-) mice is associated with behavioral phenotype of anxiety and a bias for threat. This is likely related to a failure to inhibit the amydgala response, which is an effect of the genotype. These results suggest that the alteration in PKA signaling in Prkar1a(+/-) mice is not ubiquitous in the brain; tissue-specific effects of the cAMP/PKA pathway are related to threat detection and fear sensitization. Published by Elsevier Ltd. on behalf of IBRO. C1 [Keil, M. F.; Briassoulis, G.; Nesterova, M.; Miraftab, N.; Gokarn, N.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Keil, M. F.; Wu, T. J.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Keil, M. F.; Wu, T. J.] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. RP Keil, MF (reprint author), NICHD, NIH, PDEGEN, 10 Ctr Dr,Bldg 10 CRC,Room 1 E 3330, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU NICHD, NIH [Z01-HD-000642-04]; Department of Pediatrics, University of Crete, Heraklion, Crete, Greece; Uniformed Services University of the Health Sciences; Department of Defense [CO85DP, DMRDP 061 I-10 J6 125] FX This work was supported by NICHD, NIH intramural project Z01-HD-000642-04 to Dr. C. A. Stratakis. It was also supported in part by the Department of Pediatrics, University of Crete, Heraklion, Crete, Greece (G. Briassoulis). Finally, part of this work was also supported by intramural graduate student grant from the Uniformed Services University of the Health Sciences (MFK) and Department of Defense grants CO85DP and DMRDP 061 I-10 J6 125 (TJW). NR 67 TC 3 Z9 4 U1 1 U2 6 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 JUN 25 PY 2013 VL 241 BP 206 EP 214 DI 10.1016/j.neuroscience.2013.03.027 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 146MY UT WOS:000319096400020 PM 23531435 ER PT J AU Becker, AM Dao, KH Han, BK Kornu, R Lakhanpal, S Mobley, AB Li, QZ Lian, Y Wu, TF Reimold, AM Olsen, NJ Karp, DR Chowdhury, FZ Farrar, JD Satterthwaite, AB Mohan, C Lipsky, PE Wakeland, EK Davis, LS AF Becker, Amy M. Dao, Kathryn H. Han, Bobby Kwanghoon Kornu, Roger Lakhanpal, Shuchi Mobley, Angela B. Li, Quan-Zhen Lian, Yun Wu, Tianfu Reimold, Andreas M. Olsen, Nancy J. Karp, David R. Chowdhury, Fatema Z. Farrar, J. David Satterthwaite, Anne B. Mohan, Chandra Lipsky, Peter E. Wakeland, Edward K. Davis, Laurie S. TI SLE Peripheral Blood B Cell, T Cell and Myeloid Cell Transcriptomes Display Unique Profiles and Each Subset Contributes to the Interferon Signature SO PLOS ONE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DISEASE-ACTIVITY; GENE-EXPRESSION; AUTOIMMUNE-DISEASE; PROTEIN-INTERACTION; IFN-ALPHA; MEMORY; ACTIVATION; ANTIBODIES; PATHWAYS AB Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+) CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+) CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE. C1 [Becker, Amy M.; Mobley, Angela B.; Li, Quan-Zhen; Lian, Yun; Chowdhury, Fatema Z.; Farrar, J. David; Satterthwaite, Anne B.; Mohan, Chandra; Wakeland, Edward K.] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Becker, Amy M.; Dao, Kathryn H.; Han, Bobby Kwanghoon; Kornu, Roger; Lakhanpal, Shuchi; Wu, Tianfu; Reimold, Andreas M.; Olsen, Nancy J.; Karp, David R.; Satterthwaite, Anne B.; Mohan, Chandra; Davis, Laurie S.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Lipsky, Peter E.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Davis, LS (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. EM Laurie.Davis@UTSouthwestern.edu OI Wu, Tianfu/0000-0001-8235-5929 FU National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [P50AR055503, R01AR45293]; UT Southwestern Arthritis Center Flow Cytometry Core; MedImmune; Novo Nordisk; Novo Nordisk, Genentech/Roche; Human Genome Sciences FX This work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant P50AR055503 (Mohan), the UT Southwestern Arthritis Center Flow Cytometry Core (Davis) and the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR45293 (Davis). Dr. Nancy Olsen has equity interest in a company, ArthroChip LLC, which develops assays for autoimmune diseases and she has also obtained funding from MedImmune, Novo Nordisk, Genentech/Roche and Human Genome Sciences. Dr. David Karp has received research funding from Human Genome Sciences. None of these funds were used for the current study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 33 Z9 33 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2013 VL 8 IS 6 AR e67003 DI 10.1371/journal.pone.0067003 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400092 PM 23826184 ER PT J AU Harel, A Bentin, S AF Harel, Assaf Bentin, Shlomo TI Are All Types of Expertise Created Equal? Car Experts Use Different Spatial Frequency Scales for Subordinate Categorization of Cars and Faces SO PLOS ONE LA English DT Article ID OBJECT RECOGNITION; VISUAL EXPERTISE; BASIC-LEVEL; AREA; PERCEPTION; INFORMATION; CORTEX; INTERFERENCE; SENSITIVITY; COMPETITION AB A much-debated question in object recognition is whether expertise for faces and expertise for non-face objects utilize common perceptual information. We investigated this issue by assessing the diagnostic information required for different types of expertise. Specifically, we asked whether face categorization and expert car categorization at the subordinate level relies on the same spatial frequency (SF) scales. Fifteen car experts and fifteen novices performed a category verification task with spatially filtered images of faces, cars, and airplanes. Images were categorized based on their basic (e.g. "car'') and subordinate level (e.g. "Japanese car'') identity. The effect of expertise was not evident when objects were categorized at the basic level. However, when the car experts categorized faces and cars at the subordinate level, the two types of expertise required different kinds of SF information. Subordinate categorization of faces relied on low SFs more than on high SFs, whereas subordinate expert car categorization relied on high SFs more than on low SFs. These findings suggest that expertise in the recognition of objects and faces do not utilize the same type of information. Rather, different types of expertise require different types of diagnostic visual information. C1 [Harel, Assaf] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Bentin, Shlomo] Hebrew Univ Jerusalem, Ctr Neural Computat, Jerusalem, Israel. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Harel, Assaf/0000-0002-4899-6156 FU NIMH [R01 MH 64458] FX This study was funded by NIMH grant R01 MH 64458 to Shlomo Bentin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 8 Z9 8 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2013 VL 8 IS 6 AR e67024 DI 10.1371/journal.pone.0067024 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400095 PM 23826188 ER PT J AU Hoobler, EK Rai, G Warrilow, AGS Perry, SC Smyrniotis, CJ Jadhav, A Simeonov, A Parker, JE Kelly, DE Maloney, DJ Kelly, SL Holman, TR AF Hoobler, Eric K. Rai, Ganesha Warrilow, Andrew G. S. Perry, Steven C. Smyrniotis, Christopher J. Jadhav, Ajit Simeonov, Anton Parker, Josie E. Kelly, Diane E. Maloney, David J. Kelly, S. L. Holman, Theodore R. TI Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy SO PLOS ONE LA English DT Article ID MONOXIDE-BINDING PIGMENT; SELECTIVE INHIBITORS; CANDIDA-ALBICANS; PHENYLENEDIAMINE DERIVATIVES; NORDIHYDROGUAIARETIC ACID; SEBORRHEIC DERMATITIS; LIVER MICROSOMES; ACCURATE DOCKING; WHOLE-BLOOD; LIPOXYGENASE AB We report the discovery of a novel dual inhibitor targeting fungal sterol 14 alpha-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 mu M. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component. C1 [Hoobler, Eric K.; Perry, Steven C.; Smyrniotis, Christopher J.; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Rai, Ganesha; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Warrilow, Andrew G. S.; Parker, Josie E.; Kelly, Diane E.; Kelly, S. L.] Swansea Univ, Coll Med, Inst Life Sci, Swansea, W Glam, Wales. RP Maloney, DJ (reprint author), NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM maloneyd@mail.nih.gov; s.l.kelly@swansea.ac.uk; holman@ucsc.edu OI Warrilow, Andrew/0000-0003-0183-8334; Parker, Josie/0000-0002-3855-4194 FU National Institutes of Health [GM56062, S10-RR20939]; Welsh Government (SLK); ERDF, via the Beacon project FX This work was supported by the National Institutes of Health (GM56062 (TRH) S10-RR20939 (UCSC MS Equipment grant), the Welsh Government (SLK) and the ERDF, via the Beacon project (SLK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 5 Z9 5 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2013 VL 8 IS 6 AR e65928 DI 10.1371/journal.pone.0065928 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400006 PM 23826084 ER PT J AU Perl, S Perlman, J Weitzel, RP Phang, O Hsieh, MM Tisdale, J AF Perl, Shira Perlman, Jordan Weitzel, R. P. Phang, Oswald Hsieh, Matthew M. Tisdale, John TI Addition of Rapamycin to Anti-CD3 Antibody Improves Long-Term Glycaemia Control in Diabetic NOD Mice SO PLOS ONE LA English DT Article ID T-CELLS; TYPE-1; TRIAL AB Aims/Hypothesis: Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia. Methods: Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control. Results: Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35). Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05). Conclusions/Interpretation: The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice. C1 [Perl, Shira] NHLBI, Ctr Human Immunol, NIH, Bethesda, MD 20892 USA. [Perl, Shira; Perlman, Jordan; Weitzel, R. P.; Phang, Oswald; Hsieh, Matthew M.; Tisdale, John] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Perl, S (reprint author), NHLBI, Ctr Human Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM perls@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute at the National Institutes of Health FX This work is supported by the intramural research program of the National Heart, Lung, and Blood Institute at the 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 11 TC 4 Z9 4 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2013 VL 8 IS 6 AR e67189 DI 10.1371/journal.pone.0067189 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400116 PM 23826229 ER PT J AU Wang, XJ Misawa, R Zielinski, MC Cowen, P Jo, JH Periwal, V Ricordi, C Khan, A Szust, J Shen, JH Millis, M Witkowski, P Hara, M AF Wang, Xiaojun Misawa, Ryosuke Zielinski, Mark C. Cowen, Peter Jo, Junghyo Periwal, Vipul Ricordi, Camillo Khan, Aisha Szust, Joel Shen, Junhui Millis, Michael Witkowski, Piotr Hara, Manami TI Regional Differences in Islet Distribution in the Human Pancreas - Preferential Beta-Cell Loss in the Head Region in Patients with Type 2 Diabetes SO PLOS ONE LA English DT Article ID RAT; ARCHITECTURE; POLYPEPTIDE; CANCER; SECRETION; SURVIVAL; INSULIN; MICE; MASS; QUANTIFICATION AB While regional heterogeneity in islet distribution has been well studied in rodents, less is known about human pancreatic histology. To fill gaps in our understanding, regional differences in the adult human pancreas were quantitatively analyzed including the pathogenesis of type 2 diabetes (T2D). Cadaveric pancreas specimens were collected from the head, body and tail regions of each donor, including subjects with no history of diabetes or pancreatic diseases (n = 23) as well as patients with T2D (n = 12). The study further included individuals from whom islets were isolated (n = 7) to study islet yield and function in a clinical setting of islet transplantation. The whole pancreatic sections were examined using an innovative large-scale image capture and unbiased detailed quantitative analyses of the characteristics of islets from each individual (architecture, size, shape and distribution). Islet distribution/density is similar between the head and body regions, but is >2-fold higher in the tail region. In contrast to rodents, islet cellular composition and architecture were similar throughout the pancreas and there was no difference in glucose-stimulated insulin secretion in islets isolated from different regions of the pancreas. Further studies revealed preferential loss of large islets in the head region in patients with T2D. The present study has demonstrated distinct characteristics of the human pancreas, which should provide a baseline for the future studies integrating existing research in the field and helping to advance bi-directional research between humans and preclinical models. C1 [Wang, Xiaojun; Misawa, Ryosuke; Millis, Michael; Witkowski, Piotr] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Wang, Xiaojun] Third Mil Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing, Peoples R China. [Zielinski, Mark C.; Cowen, Peter; Shen, Junhui; Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Jo, Junghyo; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Ricordi, Camillo; Khan, Aisha; Szust, Joel] Univ Miami, Cell Transplant Ctr, Miami, FL USA. RP Hara, M (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM mhara@uchicago.edu RI Jo, Junghyo/D-4889-2011; OI Zielinski, Mark/0000-0002-6950-6689; Ricordi, Camillo/0000-0001-8092-7153 FU US Public Health Service Grant [DK-020595, DK-072473, AG-042151]; intramural research program of the NIH, NIDDK FX The study is supported by US Public Health Service Grant DK-020595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, AG-042151, and a gift from the Kovler Family Foundation (to MH); and the intramural research program of the NIH, NIDDK (to JJ and VP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 25 Z9 25 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2013 VL 8 IS 6 AR e67454 DI 10.1371/journal.pone.0067454 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JP UT WOS:000321738400149 PM 23826303 ER PT J AU Schwartz, JAT Pearson, SD AF Schwartz, Jennifer A. T. Pearson, Steven D. TI Cost Consideration in the Clinical Guidance Documents of Physician Specialty Societies in the United States SO JAMA INTERNAL MEDICINE LA English DT Article ID PRACTICE GUIDELINES; AMERICAN-COLLEGE; TASK-FORCE; HEART-ASSOCIATION; MEDICINE; ALLOCATION; CARDIOLOGY; ISSUES; CARE AB Importance: Despite increasing concerns regarding the cost of health care, the consideration of costs in the development of clinical guidance documents by physician specialty societies has received little analysis. Objective: To evaluate the approach to consideration of cost in publicly available clinical guidance documents and methodological statements produced between 2008 and 2012 by the 30 largest US physician specialty societies. Design: Qualitative document review. Main Outcomes and Measures: Whether costs are considered in clinical guidance development, mechanism of cost consideration, and the way that cost issues were used in support of specific clinical practice recommendations. Results: Methodological statements for clinical guidance documents indicated that 17 of 30 physician societies (57%) explicitly integrated costs, 4 (13%) implicitly considered costs, 3 (10%) intentionally excluded costs, and 6 (20%) made no mention. Of the 17 societies that explicitly integrated costs, 9 (53%) consistently used a formal system in which the strength of recommendation was influenced in part by costs, whereas 8 (47%) were inconsistent in their approach or failed to mention the exact mechanism for considering costs. Among the 138 specific recommendations in these guidance documents that included cost as part of the rationale, the most common form of recommendation (50 [36%]) encouraged the use of a specific medical service because of equal effectiveness and lower cost. Conclusions and Relevance: Slightly more than half of the largest US physician societies explicitly consider costs in developing their clinical guidance documents; among these, approximately half use an explicit mechanism for integrating costs into the strength of recommendations. Many societies remain vague in their approach. Physician specialty societies should demonstrate greater transparency and rigor in their approach to cost consideration in documents meant to influence care decisions. C1 [Schwartz, Jennifer A. T.; Pearson, Steven D.] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Review, Inst Technol Assessment, Boston, MA 02114 USA. RP Pearson, SD (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM pearsonsd@cc.nih.gov NR 39 TC 19 Z9 19 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUN 24 PY 2013 VL 173 IS 12 BP 1091 EP 1097 DI 10.1001/jamainternmed.2013.817 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 170OE UT WOS:000320861700014 PM 23649494 ER PT J AU Weigert, R Porat-Shliom, N Amornphimoltham, P AF Weigert, Roberto Porat-Shliom, Natalie Amornphimoltham, Panomwat TI Imaging cell biology in live animals: Ready for prime time SO JOURNAL OF CELL BIOLOGY LA English DT Review ID RAMAN SCATTERING MICROSCOPY; INTRAVITAL 2-PHOTON MICROSCOPY; GREEN FLUORESCENT PROTEIN; CD8(+) T-CELLS; IN-VIVO; SKELETAL-MUSCLE; DRUG-DELIVERY; LIVING MICE; BLOOD-FLOW; TUMOR MICROENVIRONMENT AB Time-lapse fluorescence microscopy is one of the main tools used to image subcellular structures in living cells. Yet for decades it has been applied primarily to in vitro model systems. Thanks to the most recent advancements in intravital microscopy, this approach has finally been extended to live rodents. This represents a major breakthrough that will provide unprecedented new opportunities to study mammalian cell biology in vivo and has already provided new insight in the fields of neurobiology, immunology, and cancer biology. C1 [Weigert, Roberto; Porat-Shliom, Natalie; Amornphimoltham, Panomwat] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 128 TC 34 Z9 35 U1 1 U2 43 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 JUN 24 PY 2013 VL 201 IS 7 BP 969 EP 979 DI 10.1083/jcb.201212130 PG 11 WC Cell Biology SC Cell Biology GA 169IK UT WOS:000320773500003 PM 23798727 ER PT J AU Michailidis, E Ryan, EM Hachiya, A Kirby, KA Marchand, B Leslie, MD Huber, AD Ong, YT Jackson, JC Singh, K Kodama, EN Mitsuya, H Parniak, MA Sarafianos, SG AF Michailidis, Eleftherios Ryan, Emily M. Hachiya, Atsuko Kirby, Karen A. Marchand, Bruno Leslie, Maxwell D. Huber, Andrew D. Ong, Yee T. Jackson, Jacob C. Singh, Kamalendra Kodama, Eiichi N. Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA SO RETROVIROLOGY LA English DT Article DE HIV-1; RT; EFdA; K65R ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; IN-VITRO SELECTION; DEPENDENT PRIMER UNBLOCKING; THYMIDINE ANALOG MUTATIONS; TREATMENT-NAIVE PATIENTS; HIGH-LEVEL RESISTANCE; DRUG-RESISTANCE; MOLECULAR-MECHANISMS; ANGSTROM RESOLUTION AB Background: The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials. Results: Here we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent. Conclusion: We have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains. C1 [Michailidis, Eleftherios; Ryan, Emily M.; Kirby, Karen A.; Marchand, Bruno; Leslie, Maxwell D.; Huber, Andrew D.; Ong, Yee T.; Jackson, Jacob C.; Singh, Kamalendra; Sarafianos, Stefan G.] Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Hachiya, Atsuko] Natl Hosp Org, Nagoya Med Ctr, Dept Infect Dis & Immunol, Clin Res Ctr, Nagoya, Aichi 4600001, Japan. [Kodama, Eiichi N.] Tohoku Univ, Div Emerging Infect Dis, Sendai, Miyagi 9808575, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Internal Med, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Parniak, Michael A.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. RP Sarafianos, SG (reprint author), Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Sarafianos, Stefan G/0000-0002-5840-154X; Kirby, Karen A./0000-0003-2468-4796 FU National Institutes of Health [AI076119, AI074389, AI076119-S1, AI076119-02S1, AI100890, AI099284, GM103368, AI079801] FX Dr. Tatiana Ilina's contribution in the preparation of the RT plasmids is acknowledged. This work was supported, in whole or in part, by National Institutes of Health grants AI076119, AI074389, AI076119-S1, AI076119-02S1, AI100890, AI099284, and GM103368 (S. G. S.) and AI079801 (M. A. P.). NR 72 TC 12 Z9 12 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 JUN 24 PY 2013 VL 10 AR 65 DI 10.1186/1742-4690-10-65 PG 12 WC Virology SC Virology GA 172QC UT WOS:000321018200001 PM 23800377 ER PT J AU Iordanova, MD Haralambous, T McNally, GP Westbrook, RF AF Iordanova, Mihaela D. Haralambous, Tatiana McNally, Gowan P. Westbrook, R. Frederick TI Accumbal opioid receptors modulate cue competition in one-trial overshadowing SO BRAIN RESEARCH LA English DT Article DE Fear; Rat; Ventral striatum; Attention; Morphine; Learning; Memory ID STIMULI; BLOCKING; LESIONS; SHELL; MODEL; RATS AB The contribution of opioid receptors in the nucleus accumbens to contextual and auditory fear conditioning was examined. Impairment in contextual fear conditioning was found when training occurred under accumbal infusions of the opioid receptor agonist morphine in a dose-dependent and receptor specific fashion, only when shock onset coincided with auditory stimulus offset. Contextual fear conditioning was spared, however when the delivery of shock was not signalled by an auditory stimulus, the auditory stimulus was of low intensity (70 dB), or an interval (10 s or 30 s) was interpolated between auditory stimulus offset and shock onset. These results provide evidence that opioid receptors in the nucleus accumbens regulate competition between contextual and discrete auditory stimuli for association formation. (C) 2013 Elsevier B.V. All rights reserved. C1 [Iordanova, Mihaela D.; Haralambous, Tatiana; McNally, Gowan P.; Westbrook, R. Frederick] Univ New S Wales, Sch Psychol, Sydney, NSW 2031, Australia. [Iordanova, Mihaela D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Iordanova, Mihaela D.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Iordanova, MD (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 20 Penn St,HSF 2, Baltimore, MD 21201 USA. EM iordanovam@gmail.com OI Iordanova, Mihaela/0000-0001-6232-448X FU Australian Research Council [DP110105136]; Australian Commonwealth Post Graduate Award [K99DA032649] FX This work was supported by a grant DP110105136 from the Australian Research Council to RFW, an Australian Commonwealth Post Graduate Award to TH, and grant K99DA032649 to MDI. NR 20 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 23 PY 2013 VL 1517 BP 57 EP 67 DI 10.1016/j.brainres.2013.04.019 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 173ME UT WOS:000321082800006 PM 23603410 ER PT J AU Golubeva, YG Smith, RM Sternberg, LR AF Golubeva, Yelena G. Smith, Roberta M. Sternberg, Lawrence R. TI Optimizing Frozen Sample Preparation for Laser Microdissection: Assessment of CryoJane Tape-Transfer System (R) SO PLOS ONE LA English DT Article ID CAPTURE MICRODISSECTION; TISSUE SAMPLES; EXPRESSION; SECTIONS; CANCER; BONE; RNA; DNA AB Laser microdissection is an invaluable tool in medical research that facilitates collecting specific cell populations for molecular analysis. Diversity of research targets (e.g., cancerous and precancerous lesions in clinical and animal research, cell pellets, rodent embryos, etc.) and varied scientific objectives, however, present challenges toward establishing standard laser microdissection protocols. Sample preparation is crucial for quality RNA, DNA and protein retrieval, where it often determines the feasibility of a laser microdissection project. The majority of microdissection studies in clinical and animal model research are conducted on frozen tissues containing native nucleic acids, unmodified by fixation. However, the variable morphological quality of frozen sections from tissues containing fat, collagen or delicate cell structures can limit or prevent successful harvest of the desired cell population via laser dissection. The CryoJane Tape-Transfer System (R), a commercial device that improves cryosectioning outcomes on glass slides has been reported superior for slide preparation and isolation of high quality osteocyte RNA (frozen bone) during laser dissection. Considering the reported advantages of CryoJane for laser dissection on glass slides, we asked whether the system could also work with the plastic membrane slides used by UV laser based microdissection instruments, as these are better suited for collection of larger target areas. In an attempt to optimize laser microdissection slide preparation for tissues of different RNA stability and cryosectioning difficulty, we evaluated the CryoJane system for use with both glass (laser capture microdissection) and membrane (laser cutting microdissection) slides. We have established a sample preparation protocol for glass and membrane slides including manual coating of membrane slides with CryoJane solutions, cryosectioning, slide staining and dissection procedure, lysis and RNA extraction that facilitated efficient dissection and high quality RNA retrieval from CryoJane preparations. CryoJane technology therefore has the potential to facilitate standardization of laser microdissection slide preparation from frozen tissues. C1 [Golubeva, Yelena G.; Smith, Roberta M.; Sternberg, Lawrence R.] Sci Applicat Int Corp, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Golubeva, YG (reprint author), Sci Applicat Int Corp, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. EM golubevay@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 2 Z9 2 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 21 PY 2013 VL 8 IS 6 AR e66854 DI 10.1371/journal.pone.0066854 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500109 PM 23805281 ER PT J AU Parra, GI Azure, J Fischer, R Bok, K Sandoval-Jaime, C Sosnovtsev, SV Sander, P Green, KY AF Parra, Gabriel I. Azure, JoLynn Fischer, Renate Bok, Karin Sandoval-Jaime, Carlos Sosnovtsev, Stanislav V. Sander, Peter Green, Kim Y. TI Identification of a Broadly Cross-Reactive Epitope in the Inner Shell of the Norovirus Capsid SO PLOS ONE LA English DT Article ID VIRUS-LIKE PARTICLES; BLOOD GROUP ANTIGENS; MONOCLONAL-ANTIBODIES; GENOGROUP-II; PROTEIN; GASTROENTERITIS; EXPRESSION; INFECTION; VACCINE; DETERMINANTS AB Noroviruses are major pathogens associated with acute gastroenteritis. They are diverse viruses, with at least six genogroups (GI-GVI) and multiple genotypes defined by differences in the major capsid protein, VP1. This diversity has challenged the development of broadly cross-reactive vaccines as well as efficient detection methods. Here, we report the characterization of a broadly cross-reactive monoclonal antibody (MAb) raised against the capsid protein of a GII. 3 norovirus strain. The MAb reacted with VLPs and denatured VP1 protein from GI, GII, GIV and GV noroviruses, and mapped to a linear epitope located in the inner shell domain. An alignment of all available VP1 sequences showed that the putative epitope (residues 52-56) is highly conserved across the genus Norovirus. This broadly cross-reactive MAb thus constitutes a valuable reagent for the diagnosis and study of these diverse viruses. C1 [Parra, Gabriel I.; Azure, JoLynn; Bok, Karin; Sandoval-Jaime, Carlos; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, DHHS,NIH, Bethesda, MD 20892 USA. [Fischer, Renate; Sander, Peter] R Biopharm AG, Clin Diagnost, Darmstadt, Germany. RP Parra, GI (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, DHHS,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM parrag@niaid.nih.gov; kgreen@niaid.nih.gov OI Parra, Gabriel/0000-0002-1102-4740 FU NIH, NIAID FX This research was partially supported by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 43 TC 14 Z9 14 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 21 PY 2013 VL 8 IS 6 AR e67592 DI 10.1371/journal.pone.0067592 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500147 PM 23805319 ER PT J AU Yin, J Wang, C Mody, A Bao, L Hung, SH Svoronos, SA Tseng, Y AF Yin, Jun Wang, Chengyuan Mody, Aaron Bao, Lin Hung, Shen-Hsiu Svoronos, Spyros A. Tseng, Yiider TI The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells SO PLOS ONE LA English DT Article ID PC12 CELLS; IN-VITRO; RHO AB Z-ligustilide (LIG), an essential oil extract from Radix Angelica sinensis, has broad pharmaceutical applications in treating cardio-vascular diseases and ischemic brain injury. Recently, LIG has been connected to Glioblastoma multiforme (GBM) because of its structural similarity to 3-n-alkyphthalide (NBP), which is specifically cytotoxic to GBM cells. Hence, we investigated LIG's effect on GBM T98G cells. The study shows that LIG can significantly reduce T98G cells' migration in a dose-dependent manner. Furthermore, the attenuation of cellular mobility can be linked to the activity of the Rho GTPases (RhoA, Rac1 and Cdc42), the three critical molecular switches governing cytoskeleton remodeling; thus, regulating cell migration. LIG significantly reduces the expression of RhoA and affects in a milder manner the expression of Cdc42 and Rac1. C1 [Yin, Jun; Mody, Aaron; Bao, Lin; Hung, Shen-Hsiu; Svoronos, Spyros A.; Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. [Wang, Chengyuan] Chongqing Technol & Business Univ, Res Ctr Med Chem & Chem Biol, Chongqing, Peoples R China. [Yin, Jun; Hung, Shen-Hsiu; Tseng, Yiider] NCI, Phys Sci Oncol Ctr, Gainesville, FL USA. [Tseng, Yiider] Inst Cell Engn & Regenerat Med, Gainesville, FL USA. RP Tseng, Y (reprint author), Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. EM ytseng@che.ufl.edu FU NIH/NCI [U54CA143868] FX This study was supported in part by grants from NIH/NCI U54CA143868. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 17 TC 7 Z9 8 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 21 PY 2013 VL 8 IS 6 AR e66598 DI 10.1371/journal.pone.0066598 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170JP UT WOS:000320846500073 PM 23805245 ER PT J AU Johnson, TP Tyagi, R Patel, K Schiess, N Calabresi, PA Nath, A AF Johnson, Tory P. Tyagi, Richa Patel, Karan Schiess, Nicoline Calabresi, Peter A. Nath, Avindra TI Impaired toll-like receptor 8 signaling in multiple sclerosis SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Toll-like receptor; Multiple sclerosis; Gene expression; Interleukin 12; TLR8 ID T-CELLS; ACTIVATION; DISEASE; ALPHA AB Background: The etiology and immunopathology of multiple sclerosis (MS) is not well understood. It is recognized that although autoreactive T cells are the main early mediators of disease, other cell types, including cells of the innate immune system contribute to MS pathogenesis. The objective of this study was to determine if Toll-like receptor (TLR) signaling is functionally altered in patients with MS. Findings: Peripheral blood mononuclear cells from healthy donors and patients with relapsing remitting MS were stimulated with specific agonists of TLRs 3, 7, 8 and 9. Using quantitative polymerase chain reaction transcript levels of tumor necrosis factor-a, interferon-a and interleukin (IL)-12 beta were quantified from patients with MS and healthy donors. TLR8-induced production of IL12B transcripts and protein was functionally impaired in patients with MS as compared to healthy controls (P < 0.05 and P < 0.005, respectively). Patients with MS also expressed lower baseline levels of TLR8 as compared to healthy controls (P < 0.05). Conclusions: TLR8 expression and signaling is impaired in peripheral blood mononuclear cells from patients with MS. This finding suggests that loss of TLR8 signaling may be contributing to autoimmune processes in MS. C1 [Johnson, Tory P.; Tyagi, Richa; Patel, Karan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Schiess, Nicoline; Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10,7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM avindra.nath@nih.gov FU National Multiple Sclerosis Society [TR 3760-A-3]; Stegg family; NINDS FX The authors would like to acknowledge Dr. Steve Jacobson for providing the clinical samples. This work was supported by the National Multiple Sclerosis Society (grant number TR 3760-A-3); a generous grant from the Stegg family; and NINDS intramural funds. NR 18 TC 7 Z9 8 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUN 21 PY 2013 VL 10 AR 74 DI 10.1186/1742-2094-10-74 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 171IS UT WOS:000320920000001 PM 23787171 ER PT J AU Xu, Y Liu, YF Lee, JG Ye, YH AF Xu, Yue Liu, Yanfen Lee, Jin-Gu Ye, Yihong TI A Ubiquitin-like Domain Recruits an Oligomeric Chaperone to a Retrotranslocation Complex in Endoplasmic Reticulum-associated Degradation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID QUALITY-CONTROL; MEMBRANE-PROTEINS; LIGASE; HRD1P; GP78; BAT3; DIMETHYLATION; POLYPEPTIDES; ELIMINATION; INTEGRATION AB The Bag6-Ubl4A-Trc35 complex is a multifunctional chaperone that regulates various cellular processes. The diverse functions of Bag6 are supported by its ubiquitous localization to the cytoplasm, the nucleus, and membranes of the endoplasmic reticulum (ER) in cells. In ER-associated degradation (ERAD) pathways, Bag6 can interact with the membrane-associated ubiquitin ligase gp78 via its ubiquitin-like (UBL) domain, but the relative low affinity of this interaction does not reconcile with the fact that a fraction of Bag6 is tightly bound to the membranes. Here, we demonstrate that the UBL domain of Bag6 is required for interaction with the ER membranes. We find that in addition to gp78, the Bag6 UBL domain also binds a UBL-binding motif in UbxD8, an essential component of the gp78 ubiquitinating machinery. Importantly, Bag6 contains a proline-rich (PR) domain termed PDP (Proline rich-DUF3587-Proline rich) that forms homo-oligomer, allowing the UBL domain to form multivalent interactions with gp78 and UbxD8, which are essential for recruitment of Bag6 to the ER membrane. Furthermore, the PR domain comprises largely intrinsically disordered segments, which are sufficient for interaction with an unfolded substrate. We propose that simultaneous association with multiple ERAD factors helps to anchor a disordered chaperone oligomer to the site of retrotranslocation to prevent protein aggregation in ERAD. C1 [Xu, Yue; Liu, Yanfen; Lee, Jin-Gu; Ye, Yihong] NIH, NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIH, NIDDK, Mol Biol Lab, 5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov RI Xu, Yue/F-8188-2015 FU NIDDK at the National Institutes of Health FX This work was supported by the Intramural Research Program of the NIDDK at the National Institutes of Health. NR 35 TC 24 Z9 24 U1 0 U2 15 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 JUN 21 PY 2013 VL 288 IS 25 BP 18068 EP 18076 DI 10.1074/jbc.M112.449199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900013 PM 23665563 ER PT J AU Chertova, E Bergamaschi, C Chertov, O Sowder, R Bear, J Roser, JD Beach, RK Lifson, JD Felber, BK Pavlakis, GN AF Chertova, Elena Bergamaschi, Cristina Chertov, Oleg Sowder, Raymond Bear, Jenifer Roser, James D. Beach, Rachel K. Lifson, Jeffrey D. Felber, Barbara K. Pavlakis, George N. TI Characterization and Favorable in Vivo Properties of Heterodimeric Soluble IL-15 center dot IL-15R alpha Cytokine Compared to IL-15 Monomer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CD8(+) T-CELLS; RECEPTOR-ALPHA-CHAIN; NATURAL-KILLER-CELLS; SIGNAL PEPTIDE; INTERLEUKIN (IL)-15; ESTABLISHED TUMORS; TRANS PRESENTATION; NONHUMAN-PRIMATES; RHESUS MACAQUES; CD4(+) CELLS AB Interleukin-15 (IL-15), a 114-amino acid cytokine related to IL-2, regulates immune homeostasis and the fate of many lymphocyte subsets. We reported that, in the blood of mice and humans, IL-15 is present as a heterodimer associated with soluble IL-15 receptor alpha (sIL-15R alpha). Here, we show efficient production of this noncovalently linked but stable heterodimer in clonal human HEK293 cells and release of the processed IL-15 center dot sIL-15R alpha heterodimer in the medium. Purification of the IL-15 and sIL-15R alpha polypeptides allowed identification of the proteolytic cleavage site of IL-15R alpha and characterization of multiple glycosylation sites. Administration of the IL-15 center dot sIL-15R alpha heterodimer reconstituted from purified subunits resulted in sustained plasma IL-15 levels and in robust expansion of NK and T cells in mice, demonstrating pharmacokinetics and in vivo bioactivity superior to single chain IL-15. These identified properties of heterodimeric IL-15 provide a strong rationale for the evaluation of this molecule for clinical applications. C1 [Chertova, Elena; Sowder, Raymond; Roser, James D.; Lifson, Jeffrey D.] Frederick Natl Lab, AIDS & Canc Virus Program, Ft Detrick, MD 21702 USA. [Chertov, Oleg] Frederick Natl Lab, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Bergamaschi, Cristina; Beach, Rachel K.; Pavlakis, George N.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Sect, Frederick, MD 21702 USA. [Bear, Jenifer; Beach, Rachel K.; Felber, Barbara K.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. RP Pavlakis, GN (reprint author), NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Sect, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov FU Intramural Research Program, National Cancer Institute, National Institutes of Health (NCI/National Institutes of Health); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program, National Cancer Institute, National Institutes of Health (NCI/National Institutes of Health) and federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. NR 60 TC 22 Z9 22 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2013 VL 288 IS 25 BP 18093 EP 18103 DI 10.1074/jbc.M113.461756 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900015 PM 23649624 ER PT J AU Zhang, SF Schones, DE Malicet, C Rochman, M Zhou, M Foisner, R Bustin, M AF Zhang, Shaofei Schones, Dustin E. Malicet, Cedric Rochman, Mark Zhou, Ming Foisner, Roland Bustin, Michael TI High Mobility Group Protein N5 (HMGN5) and Lamina-associated Polypeptide 2 alpha (LAP2 alpha) Interact and Reciprocally Affect Their Genome-wide Chromatin Organization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMOSOMAL-PROTEINS; LINKER HISTONE; RNA-SEQ; DIFFERENTIATION; H1; NUCLEOSOMES; COMPLEXES AB The interactions of nuclear lamins with the chromatin fiber play an important role in regulating nuclear architecture and chromatin function; however, the full spectrum of these interactions is not known. We report that the N-terminal domain of the nucleosome-binding protein HMGN5 interacts with the C-terminal domain of the lamin-binding protein LAP2 alpha and that these proteins reciprocally alter their interaction with chromatin. Chromatin immunoprecipitation analysis of cells lacking either HMGN5 or LAP2 alpha reveals that loss of either protein affects the genome-wide distribution of the remaining partner. Our study identifies a new functional link between chromatin-binding and lamin-binding proteins. C1 [Zhang, Shaofei; Malicet, Cedric; Rochman, Mark; Bustin, Michael] NCI, NIH, Prot Sect, Lab Metab,Ctr Canc Res, Bethesda, MD 20892 USA. [Schones, Dustin E.] Beckman Res Inst City Hope, Dept Canc Biol, Duarte, CA 91010 USA. [Zhou, Ming] NCI Frederick, SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Foisner, Roland] Med Univ Vienna, Max Perutz Labs, A-1030 Vienna, Austria. RP Bustin, M (reprint author), NCI, NIH, Prot Sect, Lab Metab,Ctr Canc Res, Bethesda, MD 20892 USA. EM Bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health; United States-Israel Binational Science Foundation (BSF) [2009236]; NCI [K22 HL101950]; Austrian Research Fund (FWF) [P22043-B12] FX This work was supported, in whole or in part, by the Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health (to M. B.). This work was also supported by United States-Israel Binational Science Foundation (BSF) Grants 2009236 (to M. B.) and NCI Grant K22 HL101950 (to D. E. S.) and by Grant P22043-B12 of the Austrian Research Fund (FWF) (to R. F.). NR 27 TC 10 Z9 10 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2013 VL 288 IS 25 BP 18104 EP 18109 DI 10.1074/jbc.C113.469544 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900016 PM 23673662 ER PT J AU Allende, ML Sipe, LM Tuymetova, G Wilson-Henjum, KL Chen, WP Proia, RL AF Allende, Maria L. Sipe, Laura M. Tuymetova, Galina Wilson-Henjum, Kelsey L. Chen, Weiping Proia, Richard L. TI Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERMEABILITY BARRIER; CELL-DEATH; IN-VITRO; SKIN; PHOSPHOHYDROLASE; SPHINGOLIPIDS; CERAMIDE; METABOLISM; EXPRESSION; RECEPTOR AB Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphorylated by the actions of two S1P-specific phosphatases, sphingosine-1-phosphate phosphatases 1 and 2. To identify the physiological functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1(-/-) mice appeared normal at birth, but during the 1st week of life they exhibited stunted growth and suffered desquamation, with most dying before weaning. Both Sgpp1(-/-) pups and surviving adults exhibited multiple epidermal abnormalities. Interestingly, the epidermal permeability barrier developed normally during embryogenesis in Sgpp1(-/-) mice. Keratinocytes isolated from the skin of Sgpp1(-/-) pups had increased intracellular S1P levels and displayed a gene expression profile that indicated overexpression of genes associated with keratinocyte differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis. C1 [Allende, Maria L.; Sipe, Laura M.; Tuymetova, Galina; Wilson-Henjum, Kelsey L.; Chen, Weiping; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, Bldg 10,Rm 9D-06,10 Ctr Dr MSC 1821, Bethesda, MD 20892 USA. EM rp36y@nih.gov FU National Institutes of Health from NIDDK [P30 CA138313, P20 RR017677] FX This work was supported, in whole or in part, by National Institutes of Health grants from NIDDK, Grant P30 CA138313 (to Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina), and Grant P20 RR017677 (to Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE). NR 63 TC 10 Z9 10 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2013 VL 288 IS 25 BP 18381 EP 18391 DI 10.1074/jbc.M113.478420 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168QZ UT WOS:000320721900041 PM 23637227 ER PT J AU Jorgensen, NW Sibley, CT McClelland, RL AF Jorgensen, Neal W. Sibley, Christopher T. McClelland, Robyn L. TI Using imputed pre-treatment cholesterol in a propensity score model to reduce confounding by indication: results from the multi-ethnic study of atherosclerosis SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Multiple imputation; Confounding by indication; Propensity score; Inverse probability of treatment weights; Statins ID RANDOMIZED CONTROLLED-TRIALS; MULTIPLE IMPUTATION; MISSING-DATA; METAANALYSIS; ASSOCIATIONS; SURVIVAL; THERAPY; WEIGHTS; STATINS; RISK AB Background: Studying the effects of medications on endpoints in an observational setting is an important yet challenging problem due to confounding by indication. The purpose of this study is to describe methodology for estimating such effects while including prevalent medication users. These techniques are illustrated in models relating statin use to cardiovascular disease (CVD) in a large multi-ethnic cohort study. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45-84 years free of CVD. Confounding by indication was mitigated using a two step approach: First, the untreated values of cholesterol were treated as missing data and the values imputed as a function of the observed treated value, dose and type of medication, and participant characteristics. Second, we construct a propensity-score modeling the probability of medication initiation as a function of measured covariates and estimated pre-treatment cholesterol value. The effect of statins on CVD endpoints were assessed using weighted Cox proportional hazard models using inverse probability weights based on the propensity score. Results: Based on a meta-analysis of randomized controlled trials (RCT) statins are associated with a reduced risk of CVD (relative risk ratio = 0.73, 95% CI: 0.70, 0.77). In an unweighted Cox model adjusting for traditional risk factors we observed little association of statins with CVD (hazard ratio (HR) = 0.97, 95% CI: 0.60, 1.59). Using weights based on a propensity model for statins that did not include the estimated pre-treatment cholesterol we observed a slight protective association (HR = 0.92, 95% CI: 0.54-1.57). Results were similar using a new-user design where prevalent users of statins are excluded (HR = 0.91, 95% CI: 0.45-1.80). Using weights based on a propensity model with estimated pre-treatment cholesterol the effects of statins (HR = 0.74, 95% CI: 0.38, 1.42) were consistent with the RCT literature. Conclusions: The imputation of pre-treated cholesterol levels for participants on medication at baseline in conjunction with a propensity score yielded estimates that were consistent with the RCT literature. These techniques could be useful in any example where inclusion of participants exposed at baseline in the analysis is desirable, and reasonable estimates of pre-exposure biomarker values can be estimated. C1 [Jorgensen, Neal W.; McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Jorgensen, NW (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM njorgens@u.washington.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; [R01 HL 103729-01A1] FX Analysis for this project was supported by R01 HL 103729-01A1. The MESA study was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 25 TC 0 Z9 0 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JUN 21 PY 2013 VL 13 AR 81 DI 10.1186/1471-2288-13-81 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 171LU UT WOS:000320931200001 PM 23800038 ER PT J AU Kellman, P Arai, AE Xue, H AF Kellman, Peter Arai, Andrew E. Xue, Hui TI T1 and extracellular volume mapping in the heart: estimation of error maps and the influence of noise on precision SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 Map; Error; Precision; MOLLI; Extracellular; Diffuse Fibrosis; Cardiovascular Magnetic Resonance ID DIFFUSE MYOCARDIAL FIBROSIS; INVERSION-RECOVERY MOLLI; MAGNETIC-RESONANCE; QUANTIFICATION; INFARCTION; VALIDATION; REGRESSION AB Background: Quantitative measurements in the myocardium may be used to detect both focal and diffuse disease processes that result in an elevation of T1 and/or extracellular volume (ECV) fraction. Detection of abnormal myocardial tissue by these methods is affected by both the accuracy and precision. The sensitivity for detecting abnormal elevation of T1 and ECV is limited by the precision of T1 estimates which is a function of the number and timing of measurements along the T1-inversion recovery curve, the signal-to-noise ratio (SNR), the tissue T1, and the method of fitting. Methods: The standard deviation (SD) of T1 and ECV estimates are formulated and SD maps are calculated on a pixel-wise basis using the Modified Look-Locker Inversion recovery (MOLLI) method. SD estimates are validated by numerical simulation using Monte-Carlo analysis and with phantoms using repeated trials. SD estimates are provided for pre- and post-contrast optimized protocols for a range of T1s and SNRs. In-vivo examples are provide for normal, myocarditis, and HCM in human subjects. The formulation of SD maps was extended to R1 and ECV. Results: The measured myocardial SNR ranged from 23 to 43 across the heart using the specific T1-mapping protocol in this study. In this range of SNRs, the estimated SD for T1 was approximately 20-45 ms for pre-contrast myocardial T1 around 1000 ms, and was approximately 10-20 ms for post contrast T1 around 400 ms. The proposed estimate of SD was an unbiased estimate of the standard deviation of T1 validated by numerical simulation and had > 99% correlation with phantom measurements. The measured SD maps exhibited variation across the heart due to drop off in surface coil sensitivity as expected for the variation in SNR. Focal elevation in T1 and ECV was shown to have statistical significance on a pixel-wise basis for in-vivo examples. Conclusions: Pixel-wise estimates of T1 mapping errors have been formulated and validated, and the formulation has been extended to ECV. The ability to quantify the measurement error has potential to determine the statistical significance of subtle abnormalities that arise due to diffuse disease processes involving fibrosis and/or edema and is useful both as a confidence metric for overall quality, and in optimization and comparison of imaging protocols. C1 [Kellman, Peter; Arai, Andrew E.; Xue, Hui] Natl Heart Lung & Blood Inst, Natl Inst Hlth, DHHS, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), Natl Heart Lung & Blood Inst, Natl Inst Hlth, DHHS, 10 Ctr Dr MSC 1061, Bethesda, MD 20892 USA. EM kellman@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB] FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 29 TC 37 Z9 37 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUN 21 PY 2013 VL 15 AR 56 DI 10.1186/1532-429X-15-56 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 177KP UT WOS:000321374200001 PM 23800276 ER PT J AU Rietveld, CA Medland, SE Derringer, J Yang, J Esko, T Martin, NW Westra, HJ Shakhbazov, K Abdellaoui, A Agrawal, A Albrecht, E Alizadeh, BZ Amin, N Bamard, J Baumeister, SE Benke, KS Bielak, LF Boatman, JA Boyle, PA Davies, G De Leeuw, C Eklund, N Evans, DS Ferhmann, R Fischer, K Gieger, C Gjessing, HK Hagg, S Harris, JR Hayward, C Holzapfel, C Ibrahim-Verbaas, CA Ingelsson, E Jacobsson, B Joshi, PK Jugessur, A Kaakinen, M Kanoni, S Karjalainen, J Kolcic, I Kristiansson, K Kutalik, Z Lahti, J Lee, SH Lin, P Lind, PA Liu, YM Lohman, K Loitfelder, M McMahon, G Vidal, PM Meirelles, O Milani, L Myhre, R Nuotio, ML Oldmeadow, CJ Petrovic, KE Peyrot, WJ Polasek, O Quaye, L Reinmaa, E Rice, JP Rizzi, TS Schmidt, H Schmidt, R Smith, AV Smith, JA Tanaka, T Terracciano, A van der Loos, MJHM Vitart, V Volzke, H Wellmann, J Yu, L Zhao, W Allik, J Attia, JR Bandinelli, S Bastardot, F Beauchamp, J Bennett, DA Berger, K Bierut, LJ Boomsma, DI Bultmann, U Campbell, H Chabris, CF Cherkas, L Chung, MK Cucca, F de Andrade, M De Jager, PL De Neve, JE Deary, IJ Dedoussis, GV Deloukas, P Dimitriou, M Eiriksdottir, G Elderson, MF Eriksson, JG Evans, DM Faul, JD Ferrucci, L Garcia, ME Gronberg, H Guonason, V Hall, P Harris, JM Harris, TB Hastie, ND Heath, AC Hernandez, DG Hoffmann, W Hofman, A Holle, R Holliday, EG Hottenga, JJ Iacono, WG Illig, T Jarvelin, MR Kahonen, M Kaprio, J Kirkpatrick, RM Kowgier, M Latvala, A Launer, LJ Lawlor, DA Lehtimaki, T Li, JM Lichtenstein, P Lichtner, P Liewald, DC Madden, PA Magnusson, PKE Makinen, TE Masala, M McGue, M Metspalu, A Mielck, A Miller, MB Montgomery, GW Mukherjee, S Nyholt, DR Oostra, BA Palmer, LJ Palotie, A Penninx, BWJH Perola, M Peyser, PA Preisig, M Raikkonen, K Raitakari, OT Realo, A Ring, SM Ripatti, S Rivadeneira, F Rudan, I Rustichini, A Salomaa, V Sarin, AP Schlessinger, D Scott, RJ Snieder, H St Pourcain, B Starr, JM Sul, JH Surakka, I Svento, R Teumer, A Tiemeier, H van Rooij, FJA Van Wagoner, DR Vartiainen, E Viikari, J Vollenweider, P Vonk, JM Waeber, G Weir, DR Wichmann, HE Widen, E Willemsen, G Wilson, JF Wright, AF Conley, D Davey-Smith, G Franke, L Groenen, PJF Hofman, A Johannesson, M Kardia, SLR Krueger, RF Laibson, D Martin, NG Meyer, MN Posthuma, D Thurik, AR Timpson, NJ Uitterlinden, AG van Duijn, CM Visscher, PM Benjamin, DJ Cesarini, D Koellinger, PD AF Rietveld, Cornelius A. Medland, Sarah E. Derringer, Jaime Yang, Jian Esko, Tonu Martin, Nicolas W. Westra, Harm-Jan Shakhbazov, Konstantin Abdellaoui, Abdel Agrawal, Arpana Albrecht, Eva Alizadeh, Behrooz Z. Amin, Najaf Bamard, John Baumeister, Sebastian E. Benke, Kelly S. Bielak, Lawrence F. Boatman, Jeffrey A. Boyle, Patricia A. Davies, Gail De Leeuw, Christiaan Eklund, Niina Evans, Daniel S. Ferhmann, Rudolf Fischer, Krista Gieger, Christian Gjessing, Hakon K. Haegg, Sara Harris, Jennifer R. Hayward, Caroline Holzapfel, Christina Ibrahim-Verbaas, Carla A. Ingelsson, Erik Jacobsson, Bo Joshi, Peter K. Jugessur, Astanand Kaakinen, Marika Kanoni, Stavroula Karjalainen, Juha Kolcic, Ivana Kristiansson, Kati Kutalik, Zoltan Lahti, Jari Lee, Sang H. Lin, Peng Lind, Penelope A. Liu, Yongmei Lohman, Kurt Loitfelder, Marisa McMahon, George Vidal, Pedro Marques Meirelles, Osorio Milani, Lili Myhre, Ronny Nuotio, Marja-Liisa Oldmeadow, Christopher J. Petrovic, Katja E. Peyrot, Wouter J. Polasek, Ozren Quaye, Lydia Reinmaa, Eva Rice, John P. Rizzi, Thais S. Schmidt, Helena Schmidt, Reinhold Smith, Albert V. Smith, Jennifer A. Tanaka, Toshiko Terracciano, Antonio van der Loos, Matthijs J. H. M. Vitart, Veronique Voelzke, Henry Wellmann, Juergen Yu, Lei Zhao, Wei Allik, Jueri Attia, John R. Bandinelli, Stefania Bastardot, Franois Beauchamp, Jonathan Bennett, David A. Berger, Klaus Bierut, Laura J. Boomsma, Dorret I. Bueltmann, Ute Campbell, Harry Chabris, Christopher F. Cherkas, Lynn Chung, Mina K. Cucca, Francesco de Andrade, Mariza De Jager, Philip L. De Neve, Jan-Emmanuel Deary, Ian J. Dedoussis, George V. Deloukas, Panos Dimitriou, Maria Eiriksdottir, Guony Elderson, Martin F. Eriksson, Johan G. Evans, David M. Faul, Jessica D. Ferrucci, Luigi Garcia, Melissa E. Groenberg, Henrik Guonason, Vilmundur Hall, Per Harris, Juliette M. Harris, Tamara B. Hastie, Nicholas D. Heath, Andrew C. Hernandez, Dena G. Hoffmann, Wolfgang Hofman, Adriaan Holle, Rolf Holliday, Elizabeth G. Hottenga, Jouke-Jan Iacono, William G. Illig, Thomas Jaervelin, Marjo-Riitta Kaehoenen, Mika Kaprio, Jaakko Kirkpatrick, Robert M. Kowgier, Matthew Latvala, Antti Launer, Lenore J. Lawlor, Debbie A. Lehtimaeki, Terho Li, Jingmei Lichtenstein, Paul Lichtner, Peter Liewald, David C. Madden, Pamela A. Magnusson, Patrik K. E. Maekinen, Tomi E. Masala, Marco McGue, Matt Metspalu, Andres Mielck, Andreas Miller, Michael B. Montgomery, Grant W. Mukherjee, Sutapa Nyholt, Dale R. Oostra, Ben A. Palmer, Lyle J. Palotie, Aarno Penninx, Brenda W. J. H. Perola, Markus Peyser, Patricia A. Preisig, Martin Raeikkoenen, Katri Raitakari, Olli T. Realo, Anu Ring, Susan M. Ripatti, Samuli Rivadeneira, Fernando Rudan, Igor Rustichini, Aldo Salomaa, Veikko Sarin, Antti-Pekka Schlessinger, David Scott, Rodney J. Snieder, Harold St Pourcain, Beate Starr, John M. Sul, Jae Hoon Surakka, Ida Svento, Rauli Teumer, Alexander Tiemeier, Henning van Rooij, Frank J. A. Van Wagoner, David R. Vartiainen, Erkki Viikari, Jorma Vollenweider, Peter Vonk, Judith M. Waeber, Gerard Weir, David R. Wichmann, H. -Erich Widen, Elisabeth Willemsen, Gonneke Wilson, James F. Wright, Alan F. Conley, Dalton Davey-Smith, George Franke, Lude Groenen, Patrick J. F. Hofman, Albert Johannesson, Magnus Kardia, Sharon L. R. Krueger, Robert F. Laibson, David Martin, Nicholas G. Meyer, Michelle N. Posthuma, Danielle Thurik, A. Roy Timpson, Nicholas J. Uitterlinden, Andre G. van Duijn, Cornelia M. Visscher, Peter M. Benjamin, Daniel J. Cesarini, David Koellinger, Philipp D. CA LifeLines Cohort Study TI GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment SO SCIENCE LA English DT Article ID ENVIRONMENT; PREFERENCES; LOCI AB A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R-2 approximate to 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximate to 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. C1 [Rietveld, Cornelius A.; van der Loos, Matthijs J. H. M.; Thurik, A. Roy; Koellinger, Philipp D.] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, NL-3000 DR Rotterdam, Netherlands. [Rietveld, Cornelius A.; van der Loos, Matthijs J. H. M.; Rivadeneira, Fernando; Tiemeier, Henning; van Rooij, Frank J. A.; Hofman, Albert; Uitterlinden, Andre G.; Koellinger, Philipp D.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Medland, Sarah E.; Martin, Nicolas W.; Lee, Sang H.; Lind, Penelope A.; Montgomery, Grant W.; Nyholt, Dale R.; Martin, Nicholas G.; Visscher, Peter M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Derringer, Jaime] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Yang, Jian; Shakhbazov, Konstantin; Visscher, Peter M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4102, Australia. [Esko, Tonu; Fischer, Krista; Milani, Lili; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Martin, Nicolas W.] Univ Queensland, Sch Psychol, Brisbane, Qld 4072, Australia. [Westra, Harm-Jan; Ferhmann, Rudolf; Karjalainen, Juha; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands. [Shakhbazov, Konstantin; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Abdellaoui, Abdel; Boomsma, Dorret I.; Hottenga, Jouke-Jan; Willemsen, Gonneke] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Agrawal, Arpana; Lin, Peng; Rice, John P.; Bierut, Laura J.; Madden, Pamela A.] Washington Univ, Dept Psychiat, Sch Med, St Louis, MO 63110 USA. [Albrecht, Eva; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Alizadeh, Behrooz Z.; Snieder, Harold; Vonk, Judith M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Amin, Najaf; Ibrahim-Verbaas, Carla A.; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands. [Bamard, John; Chung, Mina K.; Van Wagoner, David R.] Cleveland Clin, Heart & Vasc & Lerner Res Inst, Cleveland, OH 44195 USA. [Baumeister, Sebastian E.; Voelzke, Henry; Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany. [Benke, Kelly S.] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Bielak, Lawrence F.; Smith, Jennifer A.; Zhao, Wei; Peyser, Patricia A.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Boatman, Jeffrey A.] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Boyle, Patricia A.; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Davies, Gail; Deary, Ian J.; Liewald, David C.; Starr, John M.] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [De Leeuw, Christiaan; Rizzi, Thais S.; Posthuma, Danielle] Vrije Univ Amsterdam, Dept Funct Genom, NL-1081 HV Amsterdam, Netherlands. [De Leeuw, Christiaan; Rizzi, Thais S.; Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, NL-1081 HV Amsterdam, Netherlands. Radboud Univ Nijmegen, Machine Learning Grp, Inst Comp & Informat Sci, Fac Sci, NL-6500 GL Nijmegen, Netherlands. [Eklund, Niina; Kristiansson, Kati; Nuotio, Marja-Liisa; Kaprio, Jaakko; Palotie, Aarno; Perola, Markus; Ripatti, Samuli; Sarin, Antti-Pekka; Surakka, Ida; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, FIN-00014 Helsinki, Finland. [Eklund, Niina; Kristiansson, Kati; Nuotio, Marja-Liisa; Perola, Markus; Ripatti, Samuli; Surakka, Ida] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki 00014, Finland. [Evans, Daniel S.; Perola, Markus] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Gjessing, Hakon K.; Harris, Jennifer R.; Jacobsson, Bo; Jugessur, Astanand; Myhre, Ronny] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, N-0403 Oslo, Norway. [Haegg, Sara; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Haegg, Sara; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75123 Uppsala, Sweden. [Haegg, Sara; Ingelsson, Erik; Groenberg, Henrik; Hall, Per; Lichtenstein, Paul; Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hayward, Caroline; Vitart, Veronique; Hastie, Nicholas D.; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Holzapfel, Christina] Tech Univ Munich, Univ Hosp, Klinikum Rechts Isar, Else Kroener Fresenius Ctr Nutr Med, D-81675 Munich, Germany. [Holzapfel, Christina; Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Ibrahim-Verbaas, Carla A.] Erasmus MC, Dept Neurol, NL-3000 CA Rotterdam, Netherlands. [Jacobsson, Bo] Sahgrenska Univ Hosp, Sahlgrenska Acad, Inst Publ Hlth, Dept Obstet & Gynecol, S-41345 Gothenburg, Sweden. [Joshi, Peter K.; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Kaakinen, Marika; Jaervelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu 90014, Finland. [Kaakinen, Marika; Jaervelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. [Kanoni, Stavroula; Deloukas, Panos; Palotie, Aarno; Ripatti, Samuli] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Split 21000, Croatia. [Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Kutalik, Zoltan] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Lahti, Jari; Raeikkoenen, Katri] Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland. [Liu, Yongmei] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [Lohman, Kurt] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Loitfelder, Marisa; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Div Neurogeriatr, A-8036 Graz, Austria. [McMahon, George; Ring, Susan M.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PR, Avon, England. [Vidal, Pedro Marques] Univ Lausanne Hosp, Inst Social & Prevent Med, CH-1005 Lausanne, Switzerland. [Meirelles, Osorio; Tanaka, Toshiko; Terracciano, Antonio; Ferrucci, Luigi; Garcia, Melissa E.; Harris, Tamara B.; Hernandez, Dena G.; Launer, Lenore J.; Schlessinger, David] NIA, NIH, Baltimore, MD 20892 USA. [Oldmeadow, Christopher J.; Attia, John R.; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2308, Australia. [Oldmeadow, Christopher J.; Attia, John R.; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Fac Hlth, Newcastle, NSW 2308, Australia. [Petrovic, Katja E.] Gen Hosp, Div Gen Neurol, Dept Neurol, A-8036 Graz, Austria. [Petrovic, Katja E.] Med Univ Graz, A-8036 Graz, Austria. [Peyrot, Wouter J.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands. [Quaye, Lydia; Cherkas, Lynn; Harris, Juliette M.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, A-8036 Graz, Austria. [Smith, Albert V.; Eiriksdottir, Guony; Guonason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Guonason, Vilmundur] Univ Iceland, Dept Med, IS-101 Reykjavik, Iceland. [Terracciano, Antonio] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Wellmann, Juergen; Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, D-48129 Munster, Germany. [Allik, Jueri; Realo, Anu] Univ Tartu, Dept Psychol, EE-50410 Tartu, Estonia. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. [Bastardot, Franois; Preisig, Martin; Vollenweider, Peter; Waeber, Gerard] Univ Lausanne Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Beauchamp, Jonathan] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Bueltmann, Ute] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci Community & Occupat Med, NL-9700 AD Groningen, Netherlands. [Chabris, Christopher F.] Union Coll, Dept Psychol, Schenectady, NY 12308 USA. [Cucca, Francesco; Masala, Marco] Consejo Invest Nacl Italiano CNR, Ist Ric Genet & Biomed, I-09042 Cagliari, Italy. [Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Ss, Italy. [de Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat Neuropsychiat Genom, Boston, MA 02115 USA. [De Neve, Jan-Emmanuel] UCL, Sch Publ Policy, London WC1H 9QU, England. [De Neve, Jan-Emmanuel] London Sch Econ, Ctr Econ Performance, London WC2A 2AE, England. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Dedoussis, George V.; Dimitriou, Maria] Harokopio Univ Athens, Dept Nutr & Dietet, Athens 17671, Greece. [Elderson, Martin F.; LifeLines Cohort Study] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki 00280, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki 00250, Finland. [Eriksson, Johan G.] Vaasa Cent Hosp, Vaasa 65130, Finland. [Evans, David M.; Lawlor, Debbie A.; St Pourcain, Beate; Davey-Smith, George; Timpson, Nicholas J.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2PR, Avon, England. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48106 USA. [Heath, Andrew C.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO 63110 USA. [Hofman, Adriaan] Univ Groningen, Fac Behav & Social Sci, NL-9747 AD Groningen, Netherlands. [Iacono, William G.; Kirkpatrick, Robert M.; McGue, Matt; Miller, Michael B.; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Holle, Rolf; Mielck, Andreas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Hlth Econ & Hlth Care Management, D-85764 Neuherberg, Germany. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Jaervelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Jaervelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu 90220, Finland. [Jaervelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu 90101, Finland. [Kaehoenen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33520, Finland. [Kaehoenen, Mika] Univ Tampere, Sch Med, Tampere 33520, Finland. [Kaprio, Jaakko; Latvala, Antti] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Kaprio, Jaakko; Latvala, Antti] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki 00300, Finland. [Kowgier, Matthew; Palmer, Lyle J.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Lehtimaeki, Terho] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, Tampere 33520, Finland. [Li, Jingmei] Genome Inst Singapore, Singapore 138672, Singapore. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Maekinen, Tomi E.] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Helsinki 00271, Finland. [Mukherjee, Sutapa] Sir Charles Gairdner Hosp, Western Australia Sleep Disorders Res Inst, Perth, WA 6009, Australia. [Mukherjee, Sutapa] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. [Mukherjee, Sutapa] Univ Toronto, Womens Coll Res Inst, Toronto, ON M5G 1N8, Canada. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki 00014, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Rustichini, Aldo] Univ Minnesota, Dept Econ, Minneapolis, MN 55455 USA. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol Unit, Helsinki 00271, Finland. [St Pourcain, Beate] Univ Bristol, Sch Oral & Dent Sci, Bristol BS1 2LY, Avon, England. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Sul, Jae Hoon] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Svento, Rauli] Univ Oulu, Oulu Business Sch, Dept Econ, Oulu 90014, Finland. [Teumer, Alexander] Univ Med Greifswald, Dept Funct Genom, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Tiemeier, Henning; Posthuma, Danielle] Erasmus MC, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands. [Vartiainen, Erkki] Natl Inst Hlth & Welf, Div Welf & Hlth Promot, Helsinki 00271, Finland. [Viikari, Jorma] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, D-81377 Munich, Germany. [Wichmann, H. -Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Conley, Dalton] NYU, Dept Sociol, New York, NY 10012 USA. [Laibson, David] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Meyer, Michelle N.] Harvard Univ, Sch Law, Petrie Flom Ctr Hlth Law Policy Biotechnol & Bioe, Cambridge, MA 02138 USA. [Meyer, Michelle N.] SUNY Albany, Nelson A Rockefeller Inst Govt, Albany, NY 12203 USA. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. [Groenen, Patrick J. F.] Erasmus Univ, Econometr Inst, Erasmus Sch Econ, NL-3000 DR Rotterdam, Netherlands. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Thurik, A. Roy] Panteia, NL-2701 AA Zoetermeer, Netherlands. [Thurik, A. Roy] GSCM Montpellier Business Sch, F-34185 Montpellier, France. [van Duijn, Cornelia M.] Leiden Univ, Med Ctr, Ctr Med Syst Biol, NL-2300 RC Leiden, Netherlands. [Cesarini, David] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Cesarini, David] NYU, Ctr Expt Social Sci, Dept Econ, New York, NY 10012 USA. [Cesarini, David] New York Univ Abu Dhabi, Div Social Sci, Abu Dhabi, U Arab Emirates. [Cesarini, David] Res Inst Ind Econ, S-10215 Stockholm, Sweden. RP Benjamin, DJ (reprint author), Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. EM visscher@uq.edu.au; db468@cornell.edu; dac12@nyu.edu; koellinger@ese.eur.nl RI Attia, John/F-5376-2013; Lin, P/G-7702-2014; Nyholt, Dale/C-8384-2013; Palmer, Lyle/K-3196-2014; Lee, Sang Hong/A-2569-2011; Evans, David/H-6325-2013; Li, Jingmei/I-2904-2012; Johannesson, Magnus/E-9680-2011; terracciano, antonio/B-1884-2008; Lind, Penelope/B-2553-2009; Van Wagoner, David/C-6783-2008; Colaus, PsyColaus/K-6607-2013; Deloukas, Panos/B-2922-2013; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Yang, Jian/A-5852-2010; Holle, Rolf/D-9333-2013; Hayward, Caroline/M-8818-2016; Realo, Anu/M-9524-2016; Franke, Lude/P-7036-2016; Fox, Laura /C-6249-2016; Karjalainen, Juha/P-8624-2016; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Kolcic, Ivana/E-2713-2017; Thurik, Roy/A-9386-2012; Medland, Sarah/C-7630-2013; Fehrmann, Rudolf/E-2551-2011; Marques-Vidal, Pedro/C-9449-2009; Allik, Juri/D-5609-2009; Milani, Lili/C-8759-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Rivadeneira, Fernando/O-5385-2015 OI Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Evans, David/0000-0003-0663-4621; Smith, Jennifer/0000-0002-3575-5468; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Lahti, Jari/0000-0002-4310-5297; Attia, John/0000-0001-9800-1308; Palmer, Lyle/0000-0002-1628-3055; Lee, Sang Hong/0000-0001-9701-2718; Li, Jingmei/0000-0001-8587-7511; Johannesson, Magnus/0000-0001-8759-6393; Van Wagoner, David/0000-0001-8250-9828; Deloukas, Panos/0000-0001-9251-070X; Tiemeier, Henning/0000-0002-4395-1397; Esko, Tonu/0000-0003-1982-6569; lichtenstein, paul/0000-0003-3037-5287; Kristiansson, Kati/0000-0003-4688-107X; Maki-Opas, Tomi/0000-0002-0472-719X; Gieger, Christian/0000-0001-6986-9554; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Yang, Jian/0000-0003-2001-2474; Holle, Rolf/0000-0001-5395-2695; Hayward, Caroline/0000-0002-9405-9550; Franke, Lude/0000-0002-5159-8802; Davey Smith, George/0000-0002-1407-8314; Kolcic, Ivana/0000-0001-7918-6052; Peyrot, Wouter/0000-0001-7954-8383; St Pourcain, Beate/0000-0002-4680-3517; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Groenen, Patrick/0000-0001-6683-8971; Nuotio, Marja-Liisa/0000-0002-6688-027X; Latvala, Antti/0000-0001-5695-117X; Joshi, Peter/0000-0002-6361-5059; Kaakinen, Marika/0000-0002-9228-0462; Koellinger, Philipp/0000-0001-7413-0412; Cesarini, David/0000-0002-0043-009X; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Lind, Penelope/0000-0002-3887-2598; Raikkonen, Katri/0000-0003-3124-3470; Martin, Nicholas/0000-0003-4069-8020; Thurik, Roy/0000-0002-0242-6908; Medland, Sarah/0000-0003-1382-380X; Fehrmann, Rudolf/0000-0002-7516-315X; Marques-Vidal, Pedro/0000-0002-4548-8500; Allik, Juri/0000-0002-8358-4747; Milani, Lili/0000-0002-5323-3102; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441 FU Social Science Genetic Association Consortium (SSGAC); EAGER grant from the NSF; NIH Office of Behavioral and Social Sciences Research [SES-1064089]; Ragnar Soderberg Foundation [E9/11]; National Institute on Aging (NIA)/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23] FX This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC), a cooperative enterprise among medical researchers and social scientists that coordinates genetic-association studies for social-science variables. Data for our analyses come from many studies and organizations, some of which are subject to a materials transfer agreement (5). Results from the meta-analysis are available at the Web site of the consortium, www.ssgac.org. The formation of the SSGAC was made possible by an EAGER grant from the NSF and a supplemental grant from the NIH Office of Behavioral and Social Sciences Research (SES-1064089). This research was also funded in part by the Ragnar Soderberg Foundation (E9/11); the National Institute on Aging (NIA)/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23; and the Intramural Research Program of the NIA/NIH. For a full list of acknowledgments, see (5). NR 21 TC 186 Z9 186 U1 6 U2 135 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 JUN 21 PY 2013 VL 340 IS 6139 BP 1467 EP 1471 DI 10.1126/science.1235488 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 167QL UT WOS:000320647000046 PM 23722424 ER PT J AU Gilbert, MR Dignam, J Won, M Blumenthal, DT Vogelbaum, MA Aldape, KD Colman, H Chakravarti, A Jeraj, R Armstrong, TS Wefel, JS Brown, PD Jaeckle, KA Schiff, D Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Sulman, EP Mehta, MP AF Gilbert, Mark R. Dignam, James Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Aldape, Kenneth D. Colman, Howard Chakravarti, Arnab Jeraj, Robert Armstrong, Terri S. Wefel, Jeffrey Scott Brown, Paul D. Jaeckle, Kurt A. Schiff, David Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Sulman, Erik P. Mehta, Minesh P. TI RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Houston, TX 77030 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 0 Z9 0 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 JUN 20 PY 2013 VL 31 IS 18 SU S MA 1 PG 1 WC Oncology SC Oncology GA AG6YC UT WOS:000335564000002 ER PT J AU Sulman, EP Won, M Blumenthal, DT Vogelbaum, MA Colman, H Jenkins, RB Chakravarti, A Jeraj, R Brown, PD Jaeckle, KA Schiff, D Dignam, J Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Gilbert, MR Mehta, MP Aldape, KD AF Sulman, Erik P. Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Colman, Howard Jenkins, Robert B. Chakravarti, Arnab Jeraj, Robert Brown, Paul D. Jaeckle, Kurt A. Schiff, David Dignam, James Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Gilbert, Mark R. Mehta, Minesh P. Aldape, Kenneth D. TI Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Mayo Clin, Rochester, MN USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2013 VL 31 IS 18 SU S MA LBA2010 PG 2 WC Oncology SC Oncology GA AG6YC UT WOS:000335564000020 ER PT J AU Bellon, M Ko, NL Lee, MJ Yao, Y Waldmann, TA Trepel, JB Nicot, C AF Bellon, Marcia Ko, Nga Ling Lee, Min-Jung Yao, Yuan Waldmann, Thomas A. Trepel, Jane B. Nicot, Christophe TI Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; SIGNALING PATHWAY; CONSTITUTIVE ACTIVATION; IN-VIVO; HYPERCALCEMIA; CANCER; PROLIFERATION; EXPRESSION; TARGET AB Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of <5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/beta-catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of beta-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of beta-catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes-Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome. C1 [Bellon, Marcia; Ko, Nga Ling; Yao, Yuan; Nicot, Christophe] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Ctr Viral Oncol, Kansas City, KS 66103 USA. [Lee, Min-Jung; Trepel, Jane B.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waldmann, Thomas A.] NIH, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Nicot, C (reprint author), Ctr Viral Oncol, 3901 Rainbow Blvd,3025 Wahl Hall West, Kansas City, KS 66160 USA. EM cnicot@kumc.edu FU National Institutes of Health [AI 058944, CA106258]; National Cancer Institute; Biomedical Research Training Program FX This work was supported by the National Institutes of Health (AI 058944, CA106258) (C.N.), the Intramural Research Program of the National Cancer Institute (T.A.W., J.B.T.), and the Biomedical Research Training Program (M.B.). NR 42 TC 9 Z9 9 U1 0 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 20 PY 2013 VL 121 IS 25 BP 5045 EP 5054 DI 10.1182/blood-2012-07-439109 PG 10 WC Hematology SC Hematology GA 184NR UT WOS:000321898500013 PM 23660959 ER PT J AU Niesen, MJM Bhattacharya, S Grisshammer, R Tate, CG Vaidehi, N AF Niesen, Michiel J. M. Bhattacharya, Supriyo Grisshammer, Reinhard Tate, Christopher G. Vaidehi, Nagarajan TI Thermostabilization of the beta(1)-Adrenergic Receptor Correlates with Increased Entropy of the Inactive State SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MOLECULAR-DYNAMICS SIMULATIONS; ADENOSINE A(2A) RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; CONFORMATIONAL ENSEMBLES; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; AGONIST; ACTIVATION; STABILITY AB The dynamic nature of GPCRs is a major hurdle in their purification and crystallization. Thermostabilization can facilitate GPCR structure determination, as has been shown by the structure of the thermostabilized beta(1)-adrenergic receptor (beta(1)AR) mutant, m23-beta(1)AR, which has been thermostabilized in the inactive state. However, it is undear from the structure how the six thermostabilizing mutations in m23-beta(1)AR affect receptor dynamics. We have used molecular dynamics simulations in explicit solvent to compare the conformational ensembles for both wild type beta(1)AR (wt-beta(1)AR) and m23-beta(1)AR. Thermostabilization results in an increase in the number of accessible microscopic conformational states within the inactive state ensemble, effectively increasing the side chain entropy of the inactive state at room temperature, while suppressing large-scale main chain conformational changes that lead to activation. We identified several diverse mechanisms of thermostabilization upon mutation. These include decrease of long-range correlated movement between residues in the G-protein coupling site to the extracellular region (Y227A(5.58), F338M(7.48)), formation of new hydrogen bonds (R68S), and reduction of local stress (Y227(5.58), F327(7.37), and F338(7.48)). This study provides insights into microscopic mechanisms underlying thermostability that leads to an understanding of the effect of these mutations on the structure of the receptor. C1 [Niesen, Michiel J. M.; Bhattacharya, Supriyo; Vaidehi, Nagarajan] City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. [Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Tate, Christopher G.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. RP Vaidehi, N (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM NVaidehi@coh.org RI Niesen, Michiel/L-8985-2013; Grisshammer, Reinhard/C-3089-2015 FU NIH [RO1-GM097261] FX The authors thank Mr. Jeffrey Wagner for help with some of the scripts used for analysis. This work was supported by NIH RO1-GM097261. NR 56 TC 8 Z9 8 U1 0 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUN 20 PY 2013 VL 117 IS 24 BP 7283 EP 7291 DI 10.1021/jp403207c PG 9 WC Chemistry, Physical SC Chemistry GA 171FQ UT WOS:000320910900016 PM 23697892 ER PT J AU Morens, DM Taubenberger, JK Fauci, AS AF Morens, David M. Taubenberger, Jeffery K. Fauci, Anthony S. TI Pandemic Influenza Viruses - Hoping for the Road Not Taken SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Morens, David M.; Fauci, Anthony S.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Off Director, Bethesda, MD USA. [Taubenberger, Jeffery K.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Viral Pathogenesis & Evolut Sect, Lab Infect Dis, Bethesda, MD USA. RP Morens, DM (reprint author), Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Off Director, Bethesda, MD USA. FU Intramural NIH HHS [ZIA AI000986-06] NR 5 TC 31 Z9 34 U1 0 U2 6 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 JUN 20 PY 2013 VL 368 IS 25 BP 2345 EP 2348 DI 10.1056/NEJMp1307009 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 167AE UT WOS:000320601700001 PM 23738514 ER PT J AU Hudson, KL Guttmacher, AE Collins, FS AF Hudson, Kathy L. Guttmacher, Alan E. Collins, Francis S. TI In Support of SUPPORT - A View from the NIH SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SEVERE RETINOPATHY; INFANTS C1 [Hudson, Kathy L.; Guttmacher, Alan E.; Collins, Francis S.] Natl Inst Hlth, Bethesda, MD USA. RP Hudson, KL (reprint author), Natl Inst Hlth, Bethesda, MD USA. NR 4 TC 27 Z9 27 U1 1 U2 7 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 JUN 20 PY 2013 VL 368 IS 25 BP 2349 EP 2351 DI 10.1056/NEJMp1306986 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 167AE UT WOS:000320601700003 PM 23738511 ER PT J AU Wang, P Dong, Q Zhang, C Kuan, PF Liu, Y Jeck, WR Andersen, JB Jiang, W Savich, GL Tan, TX Auman, JT Hoskins, JM Misher, AD Moser, CD Yourstone, SM Kim, JW Cibulskis, K Getz, G Hunt, HV Thorgeirsson, SS Roberts, LR Ye, D Guan, KL Xiong, Y Qin, LX Chiang, DY AF Wang, P. Dong, Q. Zhang, C. Kuan, P-F Liu, Y. Jeck, W. R. Andersen, J. B. Jiang, W. Savich, G. L. Tan, T-X Auman, J. T. Hoskins, J. M. Misher, A. D. Moser, C. D. Yourstone, S. M. Kim, J. W. Cibulskis, K. Getz, G. Hunt, H. V. Thorgeirsson, S. S. Roberts, L. R. Ye, D. Guan, K-L Xiong, Y. Qin, L-X Chiang, D. Y. TI Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas SO ONCOGENE LA English DT Article DE DNA methylation; epigenetics; tumor metabolism ID CELL SELF-RENEWAL; IDH2 MUTATIONS; COLORECTAL-CANCER; MAFFUCCI SYNDROME; OLLIER DISEASE; MAMMALIAN DNA; TET PROTEINS; STEM-CELLS; PHENOTYPE; 5-CARBOXYLCYTOSINE AB Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P = 0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors. C1 [Wang, P.; Jiang, W.; Guan, K-L; Xiong, Y.] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200032, Peoples R China. [Wang, P.; Jiang, W.; Ye, D.; Guan, K-L; Xiong, Y.] Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China. [Dong, Q.; Qin, L-X] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Dong, Q.; Qin, L-X] Fudan Univ, Zhongshan Hosp, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Zhang, C.; Liu, Y.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Kuan, P-F] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Kuan, P-F; Jeck, W. R.; Savich, G. L.; Tan, T-X; Auman, J. T.; Hoskins, J. M.; Misher, A. D.; Yourstone, S. M.; Xiong, Y.; Chiang, D. Y.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Jeck, W. R.; Savich, G. L.; Tan, T-X; Yourstone, S. M.; Chiang, D. Y.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Andersen, J. B.; Thorgeirsson, S. S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Auman, J. T.; Hoskins, J. M.; Misher, A. D.] Univ N Carolina, Inst Pharmacogen & Individualized Med, Chapel Hill, NC 27599 USA. [Moser, C. D.; Roberts, L. R.] Mayo Clin, Ctr Canc, Ctr Cell Signaling Gastroenterol, Div Gastroenterol & Hepatol, Rochester, MN USA. [Kim, J. W.] Wake Forest Univ, Baptist Med Ctr, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Cibulskis, K.; Getz, G.] 7 Cambridge Ctr, Broad Inst, Genome Sequencing Anal Program & Platform, Cambridge, MA USA. [Hunt, H. V.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Guan, K-L] Fudan Univ, Shanghai Med Coll, Dept Biochem, Shanghai 200032, Peoples R China. [Guan, K-L] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Guan, K-L] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Xiong, Y.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Xiong, Y (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295,450 West Dr, Chapel Hill, NC 27599 USA. EM yxiong@email.unc.edu; qin.lunxiu@zs-hospital.sh.cn; chiang@med.unc.edu OI Chiang, Derek/0000-0002-1131-6065; Roberts, Lewis/0000-0001-7885-8574; Andersen , Jesper B/0000-0003-1760-5244 FU 985 Program from the Chinese Ministry of Education; MOST 973 [2009CB918401, 2011CB910600, 2012CB910300, 2012CB910101]; NSFC Program of International Cooperation and Exchanges [81120108016]; China National Key Projects for Infectious Disease [2008ZX10002-021, 2012ZX10002-012]; National Institutes of Health; James S McDonnell Foundation; Samuel Waxman Cancer Research Foundation; American Gastroenterological Association Foundation for Digestive Health and Nutrition; Alfred P Sloan Foundation; Nancy Stegman Cancer Research Fund; University Cancer Research Fund FX The UNC Biospecimen Core Facility, Mammalian Genotyping Core Facility and Translational Pathology Laboratory provided technical assistance for this study. Funding for this research was provided by: the 985 Program from the Chinese Ministry of Education (KLG, YX), MOST 973 (No. 2009CB918401, No. 2011CB910600, No. 2012CB910300, No. 2012CB910101; DY, YX and KLG); the NSFC Program of International Cooperation and Exchanges (No. 81120108016; LXQ, YX) and the China National Key Projects for Infectious Disease (2008ZX10002-021, 2012ZX10002-012; LZQ), the National Institutes of Health (KLG, YX, SST, LRR), the James S McDonnell Foundation (YX), the Samuel Waxman Cancer Research Foundation (YX), the American Gastroenterological Association Foundation for Digestive Health and Nutrition (LRR), the Alfred P Sloan Foundation fellowship (DYC), the Nancy Stegman Cancer Research Fund (DYC) and the University Cancer Research Fund (DYC, YX). NR 46 TC 86 Z9 89 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 20 PY 2013 VL 32 IS 25 BP 3091 EP 3100 DI 10.1038/onc.2012.315 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 168KX UT WOS:000320705700009 PM 22824796 ER PT J AU Findley, K Oh, J Yang, J Conlan, S Deming, C Meyer, JA Schoenfeld, D Nomicos, E Park, M Kong, HH Segre, JA AF Findley, Keisha Oh, Julia Yang, Joy Conlan, Sean Deming, Clayton Meyer, Jennifer A. Schoenfeld, Deborah Nomicos, Effie Park, Morgan Kong, Heidi H. Segre, Julia A. CA NIH Intramural Sequencing Ctr Comp TI Topographic diversity of fungal and bacterial communities in human skin SO NATURE LA English DT Article ID RIBOSOMAL-RNA SEQUENCES; HUMAN MICROBIOME; RISK-FACTORS; TINEA-PEDIS; PREVALENCE; ALIGNMENT; ACCURACY; DISEASES; PROJECT; SAMPLES AB Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete's foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota(1). Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders(2-4). However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease(5). Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria(6). Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes(7). Here we sequenced and analysed fungal communities of 14 skin sites in 10 healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites-plantar heel, toenail and toe web-showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis. C1 [Findley, Keisha; Oh, Julia; Yang, Joy; Conlan, Sean; Deming, Clayton; Meyer, Jennifer A.; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Schoenfeld, Deborah; Nomicos, Effie; Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Morgan] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; jsegre@nhgri.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X FU US National Institutes of Health (NIH) NHGRI and NCI Intramural Research Programs; NIH [1K99AR059222, 1UH2AR057504-01, 4UH3AR057504-02] FX We thank J. Heitman, A. Amend, Y. Shea, M. Turner, I. Brownell and M. Udey for helpful discussions. We thank J. Fekecs for assistance with the figures. This work was supported by the US National Institutes of Health (NIH) NHGRI and NCI Intramural Research Programs, and in part by NIH grant no. 1K99AR059222 (to H. H. K.). Sequencing was funded by grants from the NIH (1UH2AR057504-01 and 4UH3AR057504-02). NR 41 TC 198 Z9 206 U1 23 U2 218 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 20 PY 2013 VL 498 IS 7454 BP 367 EP + DI 10.1038/nature12171 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900041 PM 23698366 ER PT J AU Lammermann, T Afonso, PV Angermann, BR Wang, JM Kastenmuller, W Parent, CA Germain, RN AF Laemmermann, Tim Afonso, Philippe V. Angermann, Bastian R. Wang, Ji Ming Kastenmueller, Wolfgang Parent, Carole A. Germain, Ronald N. TI Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo SO NATURE LA English DT Article ID INNATE IMMUNE-RESPONSE; STERILE INFLAMMATION; AMMATORY ARTHRITIS; IMAGING REVEALS; HOST-DEFENSE; MICE LACKING; LYMPH-NODES; BONE-MARROW; MIGRATION; RECEPTOR AB Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined(1,2). Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects(3-11). The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration(12), but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue. C1 [Laemmermann, Tim; Angermann, Bastian R.; Kastenmueller, Wolfgang; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Afonso, Philippe V.; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Kastenmueller, Wolfgang] Univ Bonn, Inst Mol Med, D-53105 Bonn, Germany. [Kastenmueller, Wolfgang] Univ Bonn, Inst Expt Immunol, D-53105 Bonn, Germany. RP Lammermann, T (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM laemmermannt@niaid.nih.gov; rgermain@niaid.nih.gov RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Human Frontiers Science Program Long-Term Fellowship; Deutsche Forschungsgemeinschaft (DFG); National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health FX We thank L. Birnbaumer, R. Fassler, E. Tuomanen, P. M. Murphy, S. Akira, S. Monkley, D. Critchley, R. Wedlich-Soldner and M. Sixt for providing mice for this study, J.G. Egen and J. Tang for assistance with imaging, M. Parsek for providing P. aeruginosa-GFP, J. H. Kehrl, P. M. Murphy, R. Varma and members of the Germain laboratory for discussions. This work was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health. T. L. was supported by a Human Frontiers Science Program Long-Term Fellowship. W. K. is presently a member of the Deutsche Forschungsgemeinschaft (DFG)-funded excellence cluster ImmunoSensation, Bonn, Germany. NR 49 TC 170 Z9 172 U1 9 U2 71 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 20 PY 2013 VL 498 IS 7454 BP 371 EP + DI 10.1038/nature12175 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900042 PM 23708969 ER PT J AU Cooper, A Garcia, M Petrovas, C Yamamoto, T Koup, RA Nabel, GJ AF Cooper, Arik Garcia, Mayra Petrovas, Constantinos Yamamoto, Takuya Koup, Richard A. Nabel, Gary J. TI HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS MOLECULAR CLONE; T-CELLS; IN-VIVO; RETROVIRAL INFECTION; QUANTITATIVE ASSAY; LYMPHOCYTES; INHIBITOR; DEPLETION; DYNAMICS AB Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide(1), ultimately the consequence of cytolytic infection of CD4(+) T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia(2-4), yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals. C1 [Cooper, Arik; Garcia, Mayra; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Petrovas, Constantinos; Yamamoto, Takuya; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. EM Gary.Nabel@sanofi.com RI Yamamoto, Takuya/L-2642-2013 OI Yamamoto, Takuya/0000-0003-3753-1211 FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health FX We thank D. Ambrozak, R. Nguyen, and S. Perfetto for help with cell sorting, U. Olshevsky, J. Casazza, D. Bolton, A. Pegu and M. Louder for discussions and technical help, and A. Tislerics and B. Hartman for manuscript preparation. This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 39 TC 90 Z9 92 U1 5 U2 56 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 20 PY 2013 VL 498 IS 7454 BP 376 EP + DI 10.1038/nature12274 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166XI UT WOS:000320592900043 PM 23739328 ER PT J AU Prater, SN Patel, TT Buckley, AF Mandel, H Vlodavski, E Banugaria, SG Feeney, EJ Raben, N Kishnani, PS AF Prater, Sean N. Patel, Trusha T. Buckley, Anne F. Mandel, Hanna Vlodavski, Eugene Banugaria, Suhrad G. Feeney, Erin J. Raben, Nina Kishnani, Priya S. TI Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Pompe disease; Glycogen storage disease type II; Enzyme replacement therapy; rhGAA; Alglucosidase alfa; Myozyme; Skeletal muscle; Pathology; Autophagy; Genetic diseases ID ACID ALPHA-GLUCOSIDASE; STORAGE-DISEASE; ALGLUCOSIDASE ALPHA; CLINICAL-OUTCOMES; DISORDERS; TETRASACCHARIDE; ULTRASTRUCTURE; BIOMARKER AB Background: Pompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD). Methods: Muscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20-40 mg/kg. Results: Median age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients' ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status. Conclusions: This is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age. C1 [Prater, Sean N.; Patel, Trusha T.; Banugaria, Suhrad G.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Buckley, Anne F.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Mandel, Hanna] Technion Israel Inst Technol, Rambam Med Ctr, Fac Med, Metab Unit,Meyer Childrens Hosp, Haifa, Israel. [Vlodavski, Eugene] Technion Israel Inst Technol, Rambam Med Ctr, Fac Med, Dept Pathol, Haifa, Israel. [Feeney, Erin J.; Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Raben, N (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov; priya.kishnani@dm.duke.edu FU Lysosomal Disease Network, a part of National Institutes of Health Rare Diseases Clinical Research Network (RDCRN); National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX We thank the patients, their families and the health-care providers who participated in and contributed to this study. This project was funded in part by the Lysosomal Disease Network, a part of National Institutes of Health Rare Diseases Clinical Research Network (RDCRN). This research was also 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 34 TC 14 Z9 14 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD JUN 20 PY 2013 VL 8 AR 90 DI 10.1186/1750-1172-8-90 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 171WC UT WOS:000320959800001 PM 23787031 ER PT J AU Kummar, S Allen, D Monks, A Polley, EC Hose, CD Ivy, SP Turkbey, IB Lawrence, S Kinders, RJ Choyke, P Simon, R Steinberg, SM Doroshow, JH Helman, L AF Kummar, Shivaani Allen, Deborah Monks, Anne Polley, Eric C. Hose, Curtis D. Ivy, S. Percy Turkbey, Ismail B. Lawrence, Scott Kinders, Robert J. Choyke, Peter Simon, Richard Steinberg, Seth M. Doroshow, James H. Helman, Lee TI Cediranib for Metastatic Alveolar Soft Part Sarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FACTOR SIGNALING INHIBITOR; SOLID TUMORS; GENE; MET; AZD2171; CANCER; ADOLESCENTS; PATTERNS; CHILDREN AB Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. (C) 2013 by American Society of Clinical Oncology C1 [Kummar, Shivaani; Allen, Deborah; Polley, Eric C.; Ivy, S. Percy; Turkbey, Ismail B.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee] NCI, Bethesda, MD 20892 USA. [Monks, Anne; Hose, Curtis D.; Lawrence, Scott; Kinders, Robert J.] Frederick Natl Lab Canc Res, SAIC Frederick, Frederick, MD USA. RP Kummar, S (reprint author), NCI, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 25 TC 59 Z9 59 U1 0 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 JUN 20 PY 2013 VL 31 IS 18 BP 2296 EP U106 DI 10.1200/JCO.2012.47.4288 PG 8 WC Oncology SC Oncology GA 164XV UT WOS:000320446700015 PM 23630200 ER PT J AU Virgo, KS Lerro, CC Klabunde, CN Earle, C Ganz, PA AF Virgo, Katherine S. Lerro, Catherine C. Klabunde, Carrie N. Earle, Craig Ganz, Patricia A. TI Barriers to Breast and Colorectal Cancer Survivorship Care: Perceptions of Primary Care Physicians and Medical Oncologists in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOLLOW-UP; SOCIETY; EXPERIENCE; PROVIDERS; QUALITY; UPDATE; ACCESS AB Purpose High-quality, well-coordinated cancer survivorship care is needed yet barriers remain owing to fragmentation in the United States health care system. This article is a nationwide survey of barriers perceived by primary care physicians (PCPs) and medical oncologists (MOs) regarding breast and colorectal cancer survivorship care beyond 5 years after treatment. Methods The Survey of Physician Attitudes Regarding the Care of Cancer Survivors was mailed out in 2009 to a nationally-representative sample (n = 3,596) of US PCPs and MOs. Ten physician-perceived cancer survivorship care barriers/concerns were compared between the two provider types. Using weighted multinomial logistic regression, we modeled each barrier, adjusting for physician demographics, reimbursement, training, and practice characteristics. Results We received responses from 2,202 physicians (1,072 PCPs; 1,130 MOs; 65.1% cooperation rate). In adjusted patient-related barriers models, MOs were more likely than PCPs to report patient language barriers (odds ratio, [OR], 1.72; 95% CI, 1.22 to 2.42), insurance restrictions impeding test/treatment use (OR, 1.42; 95% CI, 1.03 to 1.96), and patients requesting more aggressive testing (OR, 4.08; 95% CI, 2.73 to 6.10). In adjusted physician-related barriers models, PCPs were more likely to report inadequate training (OR, 3.06; 95% CI, 2.03 to 4.61) and ordering additional tests/treatments because of malpractice concerns (OR, 1.87; 95% CI, 1.20 to 2.93). MOs were more likely to report uncertainty regarding general preventive care responsibility (often/always: OR, 1.97; 95% CI, 1.13 to 3.43; sometimes: OR, 2.16; 95% CI, 1.60 to 2.93). Conclusion MOs and PCPs perceive different cancer follow-up care barriers/concerns to be problematic. Resolving inadequate training, malpractice-driven test ordering, and preventive-care responsibility concerns may require continuing education, explicit guidelines, and survivorship care plans. Reviewing care plans with survivors may also reduce patients' requests for unnecessary testing. (C) 2013 by American Society of Clinical Oncology C1 [Virgo, Katherine S.] Emory Univ, Atlanta, GA 30329 USA. [Lerro, Catherine C.] Yale Univ, New Haven, CT USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Earle, Craig] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Earle, Craig] Univ Toronto, Toronto, ON, Canada. RP Virgo, KS (reprint author), Emory Univ, Dept Hlth Policy & Management, RSPH, 1360 Stephens Dr NE, Atlanta, GA 30329 USA. EM kvirgo@emory.edu FU National Cancer Institute [HHSN261201000316C]; American Cancer Society National Home Office Intramural Research Department FX Supported by Grant No. HHSN261201000316C from the National Cancer Institute and American Cancer Society National Home Office Intramural Research Department. NR 34 TC 26 Z9 26 U1 4 U2 12 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 JUN 20 PY 2013 VL 31 IS 18 BP 2322 EP 2336 DI 10.1200/JCO.2012.45.6954 PG 15 WC Oncology SC Oncology GA 164XV UT WOS:000320446700018 PM 23690429 ER PT J AU Wang, LN Yin, QY He, GM Rossiter, SJ Holmes, EC Cui, J AF Wang, Lina Yin, Qiuyuan He, Guimei Rossiter, Stephen J. Holmes, Edward C. Cui, Jie TI Ancient invasion of an extinct gammaretrovirus in cetaceans SO VIROLOGY LA English DT Article DE Endogenous gammaretrovirus; Cetaceans; Molecular dating; Phylogeny ID ENDOGENOUS RETROVIRUSES; EVOLUTION; DISCOVERY; SEQUENCES AB Endogenous gammaretroviruses (EGVs) have been widely studied in terrestrial mammals but seldom so in marine species. A genomic mining of the bottlenose dolphin (Tursiops truncatus) genome revealed a new EGV, termed Tursiops truncatus endogenous retrovirus (TTEV), which is divergent from extant mammalian EGVs. Molecular clock dating estimated the invasion time of TTEV into the host genome to be approximately 10-19 million years ago (MYA), while a previously identified killer whale endogenous gammaretrovirus (KWERV) was estimated to have invaded the host genome approximately 3-5 MYA. Using a PCR-based technique, we then verified that similar endogenous viruses exist in nine cetacean genomes. Phylogenetic analysis revealed that these cetacean EGVs are highly divergent from their counterparts in other mammals, including KWERV from the killer whale. In sum, we conclude that there have been at least two invasion episodes of EGVs into cetaceans during their evolutionary history. (C) 2013 Elsevier Inc. All rights reserved. C1 [Wang, Lina; Yin, Qiuyuan; He, Guimei] E China Normal Univ, Inst Mol Ecol & Evolut, Inst Adv Interdisciplinary Res, Shanghai 200062, Peoples R China. [Rossiter, Stephen J.] Univ London, Sch Biol & Chem Sci, London E1 4NS, England. [Holmes, Edward C.; Cui, Jie] Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sch Biol Sci, Sydney, NSW 2006, Australia. [Holmes, Edward C.; Cui, Jie] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Cui, J (reprint author), Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sch Biol Sci, Sydney, NSW 2006, Australia. EM jiecui@yahoo.com RI Rossiter, Stephen/E-2111-2011; OI Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 NR 15 TC 3 Z9 3 U1 0 U2 16 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 JUN 20 PY 2013 VL 441 IS 1 BP 66 EP 69 DI 10.1016/j.viro1.2013.03.006 PG 4 WC Virology SC Virology GA 147PU UT WOS:000319180300009 PM 23545142 ER PT J AU Cournil, A De Vincenzi, I Gaillard, P Cames, C Fao, P Luchters, S Rollins, N Newell, ML Bork, K Read, JS AF Cournil, Amandine De Vincenzi, Isabelle Gaillard, Philippe Cames, Cecile Fao, Paulin Luchters, Stanley Rollins, Nigel Newell, Marie-Louise Bork, Kirsten Read, Jennifer S. CA Kesho Bora Study Grp TI Relationship between mortality and feeding modality among children born to HIV-infected mothers in a research setting: the Kesho Bora Study SO AIDS LA English DT Article DE Africa; breastfeeding; HIV-exposed children; marginal structural models; mortality; replacement feeding ID UNINFECTED CHILDREN; POOLED ANALYSIS; INFANTS BORN; POSTNATAL TRANSMISSION; ANTIRETROVIRAL THERAPY; PROSPECTIVE COHORT; POSITIVE MOTHERS; FREE SURVIVAL; SOUTH-AFRICA; WOMEN AB Objective:To assess the relationship between infant feeding practices and mortality by 18 months of age among children born to HIV-infected mothers in the Kesho Bora trial (Burkina-Faso, Kenya and South Africa).Methods:Enrolled HIV-infected women were counseled to choose between breastfeeding up to 6 months or replacement feeding from delivery. Multivariable Cox models were used to compare the infant mortality risks according to feeding practices over time defined as never breastfed, weaned or still breastfed. The category still breastfed' was disaggregated as exclusively, predominantly or partially breastfed to compare modes of breastfeeding. The relationship between weaning and mortality was also assessed using marginal structural models to control for time-dependent confounders, such as maternal or infant morbidity (reverse causality).Results:Among 795 mothers, 618 (77.7%) initiated breastfeeding. Mortality rates by 18 months among uninfected and infected children were 6 and 38%, respectively. Never breastfed and weaned children were at greater risk of death compared with those still breastfed. Adjusted hazard ratios were 6.7 [95% confidence interval (CI)=2.5-17.9; P<0.001] and 6.9 (CI=2.8-17.2; P<0.001) for never breastfed and weaned children, respectively. Estimation of the effect of weaning using marginal structural models led to similar results. No statistically significant differences were observed according to mode of breastfeeding (exclusive, predominant or partial).Conclusion:Within 6 months after birth, weaned or never breastfed children were at about seven-fold higher risk of dying compared with children who were still breastfed despite a context in which interventions were provided to reduce risks associated with replacement feeding. C1 [Cournil, Amandine; Cames, Cecile; Bork, Kirsten] Univ Montpellier, Inst Rech Dev, F-34059 Montpellier, France. [De Vincenzi, Isabelle; Gaillard, Philippe] WHO, CH-1211 Geneva, Switzerland. [Fao, Paulin] Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Luchters, Stanley] Int Ctr Reprod Hlth, Mombasa, Kenya. [Luchters, Stanley] Univ Ghent, Int Ctr Reprod Hlth, B-9000 Ghent, Belgium. [Luchters, Stanley] Burnet Inst, Ctr Int Hlth, Melbourne, Vic, Australia. [Rollins, Nigel] Univ KwaZulu Natal, Durban, South Africa. [Rollins, Nigel] WHO, Dept Maternal Newborn Child & Adolescent Hlth, CH-1211 Geneva, Switzerland. [Newell, Marie-Louise] Univ KwaZulu Natal, Africa Ctr Hlth & Populat Studies, Somkhele, South Africa. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Bethesda, MD USA. [Read, Jennifer S.] NVPO OASH OS DHHS, Washington, DC USA. RP Cournil, A (reprint author), Inst Rech Dev, BP 64501, F-34394 Montpellier 5, France. EM amandine.cournil@ird.fr RI Van de Perre, Philippe/B-9692-2008; OI Van de Perre, Philippe/0000-0002-3912-0427; Bork, Kirsten/0000-0002-5909-7332; Newell, Marie-Louise/0000-0002-1074-7699; Njagi, Ephantus/0000-0002-1484-0241 FU l'Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS); UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP); ANRS; WHO/HRP; European and Developing Countries Clinical Trials Partnership (EDCTP); Thrasher Research Fund; Belgian Directorate General for International Cooperation FX The Bobo-Dioulasso site was funded by l'Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP).; The Mombasa site was funded by ANRS, WHO/HRP, European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation. NR 45 TC 8 Z9 8 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2013 VL 27 IS 10 BP 1621 EP 1630 DI 10.1097/QAD.0b013e32835d5226 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HG UT WOS:000326840700011 PM 23262499 ER PT J AU Hobbs, CV De La Vega, P Penzak, SR Van Vliet, J Krzych, U Sinnis, P Borkowsky, W Duffy, PE AF Hobbs, Charlotte V. De La Vega, Patricia Penzak, Scott R. Van Vliet, Jillian Krzych, Urszula Sinnis, Photini Borkowsky, William Duffy, Patrick E. TI The effect of antiretrovirals on Plasmodium falciparum liver stages SO AIDS LA English DT Article ID TYPE-1 PROTEASE INHIBITORS; HUMAN HEPATOCYTE LINE; MALARIA PARASITES; IN-VITRO; SPOROZOITES; AGENTS C1 [Hobbs, Charlotte V.; Van Vliet, Jillian; Duffy, Patrick E.] NIAID, NIH, Lab Malaria Immunol & Vaccinol, Rockville, MD 20852 USA. [De La Vega, Patricia; Krzych, Urszula] Walter Reed Army Inst Res, Malaria Vaccine Branch, Dept Cellular Immunol, Silver Spring, MD USA. [Penzak, Scott R.] NIH, Dept Pharm, Ctr Clin, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. [Sinnis, Photini] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Borkowsky, William] NYU, Sch Med, Dept Pediat, Div Infect Dis & Immunol, New York, NY USA. RP Hobbs, CV (reprint author), NIAID, NIH, Rockville, MD 20852 USA. EM charlotte.hobbs@nih.gov FU NIH, NIAID, Division of Intramural Research; US Army and Materiel Command FX This work was funded by the NIH, NIAID, Division of Intramural Research and by the by the US Army and Materiel Command. NR 21 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2013 VL 27 IS 10 BP 1674 EP 1677 DI 10.1097/QAD.0b013e3283621dd4 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HG UT WOS:000326840700017 PM 23907270 ER PT J AU Liu, R Guo, XG Park, Y Wang, J Huang, XM Hollenbeck, A Blair, A Chen, HL AF Liu, Rui Guo, Xuguang Park, Yikyung Wang, Jian Huang, Xuemei Hollenbeck, Albert Blair, Aaron Chen, Honglei TI Alcohol Consumption, Types of Alcohol, and Parkinson's Disease SO PLOS ONE LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; PLASMA URATE; RISK; RESVERATROL; PREDICTOR; DEMENTIA; DECLINE AB Background: The epidemiologic evidence on alcohol consumption and Parkinson's disease (PD) is equivocal. We prospectively examined total alcohol consumption and consumption of specific types of alcoholic beverage in relation to future risk of PD. Methods: The study comprised 306,895 participants (180,235 male and 126,660 female) ages 50-71 years in 1995-1996 from the NIH-AARP Diet and Health Study. Consumption of alcoholic beverages in the past 12 months was assessed in 1995-1996. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models. Results: A total of 1,113 PD cases diagnosed between 2000 and 2006 were included in the analysis. Total alcohol consumption was not associated with PD. However, the association differed by types of alcoholic beverages. Compared with non-beer drinkers, the multivariate ORs for beer drinkers were 0.79 (95% CI: 0.68, 0.92) for <1 drink/day, 0.73 (95% CI: 0.50, 1.07) for 1-1.99 drinks/day, and 0.86 (95% CI: 0.60, 1.21) for >= 2 drinks/day. For liquor consumption, a monotonic increase in PD risk was suggested: ORs (95% CI) were 1.06 (0.91, 1.23), 1.22 (0.94, 1.58), and 1.35 (1.02, 1.80) for<1, 1-1.99, and >= 2 drinks/day, respectively (P for trend <0.03). Additional analyses among exclusive drinkers of one specific type of alcoholic beverage supported the robustness of these findings. The results for wine consumption were less clear, although a borderline lower PD risk was observed when comparing wine drinkers of 1-1.99 drinks/day with none drinkers (OR = 0.74, 95% CI: 0.53, 1.02). Conclusions: Our results suggest that beer and liquor consumption may have opposite associations with PD: low to moderate beer consumption with lower PD risk and greater liquor consumption with higher risk. These findings and potential underlying mechanisms warrant further investigations. C1 [Liu, Rui; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Guo, Xuguang] Westat Corp, Res Triangle Pk, NC USA. [Park, Yikyung; Blair, Aaron] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wang, Jian] Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai 200433, Peoples R China. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Liu, R (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM liur2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU National Institute of Health; National Institute of Environmental Health Sciences [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02] FX This study was supported by the intramural research program of the National Institute of Health, the National Institute of Environmental Health Sciences (Z01-ES-101986) and the National Cancer Institute (Z01 CP010196-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 5 Z9 5 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2013 VL 8 IS 6 AR e66452 DI 10.1371/journal.pone.0066452 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190ST UT WOS:000322361200081 PM 23840473 ER PT J AU Manchia, M Adli, M Akula, N Ardau, R Aubry, JM Backlund, L Banzato, CEM Baune, BT Bellivier, F Bengesser, S Biernacka, JM Brichant-Petitjean, C Bui, E Calkin, CV Cheng, ATA Chillotti, C Cichon, S Clark, S Czerski, PM Dantas, C Del Zompo, M DePaulo, JR Detera-Wadleigh, SD Etain, B Falkai, P Frisen, L Frye, MA Fullerton, J Gard, S Garnham, J Goes, FS Grof, P Gruber, O Hashimoto, R Hauser, J Heilbronner, U Hoban, R Hou, LP Jamain, S Kahn, JP Kassem, L Kato, T Kelsoe, JR Kittel-Schneider, S Kliwicki, S Kuo, PH Kusumi, I Laje, G Lavebratt, C Leboyer, M Leckband, SG Jaramillo, CAL Maj, M Malafosse, A Martinsson, L Masui, T Mitchell, PB Mondimore, F Monteleone, P Nallet, A Neuner, M Novak, T O'Donovan, C Osby, U Ozaki, N Perlis, RH Pfennig, A Potash, JB Reich-Erkelenz, D Reif, A Reininghaus, E Richardson, S Rouleau, GA Rybakowski, JK Schalling, M Schofield, PR Schubert, OK Schweizer, B Seemuller, F Grigoroiu-Serbanescu, M Severino, G Seymour, LR Slaney, C Smoller, JW Squassina, A Stamm, T Steele, J Stopkova, P Tighe, SK Tortorella, A Turecki, G Wray, NR Wright, A Zandi, PP Zilles, D Bauer, M Rietschel, M McMahon, FJ Schulze, TG Alda, M AF Manchia, Mirko Adli, Mazda Akula, Nirmala Ardau, Raffaella Aubry, Jean-Michel Backlund, Lena Banzato, Claudio E. M. Baune, Bernhard T. Bellivier, Frank Bengesser, Susanne Biernacka, Joanna M. Brichant-Petitjean, Clara Bui, Elise Calkin, Cynthia V. Cheng, Andrew Tai Ann Chillotti, Caterina Cichon, Sven Clark, Scott Czerski, Piotr M. Dantas, Clarissa Del Zompo, Maria DePaulo, J. Raymond Detera-Wadleigh, Sevilla D. Etain, Bruno Falkai, Peter Frisen, Louise Frye, Mark A. Fullerton, Jan Gard, Sebastien Garnham, Julie Goes, Fernando S. Grof, Paul Gruber, Oliver Hashimoto, Ryota Hauser, Joanna Heilbronner, Urs Hoban, Rebecca Hou, Liping Jamain, Stephane Kahn, Jean-Pierre Kassem, Layla Kato, Tadafumi Kelsoe, John R. Kittel-Schneider, Sarah Kliwicki, Sebastian Kuo, Po-Hsiu Kusumi, Ichiro Laje, Gonzalo Lavebratt, Catharina Leboyer, Marion Leckband, Susan G. Lopez Jaramillo, Carlos A. Maj, Mario Malafosse, Alain Martinsson, Lina Masui, Takuya Mitchell, Philip B. Mondimore, Frank Monteleone, Palmiero Nallet, Audrey Neuner, Maria Novak, Tomas O'Donovan, Claire Osby, Urban Ozaki, Norio Perlis, Roy H. Pfennig, Andrea Potash, James B. Reich-Erkelenz, Daniela Reif, Andreas Reininghaus, Eva Richardson, Sara Rouleau, Guy A. Rybakowski, Janusz K. Schalling, Martin Schofield, Peter R. Schubert, Oliver K. Schweizer, Barbara Seemueller, Florian Grigoroiu-Serbanescu, Maria Severino, Giovanni Seymour, Lisa R. Slaney, Claire Smoller, Jordan W. Squassina, Alessio Stamm, Thomas Steele, Jo Stopkova, Pavla Tighe, Sarah K. Tortorella, Alfonso Turecki, Gustavo Wray, Naomi R. Wright, Adam Zandi, Peter P. Zilles, David Bauer, Michael Rietschel, Marcella McMahon, Francis J. Schulze, Thomas G. Alda, Martin TI Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report SO PLOS ONE LA English DT Article ID MAPPING SUSCEPTIBILITY GENES; PROPHYLACTIC LITHIUM; OBSERVER AGREEMENT; MOOD DISORDERS; ONSET; ASSOCIATION; RELIABILITY; MORTALITY; ILLNESS; AGE AB Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (kappa)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (kappa = 0.66 and kappa = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study. C1 [Manchia, Mirko; Calkin, Cynthia V.; Garnham, Julie; O'Donovan, Claire; Slaney, Claire; Alda, Martin] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. [Adli, Mazda; Stamm, Thomas] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Akula, Nirmala; Bui, Elise; Detera-Wadleigh, Sevilla D.; Hou, Liping; Kassem, Layla; Laje, Gonzalo; Richardson, Sara; Steele, Jo; McMahon, Francis J.; Schulze, Thomas G.] NIMH, Human Genet Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Ardau, Raffaella; Chillotti, Caterina; Del Zompo, Maria] Univ Hosp Cagliari, Clin Pharmacol Unit, Cagliari, Italy. [Aubry, Jean-Michel; Malafosse, Alain; Nallet, Audrey] Hop Univ Geneve, Dept Mental Hlth & Psychiat, Geneva, Switzerland. [Backlund, Lena; Frisen, Louise; Martinsson, Lina] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Banzato, Claudio E. M.; Dantas, Clarissa] Univ Estadual Campinas, Dept Psychiat, Campinas, Brazil. [Baune, Bernhard T.; Clark, Scott; Schubert, Oliver K.] Univ Adelaide, Dept Psychiat, Adelaide, SA, Australia. [Bellivier, Frank; Brichant-Petitjean, Clara] Grp Hosp Lariboisiere F Widal, AP HP, Paris, France. [Bengesser, Susanne; Reininghaus, Eva] Med Univ Graz, Dept Psychiat, Graz, Austria. [Biernacka, Joanna M.; Frye, Mark A.; Seymour, Lisa R.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Cheng, Andrew Tai Ann] Acad Sinica, Inst Biomed Sci, Div Epidemiol & Genet, Taipei, Taiwan. [Cichon, Sven] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Czerski, Piotr M.] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Del Zompo, Maria; Severino, Giovanni; Squassina, Alessio] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy. [DePaulo, J. Raymond; Goes, Fernando S.; Mondimore, Frank; Potash, James B.; Schweizer, Barbara; Tighe, Sarah K.; Schulze, Thomas G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Fac Med, Equipe 15, Inst Mondor Rech Biomed, INSERM,Unite 955, Creteil, France. [Falkai, Peter; Seemueller, Florian] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Fullerton, Jan; Schofield, Peter R.] Neurosci Res Australia Genet Mental Illness & Bra, Sydney, NSW, Australia. [Gard, Sebastien] Hop Charles Perrens, Psychiat Serv, Bordeaux, France. [Grof, Paul] Mood Disorders Ctr Ottawa, Ottawa, ON, Canada. [Grof, Paul] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Gruber, Oliver; Heilbronner, Urs; Reich-Erkelenz, Daniela; Zilles, David; Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Hashimoto, Ryota] Osaka Univ, Grad Sch Med, Osaka, Japan. [Hauser, Joanna] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Hoban, Rebecca; Kelsoe, John R.; Leckband, Susan G.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Hoban, Rebecca; Kelsoe, John R.] Vet Affairs San Diego Healthcare Syst, Dept Psychiat, San Diego, CA USA. [Kahn, Jean-Pierre] Ctr Hosp Univ Nancy, Serv Psychiat & Psychol Clin, Nancy, France. [Kato, Tadafumi; Kusumi, Ichiro] RIKEN, Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. [Kittel-Schneider, Sarah; Neuner, Maria; Reif, Andreas] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97070 Wurzburg, Germany. [Kliwicki, Sebastian; Rybakowski, Janusz K.] Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. [Kuo, Po-Hsiu] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Kusumi, Ichiro; Masui, Takuya] Hokkaido Univ, Grad Sch Med, Dept Psychiat, Sapporo, Hokkaido, Japan. [Lavebratt, Catharina; Osby, Urban; Schalling, Martin] Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lavebratt, Catharina; Osby, Urban; Schalling, Martin] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Leckband, Susan G.] Vet Affairs San Diego Healthcare Syst, Dept Pharm, San Diego, CA USA. [Leckband, Susan G.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Lopez Jaramillo, Carlos A.] Univ Antioquia, Dept Psychiat, Medellin, Colombia. [Maj, Mario; Monteleone, Palmiero; Tortorella, Alfonso] Univ Naples Federico II, Dept Psychiat, Naples, Italy. [Mitchell, Philip B.; Wright, Adam] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Mitchell, Philip B.; Wright, Adam] Black Dog Inst, Sydney, NSW, Australia. [Novak, Tomas; Stopkova, Pavla] Univ Prague, Prague Psychiat Ctr, Prague, Czech Republic. [Ozaki, Norio] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 47011, Japan. [Ozaki, Norio] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. [Perlis, Roy H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA USA. [Pfennig, Andrea; Bauer, Michael] Tech Univ Dresden, Dept Psychiat & Psychotherapy, Dresden, Germany. [Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Rouleau, Guy A.] Univ Montreal, Ctr Hosp Univ Montreal, Ctr Excellence Neurosci, Montreal, PQ, Canada. [Rouleau, Guy A.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Grigoroiu-Serbanescu, Maria] Alexandru Obregia Psychiat Hosp, Biometr Psychiat Genet Res Unit, Bucharest, Romania. [Turecki, Gustavo] Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Montreal, PQ, Canada. [Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Zandi, Peter P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Rietschel, Marcella; Schulze, Thomas G.] Heidelberg Univ, Univ Med Ctr Mannheim, Cent Inst Mental Hlth Mannheim, Dept Genet Epidemiol Psychiat, Mannheim, Germany. RP Schulze, TG (reprint author), NIMH, Human Genet Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM thomas.schulze@med.uni-goettingen.de; malda@dal.ca RI Banzato, Claudio/B-2517-2008; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Ozaki, Norio/M-8908-2014; Hou, Liping/G-1648-2011; BELLIVIER, FRANK/H-5197-2012; Novak, Tomas/B-8008-2017; Kato, Tadafumi/J-3583-2014; Serbanescu, Maria/D-4306-2011; Hashimoto, Ryota/P-8572-2014; Wray, Naomi/C-8639-2015 OI Kuo, Po-Hsiu/0000-0003-0365-3587; Jamain, Stephane/0000-0002-4321-4100; McMahon, Francis/0000-0002-9469-305X; Backlund, Lena/0000-0001-9399-5024; Banzato, Claudio/0000-0002-8556-3982; Manchia, Mirko/0000-0003-4175-6413; Lavebratt, Catharina/0000-0003-4987-2718; Reininghaus, Eva/0000-0001-5964-4087; Kittel-Schneider, Sarah/0000-0003-3057-6150; Mitchell, Philip/0000-0002-7954-5235; Lopez, Carlos/0000-0002-1875-1369; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Ozaki, Norio/0000-0002-7360-4898; Hou, Liping/0000-0003-3972-245X; Novak, Tomas/0000-0001-9156-9654; Kato, Tadafumi/0000-0001-7856-3952; Serbanescu, Maria/0000-0002-1304-6687; Hashimoto, Ryota/0000-0002-5941-4238; Wray, Naomi/0000-0001-7421-3357 FU Canadian Institutes of Health Research [64410]; Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI), Bucharest, Romania [89/2012]; Swiss National Foundation [32003B_125469/1]; National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH), Department of Health and Human Services, United States Government; Deutsche Forschungsgemeinschaft [RI 908/7-1] FX The work on assessment of lithium response has been supported by a grant from Canadian Institutes of Health Research #64410 to MA. MG-S was supported by Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI), Bucharest, Romania (grant no. 89/2012). JMA and AN were supported by a grant from the Swiss National Foundation (#32003B_125469/1 to JM Aubry). ConLiGen is in part supported by funds from the Intramural Research Program of the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH), Department of Health and Human Services, United States Government. It is further supported by a grant from the Deutsche Forschungsgemeinschaft to MR, MB, and TGS (RI 908/7-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 25 Z9 26 U1 7 U2 32 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2013 VL 8 IS 6 AR e65636 DI 10.1371/journal.pone.0065636 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190ST UT WOS:000322361200028 PM 23840348 ER PT J AU Guo, ZY Li, CZ Li, XJ Wang, YL Mattson, MP Lu, CB AF Guo, Zhi Y. Li, Cheng Z. Li, Xiao J. Wang, Ya L. Mattson, Mark P. Lu, Cheng B. TI The developmental regulation of glutamate receptor-mediated calcium signaling in primary cultured rat hippocampal neurons SO NEUROREPORT LA English DT Article DE -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; calcium; cell culture; N-methyl-D-aspartate receptor; voltage-dependent calcium channels ID LONG-TERM POTENTIATION; NMDA RECEPTORS; AMPA RECEPTORS; CELL-DEATH AB We have studied the developmental changes of glutamate-induced calcium (Ca2+) response in primary cultured hippocampal neurons at three different stages of cultures, 3, 7-8, and 14-16 days in vitro (DIV), using fura-2 single-cell digital micro-fluorimetry. We found that glutamate-induced Ca2+ signaling was altered during development, and that two different ionotropic glutamate receptors, -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), were differently involved in the modulation of calcium response at different stages of neuronal culture. In the stages of culture at 3 and 8 DIV, glutamate-induced Ca2+ influx was mostly because of AMPAR activation and subsequent opening of voltage-dependent calcium channels, as Ca2+ response can be largely reduced by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and by nifedipine. In the advanced culture (14-17 DIV), glutamate-induced Ca2+ response was less sensitive to 6-cyano-7-nitroquinoxaline-2,3-dione and nifedipine. Furthermore, AMPA-induced Ca2+ response increased in a time-dependent manner during the cultures of 3-8 DIV and then reduced in the advanced culture of 14-17 DIV. NMDA-induced Ca2+ influx increased in a time-dependent manner, with a marked increase in the advanced culture (14-17 DIV). These results suggest that glutamate-induced Ca2+ signaling switched from AMPA-voltage-dependent calcium channel to NMDA-calcium signaling during development. C1 [Guo, Zhi Y.; Li, Cheng Z.; Li, Xiao J.; Wang, Ya L.; Lu, Cheng B.] Xinxiang Med Univ, Dept Physiol & Neurobiol, Xinxiang 453003, Peoples R China. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Lu, CB (reprint author), Xinxiang Med Univ, Dept Physiol & Neurobiol, Key Lab Brain Res Henan Prov, Xinxiang 453003, Peoples R China. EM johnlu9001@hotmail.com FU National Science Foundation [31070938, 81271422]; Intramural Research Program of the National Institute on Aging, NIH FX This research was supported by the National Science Foundation (31070938; 81271422) and the Intramural Research Program of the National Institute on Aging, NIH. NR 21 TC 5 Z9 6 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 19 PY 2013 VL 24 IS 9 BP 492 EP 497 DI 10.1097/WNR.0b013e32836206b5 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 202KH UT WOS:000323213800009 PM 23660635 ER PT J AU Poland, GA Quill, H Togias, A AF Poland, Gregory A. Quill, Helen Togias, Alkis TI Understanding the human immune system in the 21st century: The Human Immunology Project Consortium SO VACCINE LA English DT Editorial Material C1 [Poland, Gregory A.] Mayo Clin & Mayo Fdn, Mayo Vaccine Res Grp, Rochester, MN 55905 USA. [Quill, Helen] NIAID, Basic Immunol Branch, Bethesda, MD 20817 USA. [Togias, Alkis] NIAID, Allergy Asthma & Airway Biol Branch, Bethesda, MD 20817 USA. RP Poland, GA (reprint author), Mayo Clin & Mayo Fdn, Mayo Vaccine Res Grp, Rochester, MN 55905 USA. EM poland.gregory@mayo.edu; helen.quill@nih.gov; alkis.togias@nih.gov NR 0 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 19 PY 2013 VL 31 IS 28 BP 2911 EP 2912 DI 10.1016/j.vaccine.2013.04.043 PG 2 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 175KW UT WOS:000321230600001 PM 23648045 ER PT J AU Shimp, RL Rowe, C Reiter, K Chen, B Nguyen, V Aebig, J Rausch, KM Kumar, K Wu, YM Jin, AJ Jones, DS Narum, DL AF Shimp, Richard L., Jr. Rowe, Christopher Reiter, Karine Chen, Beth Vu Nguyen Aebig, Joan Rausch, Kelly M. Kumar, Krishan Wu, Yimin Jin, Albert J. Jones, David S. Narum, David L. TI Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle SO VACCINE LA English DT Article DE Pfs25; Malaria; Transmission blocking vaccine; Nanoparticle; Chemical-conjugate; Recombinant protein ID SECONDARY STRUCTURE ANALYSES; PLASMODIUM-FALCIPARUM; MEMBRANE-PROTEIN; SURFACE-PROTEINS; CANDIDATE; ANTIBODY; CRYSTALLIZATION; IMMUNOGENICITY; RESPONSES; PEPTIDES AB Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10-40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel(R) had a 75-110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel(R) formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel(R) formulation is ongoing in the United States. Published by Elsevier Ltd. C1 [Shimp, Richard L., Jr.; Rowe, Christopher; Reiter, Karine; Chen, Beth; Vu Nguyen; Aebig, Joan; Rausch, Kelly M.; Kumar, Krishan; Wu, Yimin; Jones, David S.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Narum, DL (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Room 1115, Rockville, MD 20852 USA. EM dnarum@niaid.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU Intramural Research Program of the NIH, including NIAID and NIBIB FX We acknowledge the support of those within the units of the LMIV core, especially Emma Barnafo for formulation, Lynn Lambert for excellent animal husbandry, Dominique Jones for analytical support and Olga Muratova for performing the membrane feeding assays. Dr. Svetlana Kotova provided excellent technical support for the AFM studies. We thank Drs. Michael Nold (Waters Corp.) and L. Renee Olano (Research Technology Branch, NIAID, NIH) for their critical evaluation of the quantitative peptide mapping analysis. We appreciate the work of Brian Bell and Jay Wood for the successful technology transfer to the WRAIR Biopilot Production facility. This research was supported by the Intramural Research Program of the NIH, including NIAID and NIBIB. NR 29 TC 29 Z9 30 U1 2 U2 22 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 JUN 19 PY 2013 VL 31 IS 28 BP 2954 EP 2962 DI 10.1016/j.vaccine.2013.04.034 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 175KW UT WOS:000321230600007 PM 23623858 ER PT J AU Guo, J Xu, XH Rasheed, TK Yoder, A Yu, DY Liang, HZ Yi, F Hawley, T Jin, T Ling, BH Wu, YT AF Guo, Jia Xu, Xuehua Rasheed, Taban K. Yoder, Alyson Yu, Dongyang Liang, Huizhi Yi, Fei Hawley, Todd Jin, Tian Ling, Binhua Wu, Yuntao TI Genistein interferes with SDF-1-and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells SO RETROVIROLOGY LA English DT Article DE HIV-1; Actin; SDF-1; Genistein; Sunitinib; Cofilin; LIMK1 ID MATRIX-METALLOPROTEINASE TYPE-2; TYROSINE PHOSPHORYLATION; PROSTATE-CANCER; CORTICAL ACTIN; COFILIN PHOSPHORYLATION; CHEMOKINE RECEPTOR; HUMAN MACROPHAGES; BINDING PROTEINS; NEF PROTEIN; LIM-KINASE AB Background: Binding of HIV to the chemokine coreceptor CXCR4 mediates viral fusion and signal transduction that promotes actin dynamics critical for HIV infection of blood resting CD4 T cells. It has been suggested that this gp 120-mediated actin activity resembles the chemotactic actin dynamics mediated by chemokines such as SDF-1. To determine whether inhibiting SDF-1-mediated chemotactic activity can also inhibit HIV infection, we screened several inhibitors known to reduce SDF-1-mediated chemotaxis of T cells. Results: We found that a tyrosine kinase inhibitor, genistein, inhibited both SDF-1-mediated chemotaxis and HIV infection of resting CD4 T cells. Genistein was also found to interfere with SDF-1- and HIV-mediated actin dynamics in CD4 T cells. This reduction in actin activity correlates with genistein-mediated inhibition of viral DNA accumulation in resting CD4 T cells. In addition, we also tested two other tyrosine kinase inhibitors, sunitinib and AG1478. Sunitinib, but not AG1478, inhibited HIV infection of resting CD4 T cells. We further tested the safety of genistein in 3 Chinese rhesus macaques (Macaca mulatta), and each animal was given a monotherapy of genistein at 10 mg/kg orally for 12 weeks. No adverse drug effects were observed in these animals. Conclusions: Our results suggest that novel therapeutic strategies can be developed based on targeting cellular proteins involved in HIV-dependent signaling. This approach can interfere with HIV-mediated actin dynamics and inhibit HIV infection. C1 [Guo, Jia; Rasheed, Taban K.; Yoder, Alyson; Yu, Dongyang; Liang, Huizhi; Yi, Fei; Hawley, Todd; Wu, Yuntao] George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Xu, Xuehua; Jin, Tian] NIAID, NIH, Twinbrook Facil, Immunogenet Lab,Chemotaxis Signal Sect, Rockville, MD 20852 USA. [Ling, Binhua] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Div Comparat Pathol, Covington, LA 70433 USA. RP Wu, YT (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. EM ywu8@gmu.edu RI Guo, Jia/L-2102-2013; Guo, Jia/C-8678-2014; OI xu, xuehua/0000-0002-3863-9593 FU NIH Public Health Service Grant from NIAID [1R01AI081568]; NIAID [R01 AI093307-01A1]; National Center for Research Resources; Office of Research Infrastructure Programs (ORIP) of NIH [OD011104-51]; NYCDC AIDS Ride FX We thank the George Mason University (GMU) Student Health Center for blood donations; the NIH AIDS Research and Reference Reagent Program, NIAID, NIH for reagents; Ann-Marie Johnson for technical support; the veterinary staff at the Tulane National Primate Research Center; M. Rosen and the donors and riders from the 2010 NYCDC AIDS Ride. This work was supported by NIH Public Health Service Grant grants 1R01AI081568 from NIAID to YW; R01 AI093307-01A1 from NIAID to BL; the National Center for Research Resources, and the Office of Research Infrastructure Programs (ORIP) of NIH (through grant OD011104-51). The study was supported in part by the 2010 NYCDC AIDS Ride organized by M. Rosen. NR 83 TC 6 Z9 7 U1 2 U2 11 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 JUN 19 PY 2013 VL 10 AR 62 DI 10.1186/1742-4690-10-62 PG 15 WC Virology SC Virology GA 171SL UT WOS:000320949300001 PM 23782904 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Defining "Term" Pregnancy Recommendations From the Defining "Term" Pregnancy Workgroup SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HEALTH; CARE C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Spong, CY (reprint author), NICHHD, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM spongc@mail.nih.gov NR 8 TC 95 Z9 99 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 19 PY 2013 VL 309 IS 23 BP 2445 EP 2446 DI 10.1001/jama.2013.6235 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 165SW UT WOS:000320505100023 PM 23645117 ER PT J AU Hsu, CH Ovcharenko, I AF Hsu, Chih-Hao Ovcharenko, Ivan TI Effects of gene regulatory reprogramming on gene expression in human and mouse developing hearts SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE gene regulation; lineage-specific heart enhancers; cis-regulatory evolution ID UCSC GENOME BROWSER; ELEMENTS; ENHANCERS; CHIP; TRANSCRIPTION; CHROMATIN; IDENTIFICATION; PROMOTERS; DYNAMICS; DATABASE AB Lineage-specific regulatory elements underlie adaptation of species and play a role in disease susceptibility. We compared functionally conserved and lineage-specific enhancers by cross-mapping 5042 human and 6564 mouse heart enhancers. Of these, 79 per cent are lineage-specific, lacking a functional orthologue. Heart enhancers tend to cluster and, commonly, there are multiple heart enhancers in a heart locus providing a regulatory stability to the locus. We observed little cross-clustering, however, between lineage-specific and functionally conserved heart enhancers suggesting regulatory function acquisition and development in loci previously lacking heart activity. We also identified 862 human-specific heart enhancers: 417 featuring sequence conservation with mouse (class II) and 445 with neither sequence nor function conservation (class III). Ninety-eight per cent of class III enhancers were deleted from the mouse genome, and we estimated a similar-sized enhancer gain in the human lineage. Human-specific enhancers display no detectable decrease in the negative selection pressure and are strongly associated with genes partaking in the heart regulatory programmes. The loss of a heart enhancer could be compensated by activity of a redundant heart enhancer; however, we observed redundancy in only 15 per cent of class II and III enhancer loci indicating a large-scale reprogramming of the heart regulatory programme in mammals. C1 [Hsu, Chih-Hao; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM ovcharen@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We are also grateful to the reviewers of the manuscript for their input and suggestions, which have been invaluable in improving the manuscript. NR 35 TC 3 Z9 3 U1 0 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUN 19 PY 2013 VL 368 IS 1620 AR 20120366 DI 10.1098/rstb.2012.0366 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 139WD UT WOS:000318614800008 PM 23650638 ER PT J AU Khadra, A Tomic, M Yan, ZH Zemkova, H Sherman, A Stojilkovic, SS AF Khadra, Anmar Tomic, Melanija Yan, Zonghe Zemkova, Hana Sherman, Arthur Stojilkovic, Stanko S. TI Dual Gating Mechanism and Function of P2X7 Receptor Channels SO BIOPHYSICAL JOURNAL LA English DT Article ID P2X(7) RECEPTOR; AGONIST BINDING; ACTIVATION; CALCIUM; INTERNALIZATION; PERMEATION; KINETICS; CURRENTS; CELLS; DYES AB The ATP-gated P2X7 receptor channel (P2X7R) operates as a cytolytic and apoptotic receptor but also controls sustained cellular responses, including cell growth and proliferation. However, it has not been clarified how the same receptor mediates such opposing effects. To address this question, we have combined electrophysiological, imaging, and mathematical studies using wild-type and mutant rat P2X7Rs. Activation of naive (not previously stimulated) receptors by low agonist concentrations caused monophasic slow desensitizing currents and internalization of receptors without other changes in the cellular morphology, much like other P2XRs. In contrast, saturating agonist concentrations induced high-amplitude biphasic currents, reflecting pore dilation and causing rapid cell swelling and lysis. The existence of these two signaling patterns was accounted for using a revised Markov-state model that included, in addition to naive and sensitized states, desensitized states. Occupancy of one or two ATP-binding sites of naive receptors favored a slow transition to desensitized states, whereas occupancy of the third binding site favored a transition to sensitized/dilated states. Consistent with model predictions, nondilating P2X7R mutants always generated desensitizing currents. These results suggest that the level of saturation of the ligand binding sites determines the nature of the P2X7R gating and cellular actions. C1 [Khadra, Anmar] McGill Univ, Dept Physiol, Montreal, PQ, Canada. [Tomic, Melanija; Yan, Zonghe; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Zemkova, Hana] Acad Sci Czech Republic, Inst Phys, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. [Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Khadra, A (reprint author), McGill Univ, Dept Physiol, Montreal, PQ, Canada. EM anmar.khadra@mcgill.ca RI Zemkova, Hana/C-1844-2012; Tomic, Melanija/C-3371-2016 FU National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Grant Agency of the Czech Republic [P304/12/G069]; McGill University FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, the Grant Agency of the Czech Republic (P304/12/G069), and the McGill University. NR 31 TC 17 Z9 17 U1 1 U2 6 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 JUN 18 PY 2013 VL 104 IS 12 BP 2612 EP 2621 DI 10.1016/j.bpj.2013.05.006 PG 10 WC Biophysics SC Biophysics GA 169DI UT WOS:000320757100006 PM 23790369 ER PT J AU Zheng, XH Mueller, GA DeRose, EF London, RE AF Zheng, Xunhai Mueller, Geoffrey A. DeRose, Eugene F. London, Robert E. TI Protein-Mediated Antagonism between HIV Reverse Transcriptase Ligands Nevirapine and MgATP SO BIOPHYSICAL JOURNAL LA English DT Article ID HIGH-RESOLUTION STRUCTURES; NONNUCLEOSIDE INHIBITOR; RESISTANCE MUTATIONS; CONFORMATIONAL FLEXIBILITY; CRYSTAL-STRUCTURES; DRUG-RESISTANCE; SLOW DYNAMICS; TROSY NMR; MECHANISM; COMPLEXES AB Nonnucleoside reverse transcriptase inhibitors (NNRTIs) play a central role in the treatment of AIDS, but their mechanisms of action are incompletely understood. The interaction of the NNRTI nevirapine (NVP) with HIV-1 reverse transcriptase (RT) is characterized by a preference for the open conformation of the fingers/thumb subdomains, and a reported variation of three orders of magnitude between the binding affinity of NVP for RT in the presence or absence of primer/template DNA. To investigate the relationship between conformation and ligand binding, we evaluated the use of methionine NMR probes positioned near the tip of the fingers or thumb subdomains. Such probes would be expected to be sensitive to changes in the local environment depending on the fractions of open and closed RT. Comparisons of the NMR spectra of three conservative mutations, I63M, L74M, and L289M, indicated that M63 showed the greatest shift sensitivity to the addition of NVP. The exchange kinetics of the M63 resonance are fast on the chemical shift timescale, but become slow in the presence of NVP due to the slow binding of RT with the inhibitor. The simplest model consistent with this behavior involves a rapid open/closed equilibrium coupled with a slow interaction of the inhibitor with the open conformation. Studies of RT in the presence of both NVP and MgATP indicate a strong negative cooperativity. Binding of MgATP reduces the fraction of RT bound to NVP, as indicated by the intensity of the NVP-perturbed M230 resonance, and enhances the dissociation rate constant of the NVP, resulting in an increase of the open/closed interconversion rate, so that the M63 resonance moves into the fast/intermediate-exchange regime. Protein-mediated interactions appear to explain most of the affinity variation of NVP for RT. C1 [Zheng, Xunhai; Mueller, Geoffrey A.; DeRose, Eugene F.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov RI Zheng, Xunhai/G-1187-2015 OI Zheng, Xunhai/0000-0003-0390-2491 FU Intramural National Institutes of Health (NIH) Research Program of the National Institute of Environmental Health Sciences (NIEHS) [Z01-ES050147]; NIEHS; NIH [HHSN273200700046U] FX This research was supported by the Intramural National Institutes of Health (NIH) Research Program of the National Institute of Environmental Health Sciences (NIEHS; grant Z01-ES050147 to R.E.L.). E.F.D. is supported by the NIEHS, NIH, under Delivery Order HHSN273200700046U. NVP was obtained from the NIH AIDS Research and Reference Reagent Program. NR 48 TC 5 Z9 5 U1 0 U2 8 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 JUN 18 PY 2013 VL 104 IS 12 BP 2695 EP 2705 DI 10.1016/j.bpj.2013.04.015 PG 11 WC Biophysics SC Biophysics GA 169DI UT WOS:000320757100015 PM 23790378 ER PT J AU Xu, BY Zhi, N Hu, GQ Wan, ZH Zheng, XB Liu, XH Wong, SS Kajigaya, S Zhao, KJ Mao, Q Young, NS AF Xu, Baoyan Zhi, Ning Hu, Gangqing Wan, Zhihong Zheng, Xiaobin Liu, Xiaohong Wong, Susan Kajigaya, Sachiko Zhao, Keji Mao, Qing Young, Neal S. TI Hybrid DNA virus in Chinese patients with seronegative hepatitis discovered by deep sequencing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis-associated aplastic anemia; liver failure; Solexa sequencing; virological diagnosis ID NON-A; NON-B; TRANSPLANT PATIENTS; B19 PARVOVIRUS; UNITED-STATES; NON-C; DISEASE; EVOLUTION; LIVER; ETIOLOGY AB Seronegative hepatitis-non-A, non-B, non-C, non-D, non-E hepatitis-is poorly characterized but strongly associated with serious complications. We collected 92 sera specimens from patients with non-A-E hepatitis in Chongqing, China between 1999 and 2007. Ten sera pools were screened by Solexa deep sequencing. We discovered a 3,780-bp contig present in all 10 pools that yielded BLASTx E scores of 7e-05-0.008 against parvoviruses. The complete sequence of the in silico-assembled 3,780-bp contig was confirmed by gene amplification of overlapping regions over almost the entire genome, and the virus was provisionally designated NIH-CQV. Further analysis revealed that the contig was composed of two major ORFs. By protein BLAST, ORF1 and ORF2 were most homologous to the replication-associated protein of bat circovirus and the capsid protein of porcine parvovirus, respectively. Phylogenetic analysis indicated that NIH-CQV is located at the interface of Parvoviridae and Circoviridae. Prevalence of NIH-CQV in patients was determined by quantitative PCR. Sixty-three of 90 patient samples (70%) were positive, but all those from 45 healthy controls were negative. Average virus titer in the patient specimens was 1.05 e4 copies/mu L. Specific antibodies against NIH-CQV were sought by immunoblotting. Eighty-four percent of patients were positive for IgG, and 31% were positive for IgM; in contrast, 78% of healthy controls were positive for IgG, but all were negative for IgM. Although more work is needed to determine the etiologic role of NIH-CQV in human disease, our data indicate that a parvovirus-like virus is highly prevalent in a cohort of patients with non-A-E hepatitis. C1 [Xu, Baoyan; Zhi, Ning; Wan, Zhihong; Liu, Xiaohong; Wong, Susan; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Xu, Baoyan; Mao, Qing] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing 400038, Peoples R China. [Zheng, Xiaobin] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. RP Zhi, N (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. EM zhin@nhlbi.nih.gov; qingmao@yahoo.com RI HU, GANGQING/K-5849-2012 FU National Institutes of Health Intramural Research Program FX We thank Dr. Jun Zhu at the DNA Sequencing and Genomics Core of the National Heart, Lung, and Blood Institute (NHLBI) for assistance in deep-sequencing and data analysis; Dr. Amit Kapoor of Columbia University for technical advice; and Genoveffa Franchini of the National Cancer Institute, Leonid Margolis of the National Institute of Child Health and Development, Cynthia Dunbar of the NHLBI, and Mike Fang in our laboratory for their careful reading of the manuscript. This work was supported by the National Institutes of Health Intramural Research Program. NR 42 TC 24 Z9 24 U1 1 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 JUN 18 PY 2013 VL 110 IS 25 BP 10264 EP 10269 DI 10.1073/pnas.1303744110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200056 PM 23716702 ER PT J AU Chow, HM Horovitz, SG Carr, WS Picchioni, D Coddington, N Fukunaga, M Xu, YS Balkin, TJ Duyn, JH Braun, AR AF Chow, Ho Ming Horovitz, Silvina G. Carr, Walter S. Picchioni, Dante Coddington, Nate Fukunaga, Masaki Xu, Yisheng Balkin, Thomas J. Duyn, Jeff H. Braun, Allen R. TI Rhythmic alternating patterns of brain activity distinguish rapid eye movement sleep from other states of consciousness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EEG; fMRI; thalamus; slow-wave sleep; brain dynamics ID DEFAULT MODE NETWORK; FUNCTIONAL CONNECTIVITY; HZ OSCILLATIONS; LOW-FREQUENCY; REM-SLEEP; MEMORY; FLUCTUATIONS; WAKEFULNESS; CORTICES; CORTEX AB Rapid eye movement (REM) sleep constitutes a distinct "third state" of consciousness, during which levels of brain activity are commensurate with wakefulness, but conscious awareness is radically transformed. To characterize the temporal and spatial features of this paradoxical state, we examined functional interactions between brain regions using fMRI resting-state connectivity methods. Supporting the view that the functional integrity of the default mode network (DMN) reflects "level of consciousness," we observed functional uncoupling of the DMN during deep sleep and recoupling during REM sleep (similar to wakefulness). However, unlike either deep sleep or wakefulness, REM was characterized by a more widespread, temporally dynamic interaction between two major brain systems: unimodal sensorimotor areas and the higher-order association cortices (including the DMN), which normally regulate their activity. During REM, these two systems become anticorrelated and fluctuate rhythmically, in reciprocally alternating multisecond epochs with a frequency ranging from 0.1 to 0.01 Hz. This unique spatiotemporal pattern suggests a model for REM sleep that may be consistent with its role in dream formation and memory consolidation. C1 [Chow, Ho Ming; Xu, Yisheng; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.; Fukunaga, Masaki; Duyn, Jeff H.] NINDS, Sect Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Carr, Walter S.; Picchioni, Dante; Balkin, Thomas J.] Walter Reed Army Inst Res, Behav Biol Branch, Ctr Psychiat & Neurosci, Silver Spring, MD 20910 USA. [Coddington, Nate] Univ Virginia, Dept Neurosci, Charlottesville, VA 22903 USA. [Fukunaga, Masaki] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Osaka 5650871, Japan. RP Chow, HM (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. EM chowh@nidcd.nih.gov RI Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke; Walter Reed Army Institute of Research FX The authors thank Carmen Brewer, Christopher Zalewski, Teresa Kessinger, and Jim Paterson for key collaboration and support; and Alex Martin and Kelly Barnes for insightful and critical reviews of this manuscript. This work was supported by the Intramural Research Programs of the National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke, and the Walter Reed Army Institute of Research. NR 39 TC 35 Z9 35 U1 5 U2 38 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 JUN 18 PY 2013 VL 110 IS 25 BP 10300 EP 10305 DI 10.1073/pnas.1217691110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200062 PM 23733938 ER PT J AU Kristensen, U Epanchintsev, A Rauschendorf, MA Laugel, V Stevnsner, T Bohr, VA Coin, F Egly, JM AF Kristensen, Ulrik Epanchintsev, Alexey Rauschendorf, Marc-Alexander Laugel, Vincent Stevnsner, Tinna Bohr, Vilhelm A. Coin, Frederic Egly, Jean-Marc TI Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; PURKINJE-CELL DEGENERATION; PLURIPOTENT STEM-CELLS; COUPLING FACTOR CSB/ERCC6; DE-LANGE-SYNDROME; DNA-REPAIR; ALPHA-AMANITIN; UV-IRRADIATION; NIPPED-B; IN-VIVO AB Cockayne syndrome type B ATPase (CSB) belongs to the SwItch/Sucrose nonfermentable family. Its mutations are linked to Cockayne syndrome phenotypes and classically are thought to be caused by defects in transcription-coupled repair, a subtype of DNA repair. Here we show that after UV-C irradiation, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis in CSB-deficient cells, transcription was restored rapidly in normal cells. There the synthesis of DHFR mRNA restarts on the arrival of RNA polymerase II and CSB and the subsequent release of ATF3 from its cAMP response element/ATF target site. In CSB-deficient cells ATF3 remains bound to the promoter, thereby preventing the arrival of polymerase II and the restart of transcription. Silencing of ATF3, as well as stable introduction of wild-type CSB, restores RNA synthesis in UV-irradiated CSB cells, suggesting that, in addition to its role in DNA repair, CSB activity likely is involved in the reversal of inhibitory properties on a gene-promoter region. We present strong experimental data supporting our view that the transcriptional defects observed in UV-irradiated CSB cells are largely the result of a permanent transcriptional repression of a certain set of genes in addition to some defect in DNA repair. C1 [Kristensen, Ulrik; Epanchintsev, Alexey; Rauschendorf, Marc-Alexander; Coin, Frederic; Egly, Jean-Marc] Univ Strasbourg, CNRS, INSERM, Inst Genet & Mol & Cellular Biol,Dept Funct Genom, F-67404 Illkirch Graffenstaden, France. [Laugel, Vincent] Univ Strasbourg, Lab Med Genet, F-67404 Illkirch Graffenstaden, France. [Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, CDK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Coin, F (reprint author), Univ Strasbourg, CNRS, INSERM, Inst Genet & Mol & Cellular Biol,Dept Funct Genom, F-67404 Illkirch Graffenstaden, France. EM fredr@igbmc.fr; egly@igbmc.fr RI Coin, Frederic/F-5925-2013 FU European Research Council Advanced Scientists; Institut National du Cancer Grant [INCA-2008-041]; l'Association de la Recherche contre le Cancer (ARC) [3153]; Advanced European Research Council; ARC; French Ministere des Affaires Etrangeres FX We thank R. Velez Cruz, A. Zadorin, and E. Compe for fruitful discussions; Charlotte Saint-Andre for helping with antibody production and protein expression; and the Institute of Genetics and Molecular and Cellular Biology Cell Culture Facility. This study was supported by grants from the European Research Council Advanced Scientists (to J.-M.E.), the Institut National du Cancer Grant INCA-2008-041 (to F. C.), and l'Association de la Recherche contre le Cancer (ARC) Grant 3153. U. K, was supported by a JME (Jean-Marc Egly) Advanced European Research Council grant and by an ARC fellowship for young scientists. M.-A. R. was supported by the French Ministere des Affaires Etrangeres (Sejour Scientifique de Haut Niveau). NR 64 TC 5 Z9 5 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 18 PY 2013 VL 110 IS 25 BP E2261 EP E2270 DI 10.1073/pnas.1220071110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DU UT WOS:000321500200007 PM 23733932 ER PT J AU Chukoskie, L Snider, J Mozer, MC Krauzlis, RJ Sejnowski, TJ AF Chukoskie, Leanne Snider, Joseph Mozer, Michael C. Krauzlis, Richard J. Sejnowski, Terrence J. TI Learning where to look for a hidden target SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ideal observer; oculomotor; reinforcement learning; saccades ID EYE-MOVEMENTS; VISUAL-SEARCH; PARIETAL CORTEX; SCENE CONTEXT; MATCHING BEHAVIOR; DECISION-MAKING; REINFORCEMENT; ATTENTION; SELECTION; FEATURES AB Survival depends on successfully foraging for food, for which evolution has selected diverse behaviors in different species. Humans forage not only for food, but also for information. We decide where to look over 170,000 times per day, approximately three times per wakeful second. The frequency of these saccadic eye movements belies the complexity underlying each individual choice. Experience factors into the choice of where to look and can be invoked to rapidly redirect gaze in a context and task-appropriate manner. However, remarkably little is known about how individuals learn to direct their gaze given the current context and task. We designed a task in which participants search a novel scene for a target whose location was drawn stochastically on each trial from a fixed prior distribution. The target was invisible on a blank screen, and the participants were rewarded when they fixated the hidden target location. In just a few trials, participants rapidly found the hidden targets by looking near previously rewarded locations and avoiding previously unrewarded locations. Learning trajectories were well characterized by a simple reinforcement-learning (RL) model that maintained and continually updated a reward map of locations. The RL model made further predictions concerning sensitivity to recent experience that were confirmed by the data. The asymptotic performance of both the participants and the RL model approached optimal performance characterized by an ideal-observer theory. These two complementary levels of explanation show how experience in a novel environment drives visual search in humans and may extend to other forms of search such as animal foraging. C1 [Chukoskie, Leanne; Snider, Joseph; Mozer, Michael C.; Sejnowski, Terrence J.] Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Mozer, Michael C.] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Mozer, Michael C.] Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA. [Krauzlis, Richard J.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. RP Sejnowski, TJ (reprint author), Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA. EM terry@salk.edu FU National Science Foundation (NSF) [SBE 0542013]; NSF Science of Learning Center; San Diego Foundation; Office of Naval Research Multidisciplinary University Research Initiative [N00014-10-1-0072]; Howard Hughes Medical Institute FX We thank Krista Kornylo and Natalie Dill for technical assistance. This work was supported in part by National Science Foundation (NSF) Grant SBE 0542013 to the Temporal Dynamics of Learning Center, an NSF Science of Learning Center grant (to L. C., J.S., M. C. M., and T.J.S.), a Blasker Rose-Miah grant from the San Diego Foundation (to L. C.), Office of Naval Research Multidisciplinary University Research Initiative Award N00014-10-1-0072 (to J.S. and T.J.S.), and Howard Hughes Medical Institute (T.J.S.). NR 66 TC 15 Z9 15 U1 2 U2 27 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 JUN 18 PY 2013 VL 110 SU 2 BP 10438 EP 10445 DI 10.1073/pnas.1301216110 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179DZ UT WOS:000321500900015 PM 23754404 ER PT J AU El-Haibi, CP Sharma, P Singh, R Gupta, P Taub, DD Singh, S Lillard, JW AF El-Haibi, Christelle P. Sharma, Praveen Singh, Rajesh Gupta, Pranav Taub, Dennis D. Singh, Shailesh Lillard, James W., Jr. TI Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5 SO MOLECULAR CANCER LA English DT Article DE Prostate cancer; Chemokine; G proteins; G protein-coupled receptor ID HETEROTRIMERIC G-PROTEINS; CHEMOKINE RECEPTOR; SIGNAL-TRANSDUCTION; ALPHA-SUBUNIT; GAMMA-SUBUNIT; MEDIATED PHOSPHORYLATION; COUPLED RECEPTORS; BONE METASTASIS; BETA; GROWTH AB with PCa progression, and mediate PCa cell migration and invasion following interaction with CXCL13. However, the differential expression of G protein alpha,beta, and. subunits by PCa cell lines and the precise combination of these proteins with CXCR5 has not been elucidated. Methods: We examined differences in G protein expression of normal prostate (RWPE-1) and PCa cell lines (LNCaP, C4-2B, and PC3) by western blot analysis. Further, we immunoprecipitated CXCR5 with different G protein subunits, and CXCR4, following CXCL13 stimulation. To investigate constitutive coupling of CXCR5 with CXCR4 and PAR-1 we performed invasion assay in PCa cells transfected with G(aq/i2) or G(a13) siRNA, following CXCL13 treatment. We also investigated Rac and RhoA activity by G-LISA activation assay in PCa cells following CXCL13/thrombin stimulation. Result: Of the 22 G proteins studied, G(ai1-3), G(beta 1-4), G(Y5), G(Y7), and G.10 were expressed by both normal and PCa cell lines. Gas was moderately expressed in C4-2B and PC3 cell lines, G(aq/11) was only present in RWPE-1 and LNCaP cell lines, while G(a12) and Ga-13 were expressed in C4-2B and PC3 cell lines. G.9 was expressed only in PCa cell lines. G(a16), G(beta 5), G(Y1-4), and G(Y13) were not detected in any of the cell lines studied. Surprisingly, CXCR4 co-immunoprecipitated with CXCR5 in PCa cell lines irrespective of CXCL13 treatment. We also identified specific G protein isoforms coupled to CXCR5 in its resting and active states. G(aq/11/)G(beta 3)/G(Y9) in LNCaP and G(ai2)/G(beta 3)/G(Y9) in C4-2B and PC3 cell lines, were coupled to CXCR5 and disassociated following CXCL13 stimulation. Interestingly, G(a13) co-immunoprecipitated with CXCR5 in CXCL13-treated, but not in untreated PCa cell lines. Inhibition of G(aq/i2) significantly decreased the ability of cells to invade, whereas silencing Ga13 did not affect CXCL13-dependent cell invasion. Finally, CXCL13 treatment significantly increased Rac activity in G(aq/i2) dependent manner, but not RhoA activity, in PCa cell lines. Conclusions: These findings offer insight into molecular mechanisms of PCa progression and can help to design some therapeutic strategies involving CXCR5 and/or CXCL13 blockade and specific G protein inhibition to abrogate PCa metastasis. C1 [El-Haibi, Christelle P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sharma, Praveen] Cent Univ Jharkhand, Ctr Life Sci, Sch Nat Sci, Ranchi, Bihar, India. [Singh, Rajesh; Gupta, Pranav; Singh, Shailesh; Lillard, James W., Jr.] Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. [Taub, Dennis D.] NIA, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lillard, JW (reprint author), Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. EM jlillard@msm.edu RI Sharma, Praveen/M-2810-2014 OI Sharma, Praveen/0000-0002-7020-3570 FU National Institute of Health [S21MD000101, G12RR03034, G12MD007602, U54CA118638]; Department of Defense (DoD); Prostate Cancer Research Program Award [W81XWH-06-1-0562, W81XWH-11-1-0109] FX The content of this manuscript benefited from many fruitful conversations with members of the Morehouse School of Medicine. This work benefited from the cooperation between investigators from the Morehouse School of Medicine and the Wallace Tumor Institute at the University of Alabama at Birmingham via the National Cancer Institute sponsored "Comprehensive Minority Institution / Cancer Center Partnership". This study was supported by funds from National Institute of Health Grants S21MD000101, G12RR03034, G12MD007602, U54CA118638, and Department of Defense (DoD) Prostate Cancer Research Program Award W81XWH-06-1-0562, and W81XWH-11-1-0109. NR 50 TC 9 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 18 PY 2013 VL 12 AR 64 DI 10.1186/1476-4598-12-64 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 187SJ UT WOS:000322139200001 PM 23773523 ER PT J AU Ferreira, RD Zhou, DW Ferreira, JG Silva, MCC Silva-Lucca, RA Mentele, R Paredes-Gamero, EJ Bertolin, TC Correia, MTD Paiva, PMG Gustchina, A Wlodawer, A Oliva, MLV AF Ferreira, Rodrigo da Silva Zhou, Dongwen Ferreira, Joana Gasperazzo Cabral Silva, Mariana Cristina Silva-Lucca, Rosemeire Aparecida Mentele, Reinhard Paredes-Gamero, Edgar Julian Bertolin, Thiago Carlos dos Santos Correia, Maria Tereza Guedes Paiva, Patricia Maria Gustchina, Alla Wlodawer, Alexander Vilela Oliva, Maria Luiza TI Crystal Structure of Crataeva tapia Bark Protein (CrataBL) and Its Effect in Human Prostate Cancer Cell Lines SO PLOS ONE LA English DT Article ID TRYPSIN-INHIBITOR; SERINE RESIDUE; REACTIVE SITE; BINDING; LECTIN; APOPTOSIS; MECHANISM; SEEDS; DU145; GLYCOSAMINOGLYCANS AB A protein isolated from the bark of Crataeva tapia (CrataBL) is both a Kunitz-type plant protease inhibitor and a lectin. We have determined the amino acid sequence and three-dimensional structure of CrataBL, as well as characterized its selected biochemical and biological properties. We found two different isoforms of CrataBL isolated from the original source, differing in positions 31 (Pro/Leu); 92 (Ser/Leu); 93 (Ile/Thr); 95 (Arg/Gly) and 97 (Leu/Ser). CrataBL showed relatively weak inhibitory activity against trypsin (K-iapp = 43 mu M) and was more potent against Factor Xa (K-iapp = 8.6 mu M), but was not active against a number of other proteases. We have confirmed that CrataBL contains two glycosylation sites and forms a dimer at high concentration. The high-resolution crystal structures of two different crystal forms of isoform II verified the beta-trefoil fold of CrataBL and have shown the presence of dimers consisting of two almost identical molecules making extensive contacts (similar to 645 angstrom(2)). The structure differs from those of the most closely related proteins by the lack of the N-terminal beta-hairpin. In experiments aimed at investigating the biological properties of CrataBL, we have shown that addition of 40 mM of the protein for 48 h caused maximum growth inhibition in MTT assay (47% of DU145 cells and 43% of PC3 cells). The apoptosis of DU145 and PC3 cell lines was confirmed by flow cytometry using Annexin V/FITC and propidium iodide staining. Treatment with CrataBL resulted in the release of mitochondrial cytochrome c and in the activation of caspase-3 in DU145 and PC3 cells. C1 [Ferreira, Rodrigo da Silva; Ferreira, Joana Gasperazzo; Cabral Silva, Mariana Cristina; Paredes-Gamero, Edgar Julian; Vilela Oliva, Maria Luiza] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo, Brazil. [Zhou, Dongwen; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Silva-Lucca, Rosemeire Aparecida] Univ Estadual Oeste Parana, Ctr Engn & Ciencias Exatas, Toledo, Parana, Brazil. [Mentele, Reinhard] Max Planck Inst Biochem, Inst Clin Neuroimmunol LMU, Munich, Germany. [Mentele, Reinhard] Max Planck Inst Biochem, Dept Prot Analyt, Munich, Germany. [Bertolin, Thiago Carlos] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo, Brazil. [dos Santos Correia, Maria Tereza; Guedes Paiva, Patricia Maria] Univ Fed Pernambuco, Dept Bioquim, Recife, PE, Brazil. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM wlodawer@nih.gov; olivaml.bioq@epm.br RI Silva, Mariana/B-9530-2012; Ferreira, Rodrigo/C-1763-2013; Oliva, Maria Luiza/B-9537-2012; Paredes-Gamero, Edgar/C-4791-2012; OI Ferreira, Rodrigo/0000-0003-4103-6870; Paredes-Gamero, Edgar/0000-0003-3686-8402; Paiva, Patricia/0000-0003-3467-708X FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; CAPES; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Sao Paulo Research Foundation (FAPESP) [09/53766-5]; Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. The authors are grateful to CAPES, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Sao Paulo Research Foundation (FAPESP) (Process 09/53766-5) for providing financial support. This project was also supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 4 Z9 4 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2013 VL 8 IS 6 AR e64426 DI 10.1371/journal.pone.0064426 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400001 ER PT J AU Foltz, JL Makumbi, I Sejvar, JJ Malimbo, M Ndyomugyenyi, R Atai-Omoruto, AD Alexander, LN Abang, B Melstrom, P Kakooza, AM Olara, D Downing, RG Nutman, TB Dowell, SF Lwamafa, DKW AF Foltz, Jennifer L. Makumbi, Issa Sejvar, James J. Malimbo, Mugagga Ndyomugyenyi, Richard Atai-Omoruto, Anne Deborah Alexander, Lorraine N. Abang, Betty Melstrom, Paul Kakooza, Angelina M. Olara, Dennis Downing, Robert G. Nutman, Thomas B. Dowell, Scott F. Lwamafa, D. K. W. TI An Epidemiologic Investigation of Potential Risk Factors for Nodding Syndrome in Kitgum District, Uganda SO PLOS ONE LA English DT Article ID CLINICAL CLASSIFICATION; ONCHOCERCA-VOLVULUS; SOUTHERN SUDAN; EPILEPSY; TANZANIA; SEIZURES AB Introduction: Nodding Syndrome (NS), an unexplained illness characterized by spells of head bobbing, has been reported in Sudan and Tanzania, perhaps as early as 1962. Hypothesized causes include sorghum consumption, measles, and onchocerciasis infection. In 2009, a couple thousand cases were reportedly in Northern Uganda. Methods: In December 2009, we identified cases in Kitgum District. The case definition included persons who were previously developmentally normal who had nodding. Cases, further defined as 5- to 15-years-old with an additional neurological deficit, were matched to village controls to assess risk factors and test biological specimens. Logistic regression models were used to evaluate associations. Results: Surveillance identified 224 cases; most (95%) were 5-15-years-old (range = 2-27). Cases were reported in Uganda since 1997. The overall prevalence was 12 cases per 1,000 (range by parish = 0.6-46). The case-control investigation (n = 49 case/village control pairs) showed no association between NS and previously reported measles; sorghum was consumed by most subjects. Positive onchocerciasis serology [age-adjusted odds ratio (AOR(1)) = 14.4 (2.7, 78.3)], exposure to munitions [AOR(1)= 13.9 (1.4, 135.3)], and consumption of crushed roots [AOR(1)= 5.4 (1.3, 22.1)] were more likely in cases. Vitamin B6 deficiency was present in the majority of cases (84%) and controls (75%). Conclusion: NS appears to be increasing in Uganda since 2000 with 2009 parish prevalence as high as 46 cases per 1,000 5 to 15-year old children. Our results found no supporting evidence for many proposed NS risk factors, revealed association with onchocerciasis, which for the first time was examined with serologic testing, and raised nutritional deficiencies and toxic exposures as possible etiologies. C1 [Foltz, Jennifer L.] Ctr Dis Control & Prevent, Div Nutr Phys Activ & Obes, Atlanta, GA 30333 USA. [Makumbi, Issa; Malimbo, Mugagga; Ndyomugyenyi, Richard; Atai-Omoruto, Anne Deborah; Lwamafa, D. K. W.] Uganda Minist Hlth, Kampala, Uganda. [Sejvar, James J.] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Alexander, Lorraine N.; Abang, Betty; Olara, Dennis; Downing, Robert G.] Centers Dis Control & Prevent Uganda, Div Global HIV AIDS, Entebbe, Uganda. [Melstrom, Paul] Ctr Dis Control & Prevent, Div Environm Hazards & Hlth Effects, Atlanta, GA USA. [Kakooza, Angelina M.] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Nutman, Thomas B.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Dowell, Scott F.] Ctr Dis Control & Prevent, Div Global Dis Detect & Emergency Response, Atlanta, GA USA. RP Foltz, JL (reprint author), Ctr Dis Control & Prevent, Div Nutr Phys Activ & Obes, Atlanta, GA 30333 USA. EM jfoltz@cdc.gov FU CDC; WHO; MoH Uganda for public health investigations FX The investigation was supported with resources available from CDC, WHO, and MoH Uganda for public health investigations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 31 Z9 31 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2013 VL 8 IS 6 AR e66419 DI 10.1371/journal.pone.0066419 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400106 PM 23823012 ER PT J AU Liu, HX Fang, YP Hu, Y Gonzalez, FJ Fang, JW Wan, YJY AF Liu, Hui-Xin Fang, Yaping Hu, Ying Gonzalez, Frank J. Fang, Jianwen Wan, Yu-Jui Yvonne TI PPAR beta Regulates Liver Regeneration by Modulating Akt and E2f Signaling SO PLOS ONE LA English DT Article ID ACTIVATED RECEPTOR-DELTA; CANCER CELL-LINES; ALPHA-NULL MICE; LIGAND ACTIVATION; PARTIAL-HEPATECTOMY; GENE-EXPRESSION; GROWTH-FACTOR; PEROXISOME; PROLIFERATION; METABOLISM AB The current study tests the hypothesis that peroxisome proliferator-activated receptor beta (PPAR beta) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARb in liver regeneration was studied using two-third partial hepatectomy (PH) in Wild-type (WT) and PPARb-null (KO) mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36-48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPAR beta deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1)/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f) 1-2 and E2f7-8 as well as their downstream target genes were not noted in KO livers 36-48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPAR beta-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration. C1 [Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne] Calif State Univ Sacramento, Dept Med Pathol & Lab Med, Sacramento, CA 95819 USA. [Fang, Yaping; Fang, Jianwen] Univ Kansas, Appl Bioinformat Lab, Lawrence, KS 66045 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Wan, YJY (reprint author), Calif State Univ Sacramento, Dept Med Pathol & Lab Med, Sacramento, CA 95819 USA. EM yjywan@ucdavis.edu OI Fang, Yaping/0000-0001-6075-0768 FU National Institutes of Health [CA53596, DK092100] FX This study is supported by grants funded by National Institutes of Health CA53596 and DK092100. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 14 Z9 14 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2013 VL 8 IS 6 AR e65644 DI 10.1371/journal.pone.0065644 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400016 PM 23823620 ER PT J AU Nguyen, HD Becker, J Thu, YM Costanzo, M Koch, EN Smith, S Myung, K Myers, CL Boone, C Bielinsky, AK AF Nguyen, Hai Dang Becker, Jordan Thu, Yee Mon Costanzo, Michael Koch, Elizabeth N. Smith, Stephanie Myung, Kyungjae Myers, Chad L. Boone, Charles Bielinsky, Anja-Katrin TI Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression SO PLOS ONE LA English DT Article ID DNA-LIGASE-I; YEAST SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE EXCISION-REPAIR; NEARBY INVERTED REPEATS; CELL NUCLEAR ANTIGEN; BUDDING YEAST; HOMOLOGOUS RECOMBINATION; MITOTIC RECOMBINATION; COMPLEX-FORMATION; ESSENTIAL GENES AB Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. In comparison to cdc9 single mutants, cdc9 rad59D double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest. C1 [Nguyen, Hai Dang; Becker, Jordan; Thu, Yee Mon; Bielinsky, Anja-Katrin] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Costanzo, Michael; Boone, Charles] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON, Canada. [Boone, Charles] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Koch, Elizabeth N.; Myers, Chad L.] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN USA. [Smith, Stephanie; Myung, Kyungjae] Natl Inst Hlth, Natl Human Genome Res Inst, Genet & Mol Biol Branch, Genome Instabil Sect, Bethesda, MD USA. RP Bielinsky, AK (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM bieli003@umn.edu OI Bielinsky, Anja/0000-0003-1783-619X FU National Institutes of Health (NIH) [GM074917]; National Human Genome Research Institute; NIH [HG005084, HG005853]; NSF [DBI0953881]; Canadian Institutes of Health Research [MOP-102629, MOP-97939]; Ontario Research Fund [GL2-0122] FX This work was supported by National Institutes of Health (NIH) grant GM074917 to AKB, who is a Scholar of the Leukemia and Lymphoma Society. The intramural Research Programs of the National Human Genome Research Institute supported KM. EK is a National Science Foundation (NSF) Graduate Research Fellow. EK and CLM were supported by a grant from the NIH (HG005084), and the NSF (DBI0953881). CB and CLM are supported by a grant from the NIH (HG005853). CB is supported by grants from the Canadian Institutes of Health Research (MOP-102629 and MOP-97939) and the Ontario Research Fund (GL2-0122). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 7 Z9 7 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2013 VL 8 IS 6 AR UNSP e66379 DI 10.1371/journal.pone.0066379 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166SA UT WOS:000320576400098 PM 23824283 ER PT J AU Einhorn, PT Cushman, WC Whelton, PK AF Einhorn, Paula T. Cushman, William C. Whelton, Paul K. CA ALLHAT Collaborative Res Grp TI Chlorthalidone Versus Hydrochlorothiazide SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; HYPERTENSIVE PATIENTS C1 [Einhorn, Paula T.] NHLBI, Bethesda, MD 20892 USA. [Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA. [Whelton, Paul K.] Tulane Univ, New Orleans, LA 70118 USA. RP Einhorn, PT (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-35130]; PHS HHS [HHSN268201100036C] NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 18 PY 2013 VL 158 IS 12 BP 922 EP 923 DI 10.7326/0003-4819-158-12-201306180-00018 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 167PW UT WOS:000320645000027 PM 23778917 ER PT J AU Nandhikonda, P Yasgar, A Baranowski, AM Sidhu, PS McCallum, MM Pawlak, AJ Teske, K Feleke, B Yuan, NY Kevin, C Bikle, DD Ayers, SD Webb, P Rai, G Simeonov, A Jadhav, A Maloney, D Arnold, LA AF Nandhikonda, Premchendar Yasgar, Adam Baranowski, Athena M. Sidhu, Preetpal S. McCallum, Megan M. Pawlak, Alan J. Teske, Kelly Feleke, Belaynesh Yuan, Nina Y. Kevin, Chinedum Bikle, Daniel D. Ayers, Steven D. Webb, Paul Rai, Ganesha Simeonov, Anton Jadhav, Ajit Maloney, David Arnold, Leggy A. TI Peroxisome Proliferation-Activated Receptor delta Agonist GW0742 Interacts Weakly with Multiple Nuclear Receptors, Including the Vitamin D Receptor SO BIOCHEMISTRY LA English DT Article ID CANCER-CELL-LINES; HUMAN PROSTATIC-CARCINOMA; THYROID-HORMONE RECEPTOR; FACTOR BINDING PROTEIN-3; LIGAND ACTIVATION; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; CRYSTAL-STRUCTURES; ESTROGEN-RECEPTOR; LEUKEMIA-CELLS AB A high-throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes for modulating gene regulation mediated by VDR. Peroxisome proliferator-activated receptor (PPAR) delta agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of >12.1 mu M. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor. Surprisingly, GW0742 behaved as a PPAR agonist and antagonist, activating transcription at lower concentrations and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742 increased the fluorescence intensity and level of fluorescence polarization at an excitation wavelength of 595 nm and an emission wavelength of 615 nm in a dose-dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced level of expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3, and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D-3. C1 [Nandhikonda, Premchendar; Baranowski, Athena M.; Sidhu, Preetpal S.; McCallum, Megan M.; Pawlak, Alan J.; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y.; Kevin, Chinedum; Arnold, Leggy A.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Bikle, Daniel D.] Vet Affairs Med Ctr, Dept Med, Endocrine Res Unit, San Francisco, CA 94121 USA. [Ayers, Steven D.; Webb, Paul] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Yasgar, Adam; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Arnold, LA (reprint author), Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. EM arnold2@uwm.edu RI Sidhu, Preetpal/L-5727-2013; Nandhikonda, Premchendar/K-1473-2014; Ayers, Stephen/O-4535-2014 OI Ayers, Stephen/0000-0003-1390-8969 FU University of Wisconsin-Milwaukee (UWM); UWM Research Growth Initiative (RGI Grant) [2012]; National Institutes of Health Grant [R03DA031090]; UWM Research Foundation (Catalyst grant); Lynde and Harry Bradley Foundation; Richard and Ethel Herzfeld Foundation; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681] FX This work was supported by the University of Wisconsin-Milwaukee (UWM) (L.A.A.), the UWM Research Growth Initiative (RGI Grant 2012) (L.A.A.), National Institutes of Health Grant R03DA031090 (L.A.A.), the UWM Research Foundation (Catalyst grant), the Lynde and Harry Bradley Foundation (L.A.A.), the Richard and Ethel Herzfeld Foundation (L.A.A.), and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (Grant U54MH084681) (G.R., A.S., A.J., A.Y., and D.M.). NR 71 TC 8 Z9 8 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 18 PY 2013 VL 52 IS 24 BP 4193 EP 4203 DI 10.1021/bi400321p PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169AC UT WOS:000320748300008 PM 23713684 ER PT J AU Ambroggio, XI Dommer, J Gopalan, V Dunham, EJ Taubenberger, JK Hurt, DE AF Ambroggio, Xavier I. Dommer, Jennifer Gopalan, Vivek Dunham, Eleca J. Taubenberger, Jeffery K. Hurt, Darrell E. TI HASP server: a database and structural visualization platform for comparative models of influenza A hemagglutinin proteins SO BMC BIOINFORMATICS LA English DT Article DE Influenza A; HASP; Hemagglutinin; Receptor binding; Membrane fusion; ROSETTA; Sialic acid; Flu; Homology modeling; Molecular visualization ID VIRUS HEMAGGLUTININ; SUBTYPES AB Background: Influenza A viruses possess RNA genomes that mutate frequently in response to immune pressures. The mutations in the hemagglutinin genes are particularly significant, as the hemagglutinin proteins mediate attachment and fusion to host cells, thereby influencing viral pathogenicity and species specificity. Large-scale influenza A genome sequencing efforts have been ongoing to understand past epidemics and pandemics and anticipate future outbreaks. Sequencing efforts thus far have generated nearly 9,000 distinct hemagglutinin amino acid sequences. Description: Comparative models for all publicly available influenza A hemagglutinin protein sequences (8,769 to date) were generated using the Rosetta modeling suite. The C-alpha root mean square deviations between a randomly chosen test set of models and their crystallographic templates were less than 2 angstrom, suggesting that the modeling protocols yielded high-quality results. The models were compiled into an online resource, the Hemagglutinin Structure Prediction (HASP) server. The HASP server was designed as a scientific tool for researchers to visualize hemagglutinin protein sequences of interest in a three-dimensional context. With a built-in molecular viewer, hemagglutinin models can be compared side-by-side and navigated by a corresponding sequence alignment. The models and alignments can be downloaded for offline use and further analysis. Conclusions: The modeling protocols used in the HASP server scale well for large amounts of sequences and will keep pace with expanded sequencing efforts. The conservative approach to modeling and the intuitive search and visualization interfaces allow researchers to quickly analyze hemagglutinin sequences of interest in the context of the most highly related experimental structures, and allow them to directly compare hemagglutinin sequences to each other simultaneously in their two- and three-dimensional contexts. The models and methodology have shown utility in current research efforts and the ongoing aim of the HASP server is to continue to accelerate influenza A research and have a positive impact on global public health. C1 [Ambroggio, Xavier I.; Dommer, Jennifer; Gopalan, Vivek; Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Dunham, Eleca J.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hurt, DE (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM darrellh@niaid.nih.gov FU Office of Science Management and Operations of the National Institute of Allergy and Infectious Diseases FX We are grateful to Dr. Yentram Huyen and Mike Tartakovsky for their support of the project. We also thank Dr. Michael Dolan for helpful comments on HASP, and Dr. Meghan Coakley for assistance in writing this manuscript. This research was supported in part by the Office of Science Management and Operations of the National Institute of Allergy and Infectious Diseases. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland. (http://biowulf.nih.gov). NR 17 TC 0 Z9 0 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 18 PY 2013 VL 14 AR 197 DI 10.1186/1471-2105-14-197 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 171PM UT WOS:000320941500001 PM 23777206 ER PT J AU Mofenson, LM Cotton, MF AF Mofenson, Lynne M. Cotton, Mark F. TI The challenges of success: adolescents with perinatal HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Editorial Material DE perinatal HIV infection; adolescents; HIV care ID CHILDREN; YOUTH; DISCLOSURE; DIAGNOSIS; BARRIERS AB The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults. C1 [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD 20852 USA. [Cotton, Mark F.] Univ Stellenbosch, Tygerberg Childrens Hosp, Div Infect Dis, Cape Town, South Africa. RP Mofenson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 24 TC 22 Z9 22 U1 0 U2 8 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18650 DI 10.7448/IAS.16.1.18650 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CO UT WOS:000320608300001 PM 23782484 ER PT J AU Puthanakit, T Siberry, GK AF Puthanakit, Thanyawee Siberry, George K. TI Bone health in children and adolescents with perinatal HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Review DE perinatal HIV infection; bone mineral density (BMD); fracture; dual-energy X-ray absorptiometry (DXA); peak bone mass (PBM) ID TENOFOVIR DISOPROXIL FUMARATE; B LIGAND RANKL; MINERAL DENSITY; ANTIRETROVIRAL THERAPY; ABACAVIR-LAMIVUDINE; FRACTURE RISK; MASS; CHILDHOOD; CALCIUM; COHORT AB The long-term impact on bone health of lifelong HIV infection and prolonged ART in growing and developing children is not yet known. Measures of bone health in youth must be interpreted in the context of expected developmental and physiologic changes in bone mass, size, density and strength that occur from fetal through adult life. Low bone mineral density (BMD) appears to be common in perinatally HIV-infected youth, especially outside of high-income settings, but data are limited and interpretation complicated by the need for better pediatric norms. The potential negative effects of tenofovir on BMD and bone mass accrual are of particular concern as this drug may be used more widely in younger children. Emphasizing good nutrition, calcium and vitamin D sufficiency, weight-bearing exercise and avoidance of alcohol and smoking are effective and available approaches to maintain and improve bone health in all settings. More data are needed to inform therapies and monitoring for HIV-infected youth with proven bone fragility. While very limited data suggest lack of marked increase in fracture risk for youth with perinatal HIV infection, the looming concern for these children is that they may fail to attain their expected peak bone mass in early adulthood which could increase their risk for fractures and osteoporosis later in adulthood. C1 [Puthanakit, Thanyawee] Chulalongkorn Univ, Fac Med, Dept Pediat, Bangkok 10330, Thailand. [Puthanakit, Thanyawee] Thai Red Cross AIDS Res Ctr, HIVNAT, Bangkok, Thailand. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, Bethesda, MD 20892 USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, 6100 Executive Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov FU National Research University Project of Commission of Higher Education; Ratchadapiseksomphot Endowment Fund [HR 1161A-55]; Senior Researcher Scholar, Thai Research Fund (TRF) FX Dr. Puthanakit is funded in part by the National Research University Project of Commission of Higher Education and the Ratchadapiseksomphot Endowment Fund (HR 1161A-55) and the Senior Researcher Scholar, Thai Research Fund (TRF). NR 71 TC 11 Z9 11 U1 0 U2 9 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18575 DI 10.7448/IAS.16.1.18575 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CG UT WOS:000320607500001 PM 23782476 ER PT J AU Sohn, AH Hazra, R AF Sohn, Annette H. Hazra, Rohan TI The changing epidemiology of the global paediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Review DE adolescent; HIV; outcomes; perinatal; surveillance ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITOR; BONE-MINERAL DENSITY; ACQUIRED HIV; DRUG-RESISTANCE; OBSERVATIONAL DATABASE; PSYCHIATRIC-DISORDERS; VIROLOGICAL FAILURE; METABOLIC-CHANGES AB The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) move into adolescence and adulthood, and face new challenges of living with HIV. UNAIDS reports that 3.4 million children aged below 15 years and 2 million adolescents aged between 10 and 19 years have HIV. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, making it difficult to keep track of their outcomes. Perinatally HIV-infected adolescents (PHIVA) are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and now face transition from complete dependence on adult caregivers to becoming their own caregivers. As we are unable to track long-term complications and survival of PHIVA through national and global reporting systems, local and regional cohorts are the main sources for surveillance and research among PHIVA. This global review will utilize those data to highlight the epidemiology of PHIVA infection, treatment challenges and chronic disease risks. Unless mechanisms are created to count and separate out PHIVA outcomes, we will have few opportunities to characterize the negative consequences of life-long HIV infection in order to find ways to prevent them. C1 [Sohn, Annette H.] TREAT Asia AmfAR Fdn AIDS Res, Bangkok, Thailand. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Sohn, AH (reprint author), TREAT Asia AmfAR Fdn AIDS Res, 388 Sukhumvit Rd,Suite 2104, Bangkok, Thailand. EM annette.sohn@treatasia.org NR 85 TC 24 Z9 24 U1 1 U2 14 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUN 18 PY 2013 VL 16 AR 18555 DI 10.7448/IAS.16.1.18555 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 167CB UT WOS:000320606800001 PM 23782474 ER PT J AU Torchia, MLG Conze, DB Ashwell, JD AF Giardino Torchia, Maria Letizia Conze, Dietrich B. Ashwell, Jonathan D. TI c-IAP1 and c-IAP2 Redundancy Differs between T and B Cells SO PLOS ONE LA English DT Article ID NF-KAPPA-B; ALPHA-DEPENDENT APOPTOSIS; MULTIPLE-MYELOMA; ACTIVATION; CIAP2; TRAF2; UBIQUITINATION; RECEPTOR; IAPS; INHIBITOR AB Cellular Inhibitors of Apoptosis 1 and 2 (c-IAP1 and c-IAP2) are ubiquitin protein ligases (E3s) that constitutively ubiquitinate and induce proteasomal-mediated degradation of NF-kappa B Inducing Kinase (NIK) and repress non-canonical NF-kappa B activation. Mice expressing an E3-inactive c-IAP2 mutant (c-IAP2(H570A)) have constitutive activation of non-canonical NF-kappa B, resulting in B cell hyperplasia and T cell costimulation-independence. If, and if so to what extent, c-IAP1 and c-IAP2 are redundant in NF-kappa B regulation in these mice is not known. Here we have generated mice expressing a mutant c-IAP1 that lacks E3 activity (c-IAP1(H582A)). These mice were phenotypically normal and did not have constitutive NF-kappa B activation in B cells or MEFs. siRNA-mediated knockdown of c-IAP2 showed that accumulated c-IAP2, resulting from lack of c-IAP1-dependent degradation, compensated for absent c-IAP1 E3 activity. Surprisingly, c-IAP1(H582A) T cells had a lower p100/p52 ratio than wild type T cells, and in the absence of costimulation proliferated to a degree intermediate between wild type and c-IAP2(H570A) T cells. Therefore, although c-IAP1 and c-IAP2 both can repress constitutive NF-kappa B activation, the relative importance of each varies according to cell type. C1 [Giardino Torchia, Maria Letizia; Conze, Dietrich B.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU National Institutes of Health, Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 17 PY 2013 VL 8 IS 6 AR e66161 DI 10.1371/journal.pone.0066161 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177TH UT WOS:000321397800026 ER PT J AU Liu, W Chen, Z Ma, YS Wu, XC Jin, YP Hou, S AF Liu, Wei Chen, Zhi Ma, Yansen Wu, Xiaochun Jin, Yaping Hou, Steven TI Genetic Characterization of the Drosophila Birt-Hogg-Dube Syndrome Gene SO PLOS ONE LA English DT Article ID MTOR ACTIVATION; AMINO-ACIDS; GROWTH; TUMORIGENESIS; REQUIREMENTS; MELANOGASTER; MECHANISMS; FOLLICULIN; INTERACTS; RAPAMYCIN AB Folliculin (FLCN) is a conserved tumor suppressor gene whose loss is associated with the human Birt-Hogg-Dube (BHD) syndrome. However, its molecular functions remain largely unknown. In this work, we generated a Drosophila BHD model through genomic deletion of the FLCN gene (DBHD-). The DBHD mutant larvae grew slowly and stopped development before pupation, displaying various characteristics of malnutrition. We found the growth delay was sensitive to the nutrient supplies. It became more severe upon restrictions of the dietary yeast; while high levels of yeast significantly restored the normal growth, but not viability. We further demonstrated that leucine was able to substitute for yeast to provide similar rescues. Moreover, the human FLCN could partially rescue the DBHD- phenotypes, indicating the two genes are involved in certain common mechanisms. Our work provides a new animal model of the BHD syndrome and suggests that modulation of the local nutrient condition might be a potential treatment of the BHD lesions. C1 [Liu, Wei; Chen, Zhi; Ma, Yansen; Wu, Xiaochun; Jin, Yaping] Northwest A&F Univ, Coll Vet Med, Minist Agr, Key Lab Anim Biotechnol, Yangling, Shaanxi, Peoples R China. [Liu, Wei; Hou, Steven] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. RP Jin, YP (reprint author), Northwest A&F Univ, Coll Vet Med, Minist Agr, Key Lab Anim Biotechnol, Yangling, Shaanxi, Peoples R China. EM yapingjin@163.com; hous@mail.nih.gov FU NSAF Foundation; Doctoral Programs Foundation of Ministry of Education of China; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by NSAF Foundation (W.L.), Doctoral Programs Foundation of Ministry of Education of China (Y.J.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (S.H). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 9 Z9 9 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 17 PY 2013 VL 8 IS 6 AR e65869 DI 10.1371/journal.pone.0065869 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177TH UT WOS:000321397800018 PM 23799055 ER PT J AU Xu, X Mackem, S AF Xu, Xing Mackem, Susan TI Tracing the Evolution of Avian Wing Digits SO CURRENT BIOLOGY LA English DT Review ID HOX GENES; SONIC HEDGEHOG; FRAME-SHIFT; LIMB BUD; BIRDS; ORIGIN; HOMOLOGY; IDENTITY; EXPRESSION; DINOSAURS AB It is widely accepted that birds are a subgroup of dinosaurs, but there is an apparent conflict: modern birds have been thought to possess only the middle three fingers (digits II-III-IV) of an idealized five-digit tetrapod hand based on embryological data, but their Mesozoic tetanuran dinosaur ancestors are considered to have the first three digits (I-II-III) based on fossil evidence. How could such an evolutionary quirk arise? Various hypotheses have been proposed to resolve this paradox. Adding to the confusion, some recent developmental studies support a designation for avian wing digits whereas some recent paleontological data are consistent with a identification of the Mesozoic tetanuran digits. A comprehensive analysis of both paleontological and developmental data suggests that the evolution of the avian wing digits may have been driven by homeotic transformations of digit identity, which are more likely to have occurred in a partial and piecemeal manner. Additionally, recent genetic studies in mouse models showing plausible mechanisms for central digit loss invite consideration of new alternative possibilities (I-II-IV or I-III-IV) for the homologies of avian wing digits. While much progress has been made, some advances point to the complexity of the problem and a final resolution to this ongoing debate demands additional work from both paleontological and developmental perspectives, which will surely yield new insights on mechanisms of evolutionary adaptation. C1 [Xu, Xing] Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origin, Beijing 100044, Peoples R China. [Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Xu, X (reprint author), Chinese Acad Sci, Inst Vertebrate Paleontol & Paleoanthropol, Key Lab Vertebrate Evolut & Human Origin, Beijing 100044, Peoples R China. EM xu.xing@ivpp.ac.cn; mackems@mail.nih.gov FU National Natural Science Foundation of China [41120124002]; 973 program [2012CB821900] FX The author thanks James Clark, Jonah Choiniere, Corwin Sullivan, David W.E. Hone, and Mikio Tanaka for discussions, and James Clark and Corwin Sullivan for constructive comments on the manuscript. This project was supported by the National Natural Science Foundation of China (grant number: 41120124002) and 973 program (2012CB821900). NR 80 TC 4 Z9 5 U1 5 U2 58 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 17 PY 2013 VL 23 IS 12 BP R538 EP R544 DI 10.1016/j.cub.2013.04.071 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 168CH UT WOS:000320682800015 PM 23787052 ER PT J AU Saleh, AD Simone, BA Palazzo, J Savage, JE Sano, Y Dan, T Jin, LJ Champ, CE Zhao, SP Lim, M Sotgia, F Camphausen, K Pestell, RG Mitchell, JB Lisanti, MP Simone, NL AF Saleh, Anthony D. Simone, Brittany A. Palazzo, Juan Savage, Jason E. Sano, Yuri Dan, Tu Jin, Lianjin Champ, Colin E. Zhao, Shuping Lim, Meng Sotgia, Frederica Camphausen, Kevin Pestell, Richard G. Mitchell, James B. Lisanti, Michael P. Simone, Nicole L. TI Caloric restriction augments radiation efficacy in breast cancer SO CELL CYCLE LA English DT Article DE caloric restriction; breast cancer; radiation; IGF; tumor regression; cytotoxic therapy ID GROWTH-FACTOR-I; RANDOMIZED CONTROLLED-TRIAL; ACTIVATED PROTEIN-KINASE; DIETARY RESTRICTION; GENE-EXPRESSION; FACTOR RECEPTOR; CELL-PROLIFERATION; OXIDATIVE STRESS; MAMMARY-TUMORS; OPEN-LABEL AB Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC. C1 [Saleh, Anthony D.; Savage, Jason E.; Zhao, Shuping; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Simone, Brittany A.; Sano, Yuri; Dan, Tu; Jin, Lianjin; Champ, Colin E.; Lim, Meng; Simone, Nicole L.] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Palazzo, Juan] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Pathol, Philadelphia, PA 19107 USA. [Sotgia, Frederica; Pestell, Richard G.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Simone, NL (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. EM nicole.simone@jeffersonhospital.org OI Champ, Colin/0000-0002-1879-7463; Dan, Tu/0000-0003-1154-0507 FU American Society for Radiation Oncology; Intramural Research Program of the NIH; Kimmel Cancer Center Radiation Oncology Facility; NCI Cancer Center [P30 CA56036]; Thomas Jefferson University; Manchester Cancer Research Centre (MCRC); Breakthrough Breast Cancer (BBC); European Research Council (ERC) FX This research was supported in part by the American Society for Radiation Oncology, the Intramural Research Program of the NIH and the Kimmel Cancer Center Radiation Oncology Facility, which is supported partly by NCI Cancer Center Grant P30 CA56036. During the course of this work, Drs Lisanti and Sotgia were funded by the resources of Thomas Jefferson University. Also, Dr Lisanti's and Dr Sotgia's current affiliation is the University of Manchester, where they receive funding from the Manchester Cancer Research Centre (MCRC), Breakthrough Breast Cancer (BBC) and The European Research Council (ERC). NR 61 TC 16 Z9 21 U1 0 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2013 VL 12 IS 12 BP 1955 EP 1963 DI 10.4161/cc.25016 PG 9 WC Cell Biology SC Cell Biology GA 201VD UT WOS:000323170200027 PM 23708519 ER PT J AU Jinnah, HA DeLong, MR Hallett, M AF Jinnah, H. A. DeLong, Mahlon R. Hallett, Mark TI The dystonias: Past, present, and future SO MOVEMENT DISORDERS LA English DT Editorial Material C1 [Jinnah, H. A.; DeLong, Mahlon R.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [DeLong, Mahlon R.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Jinnah, HA (reprint author), Emory Univ, Sch Med, Dept Neurol, 6300 Woodruff Mem Bldg, Atlanta, GA 30322 USA. EM hjinnah@emory.edu FU NCATS NIH HHS [U54 TR001456]; NINDS NIH HHS [R01 NS040470, U54 NS065701] NR 15 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 849 EP 850 DI 10.1002/mds.25564 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700001 PM 23893441 ER PT J AU Albanese, A Bhatia, K Bressman, SB DeLong, MR Fahn, S Fung, VSC Hallett, M Jankovic, J Jinnah, HA Klein, C Lang, AE Mink, JW Teller, JK AF Albanese, Alberto Bhatia, Kailash Bressman, Susan B. DeLong, Mahlon R. Fahn, Stanley Fung, Victor S. C. Hallett, Mark Jankovic, Joseph Jinnah, Hyder A. Klein, Christine Lang, Anthony E. Mink, Jonathan W. Teller, Jan K. TI Phenomenology and classification of dystonia: A consensus update SO MOVEMENT DISORDERS LA English DT Review DE dystonia; classification; definition ID PRIMARY TORSION DYSTONIA; CLINICAL CHARACTERISTICS; DYT1 PHENOTYPE; FOCAL DYSTONIA; PATHOGENESIS; DIAGNOSIS; BLEPHAROSPASM; PARKINSONISM; GUIDELINES; DISEASE AB This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. (C) 2013 Movement Disorder Society C1 [Albanese, Alberto] Univ Cattolica Sacro Cuore, Dept Neurol, I-20123 Milan, Italy. [Albanese, Alberto] Ist Nazl Neurol Carlo Besta, Dept Neurol, Milan, Italy. [Bhatia, Kailash] UCL, Sobell Dept Motor Neurosci & Movement Disorders, Inst Neurol, London, England. [Bressman, Susan B.] Beth Israel Deaconess Med Ctr, Dept Neurol, New York, NY 10003 USA. [Bressman, Susan B.] Albert Einstein Coll Med, Dept Neurol, New York, NY USA. [Bressman, Susan B.] Beth Israel Deaconess Med Ctr, Dept Neurol, Bronx, NY USA. [Bressman, Susan B.] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [DeLong, Mahlon R.; Jinnah, Hyder A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Fahn, Stanley] Columbia Univ, Dept Neurol, New York, NY USA. [Fung, Victor S. C.] Univ Sydney, Movement Disorders Unit, Dept Neurol, Westmead Hosp, Sydney, NSW 2006, Australia. [Fung, Victor S. C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA. [Jinnah, Hyder A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, Hyder A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Klein, Christine] Med Univ Lubeck, Sect Clin & Mol Neurogenet, Dept Neurol, D-23538 Lubeck, Germany. [Lang, Anthony E.] Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Univ Toronto, Toronto, ON, Canada. [Mink, Jonathan W.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Neurobiol & Anat, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Brain & Cognit Sci, Rochester, NY USA. [Mink, Jonathan W.] Univ Rochester, Dept Pediat, Rochester, NY USA. [Teller, Jan K.] Dystonia Med Res Fdn, Chicago, IL USA. RP Albanese, A (reprint author), Fdn Ist Neurol Carlo Besta, Via G Celoria 11, I-20133 Milan, Italy. EM alberto.albanese@unicatt.it OI Bhatia, Kailash/0000-0001-8185-286X FU Dystonia Medical Research Foundation; Dystonia Coalition; European Dystonia COST Action; Merz GmbH; Ipsen Pharma FX The efforts of the consensus committee were supported by the Dystonia Medical Research Foundation, The Dystonia Coalition, the European Dystonia COST Action, and unrestricted educational grants from Merz GmbH and Ipsen Pharma. NR 46 TC 298 Z9 302 U1 7 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 863 EP 873 DI 10.1002/mds.25475 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700003 PM 23649720 ER PT J AU Jinnah, HA Berardelli, A Comella, C DeFazio, G DeLong, MR Factor, S Galpern, WR Hallett, M Ludlow, CL Perlmutter, JS Rosen, AR AF Jinnah, H. A. Berardelli, Alfredo Comella, Cynthia DeFazio, Giovanni DeLong, Mahlon R. Factor, Stewart Galpern, Wendy R. Hallett, Mark Ludlow, Christy L. Perlmutter, Joel S. Rosen, Ami R. CA Dystonia Coalition Investigators TI The focal dystonias: Current views and challenges for future research SO MOVEMENT DISORDERS LA English DT Review DE focal dystonia; cervical dystonia; blepharospasm; spasmodic dysphonia; focal hand dystonia ID DEEP-BRAIN-STIMULATION; IDIOPATHIC CERVICAL DYSTONIA; BENIGN ESSENTIAL BLEPHAROSPASM; PRIMARY TORSION DYSTONIA; BOTULINUM TOXIN TREATMENT; QUALITY-OF-LIFE; GENOTYPE-PHENOTYPE CORRELATIONS; DEAFNESS/DYSTONIA PEPTIDE GENE; TONGUE PROTRUSION DYSTONIA; MOHR-TRANEBJAERG-SYNDROME AB The most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, in which the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focusing attention on less well understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders and for developing novel therapeutics. (C) 2013 Movement Disorder Society C1 [Jinnah, H. A.; DeLong, Mahlon R.; Factor, Stewart; Rosen, Ami R.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, H. A.; Factor, Stewart] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Berardelli, Alfredo] Univ Roma La Sapienza, Dept Neurol & Psychiat, I-00185 Rome, Italy. [Berardelli, Alfredo] Sci Inst Canc Res & Treatment IRCCS Neuromed Inst, Rome, Italy. [Comella, Cynthia] Rush Med Coll, Dept Neurol Sci, Chicago, IL 60612 USA. [DeFazio, Giovanni] Aldo Moro Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy. [DeLong, Mahlon R.; Factor, Stewart] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Galpern, Wendy R.] NINDS, NIH, Bethesda, MD 20892 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Ludlow, Christy L.] James Madison Univ, Dept Commun Sci & Disorders, Harrisonburg, VA 22807 USA. [Perlmutter, Joel S.] Washington Univ, Dept Neurol, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Dept Radiol, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Dept Neurobiol, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Program Occupat Therapy, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Program Phys Therapy, St Louis, MO USA. RP Jinnah, HA (reprint author), Emory Univ, Sch Med, Dept Neurol, 6300 Woodruff Mem Bldg, Atlanta, GA 30322 USA. EM hjinnah@emory.edu OI Ludlow, Christy/0000-0002-2015-6171 FU Dystonia Coalition from the Office of Rare Diseases Research in the National Center for Advancing Translational Sciences; National Institute of Neurological Disorders and Stroke at the National Institutes of Health [U54 NS065701] FX This work was sponsored in part by a grant to the Dystonia Coalition from the Office of Rare Diseases Research in the National Center for Advancing Translational Sciences and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (U54 NS065701). NR 322 TC 40 Z9 40 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 926 EP 943 DI 10.1002/mds.25567 PG 18 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700011 PM 23893450 ER PT J AU Quartarone, A Hallett, M AF Quartarone, Angelo Hallett, Mark TI Emerging concepts in the physiological basis of dystonia SO MOVEMENT DISORDERS LA English DT Review DE dystonia; sensory-motor plasticity; basal ganglia; transcranial magnetic stimulation ID FOCAL HAND DYSTONIA; TRANSCRANIAL MAGNETIC STIMULATION; PRIMARY SOMATOSENSORY CORTEX; DEEP-BRAIN-STIMULATION; HUMAN MOTOR CORTEX; PALLIDUS INTERNUS STIMULATION; PRIMARY GENERALIZED DYSTONIA; WRITERS CRAMP; GLOBUS-PALLIDUS; INTRACORTICAL INHIBITION AB Work over the past 2 decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration, leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been "learned" and are difficult to erase. These considerations might explain the delayed clinical effects of deep brain stimulation (DBS) in patients with generalized dystonia. Current lines of research will be discussed from a network perspective. (C) 2013 Movement Disorder Society C1 [Quartarone, Angelo] Univ Messina, Dept Neurosci Psychiat & Anaesthesiol Sci, I-98125 Messina, Italy. [Quartarone, Angelo] CUNY, Dept Physiol Pharmacol & Neurosci, Sophie Davis Sch Biomed Educ, New York, NY 10021 USA. [Quartarone, Angelo] NYU, Dept Neurol, Div Movement Disorders, New York, NY 10016 USA. [Quartarone, Angelo] Ist Ricovero & Cura Carattere Sci IRCSS Ctr Bonin, Messina, Italy. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Quartarone, A (reprint author), Univ Messina, Dept Neurosci Psychiat & Anaesthesiol Sci, Via Consolare Valeria 1, I-98125 Messina, Italy. EM angelo.quartarone@unime.it OI QUARTARONE, Angelo/0000-0003-1485-6590 FU Intramural NIH HHS [ZIA NS003031-05] NR 109 TC 80 Z9 81 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN 15 PY 2013 VL 28 IS 7 BP 958 EP 967 DI 10.1002/mds.25532 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 188ZH UT WOS:000322235700013 PM 23893452 ER PT J AU Li, X Zhou, Q Sunkara, M Kutys, ML Wu, ZF Rychahou, P Morris, AJ Zhu, HN Evers, BM Huang, C AF Li, Xiang Zhou, Qi Sunkara, Manjula Kutys, Matthew L. Wu, Zhaofei Rychahou, Piotr Morris, Andrew J. Zhu, Haining Evers, B. Mark Huang, Cai TI Ubiquitylation of phosphatidylinositol 4-phosphate 5-kinase type I gamma by HECTD1 regulates focal adhesion dynamics and cell migration SO JOURNAL OF CELL SCIENCE LA English DT Article DE HECTD1; PIP5K1C; Metastasis; Invasion; Ubiquitylation ID CALPAIN-MEDIATED PROTEOLYSIS; PHOSPHATE KINASE; BREAST-CANCER; INTEGRIN ACTIVATION; UBIQUITIN LIGASE; STRUCTURAL BASIS; FERM DOMAIN; TALIN; BINDING; ACTIN AB Phosphatidylinositol 4-phosphate 5-kinase type I gamma (PIPKI gamma 90) binds talin and localizes at focal adhesions (FAs). Phosphatidylinositol (4,5)-bisphosphate (PIP2) generated by PIPKI gamma 90 is essential for FA formation and cell migration. On the other hand, PIPKI gamma 90 and the beta-integrin tail compete for overlapping binding sites on talin. Enhanced PIPKI gamma 90-talin interaction suppresses talin binding to the beta-integrin. It is unknown how PIPKI gamma 90 is removed from the PIPKI gamma 90-talin complex after on-site PIP2 production during cell migration. Here we show that PIPKI gamma 90 is a substrate for HECTD1, an E3 ubiquitin ligase regulating cell migration. HECTD1 ubiquitinated PIPKI gamma 90 at lysine 97 and resulted in PIPKI gamma 90 degradation. Expression of the mutant PIPKI gamma 90(K97R) enhanced PIP2 and PIP3 production, inhibited FA assembly and disassembly and inhibited cancer cell migration, invasion and metastasis. Interestingly, mutation at tryptophan 647 abolished the inhibition of PIPKI gamma 90(K97R) on FA dynamics and partially rescued cancer cell migration and invasion. Thus, cycling PIPKI gamma 90 ubiquitylation by HECTD1 and consequent degradation remove PIPKI gamma 90 from talin after on-site PIP2 production, providing an essential regulatory mechanism for FA dynamics and cell migration. C1 [Li, Xiang; Zhou, Qi; Wu, Zhaofei; Rychahou, Piotr; Evers, B. Mark; Huang, Cai] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA. [Sunkara, Manjula; Morris, Andrew J.] Univ Kentucky, Dept Internal Med, Div Cardiovasc Med, Lexington, KY 40506 USA. [Kutys, Matthew L.] NIDCR, NIH, Bethesda, MD 20892 USA. [Zhu, Haining] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA. [Huang, Cai] Univ Kentucky, Dept Mol & Biomed Pharmacol, Lexington, KY 40506 USA. RP Huang, C (reprint author), Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA. EM cai-huang@uky.edu RI Zhu, Haining/A-6076-2008; wu, zhaofei/J-3149-2014 OI wu, zhaofei/0000-0002-2463-242X FU Markey Cancer Center, University of Kentucky; American Cancer Society [IRG 85-001-22]; National Institutes of Health [GM0503888, P20 GM103527-05]; National Institute of Dental and Craniofacial Research (NIDCR) Intramural Research Program [DE000524-21] FX This work was supported by start-up funds from Markey Cancer Center, University of Kentucky and the American Cancer Society [grant number IRG 85-001-22 to C.H.]; the National Institutes of Health [grant numbers GM0503888 and P20 GM103527-05 to A.J.M.]; and the National Institute of Dental and Craniofacial Research (NIDCR) Intramural Research Program [grant number DE000524-21 to K. Yamada for M.L.K.]. Deposited in PMC for release after 12 months. NR 48 TC 21 Z9 21 U1 0 U2 9 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 JUN 15 PY 2013 VL 126 IS 12 BP 2617 EP 2628 DI 10.1242/jcs.117044 PG 12 WC Cell Biology SC Cell Biology GA 168KT UT WOS:000320705300009 PM 23572508 ER PT J AU Craft, GE Chen, A Nairn, AC AF Craft, George E. Chen, Anshu Nairn, Angus C. TI Recent advances in quantitative neuroproteomics SO METHODS LA English DT Article DE Two-dimensional gel electrophoresis; Isobaric labeling; Label-free quantitation; Mass spectrometry; Neuropeptidomics; Proteomics; Quantitative neuroproteomics ID PROTEOMIC ANALYSIS REVEALS; DIFFERENTIAL PROTEIN EXPRESSION; POSTSYNAPTIC DENSITY PROTEINS; CEREBROSPINAL-FLUID PROTEOME; TANDEM MASS-SPECTROMETRY; MULTIPLEXED ABSOLUTE QUANTIFICATION; FRONTOTEMPORAL LOBAR DEGENERATION; TRANSLATIONAL PROFILING APPROACH; CONCATENATED SIGNATURE PEPTIDES; PARKINSONS-DISEASE PATIENTS AB The field of proteomics is undergoing rapid development in a number of different areas including improvements in mass spectrometric platforms, peptide identification algorithms and bioinformatics. In particular, new and/or improved approaches have established robust methods that not only allow for in-depth and accurate peptide and protein identification and modification, but also allow for sensitive measurement of relative or absolute quantitation. These methods are beginning to be applied to the area of neuroproteomics, but the central nervous system poses many specific challenges in terms of quantitative proteomics, given the large number of different neuronal cell types that are intermixed and that exhibit distinct patterns of gene and protein expression. This review highlights the recent advances that have been made in quantitative neuroproteomics, with a focus on work published over the last five years that applies emerging methods to normal brain function as well as to various neuropsychiatric disorders including schizophrenia and drug addiction as well as of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. While older methods such as two-dimensional polyacrylamide electrophoresis continued to be used, a variety of more in-depth MS-based approaches including both label (ICAT, iTRAQ TMT, SILAC, SILAM), label-free (label-free, MRM, SWATH) and absolute quantification methods, are rapidly being applied to neurobiological investigations of normal and diseased brain tissue as well as of cerebrospinal fluid (CSF). While the biological implications of many of these studies remain to be clearly established, that there is a clear need for standardization of experimental design and data analysis, and that the analysis of protein changes in specific neuronal cell types in the central nervous system remains a serious challenge, it appears that the quality and depth of the more recent quantitative proteomics studies is beginning to shed light on a number of aspects of neuroscience that relates to normal brain function as well as of the changes in protein expression and regulation that occurs in neuropsychiatric and neurodegenerative disorders. (C) 2013 Published by Elsevier Inc. C1 [Craft, George E.; Chen, Anshu; Nairn, Angus C.] Yale Univ, Sch Med, Connecticut Mental Hlth Ctr, Div Mol Psychiat,Abraham Ribicoff Res Facil, New Haven, CT 06508 USA. [Nairn, Angus C.] Yale Univ, Sch Med, Yale NIDA Neuroprote Ctr, New Haven, CT 06508 USA. RP Nairn, AC (reprint author), Yale Univ, Sch Med, Connecticut Mental Hlth Ctr, Div Mol Psychiat,Abraham Ribicoff Res Facil, 34 Pk St, New Haven, CT 06508 USA. EM angus.nairn@yale.edu OI Nairn, Angus/0000-0002-7075-0195 FU NIDA (the Yale/NIDA Neuroproteomics Center) [DA 18343, DA 10044]; NIMH [MH090963]; Dept. of the Army [W81XWH-09-1-0434]; State of Connecticut, Department of Mental Health and Addiction Services FX We would like to acknowledge support from NIDA (the Yale/NIDA Neuroproteomics Center - DA 18343, and DA 10044), NIMH (MH090963) and the Dept. of the Army (W81XWH-09-1-0434). Support was also obtained from the State of Connecticut, Department of Mental Health and Addiction Services. NR 349 TC 49 Z9 49 U1 3 U2 83 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JUN 15 PY 2013 VL 61 IS 3 BP 186 EP 218 DI 10.1016/j.ymeth.2013.04.008 PG 33 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 183HF UT WOS:000321804400002 PM 23623823 ER PT J AU Warren, P Golden, A Hanover, J Love, D Shephard, F Szewczyk, NJ AF Warren, Paul Golden, Andy Hanover, John Love, Dona Shephard, Freya Szewczyk, Nathaniel J. TI Evaluation of the fluids mixing enclosure system for life science experiments during a commercial Caenorhabditis elegans spaceflight experiment SO ADVANCES IN SPACE RESEARCH LA English DT Article DE Commercial spaceflight; Space life sciences; C. elegans; Fluids Mixing Enclosure; DAF-16; FOXO ID CHEMICALLY-DEFINED MEDIUM; LOW-EARTH-ORBIT; C-ELEGANS; SPACE; GENES; LONGEVITY; NEMATODES; GROWTH; EXPRESSION; RADIATION AB The Student Spaceflight Experiments Program (SSEP) is a United States national science, technology, engineering, and mathematics initiative that aims to increase student interest in science by offering opportunities to perform spaceflight experiments. The experiment detailed here was selected and flown aboard the third SSEP mission and the first SSEP mission to the International Space Station (ISS). Caenorhabditis elegans is a small, transparent, self-fertilizing hermaphroditic roundworm that is commonly used in biological experiments both on Earth and in Low Earth Orbit. Past experiments have found decreased expression of mRNA for several genes whose expression can be controlled by the FOX() transcription factor DAF-16. We flew a daf-16 mutant and control worms to determine if the effects of spaceflight on C. elegans are mediated by DAF-16. The experiment used a Type Two Fluids Mixing Enclosure (FME), developed by Nanoracks LLC, and was delivered to the ISS aboard the SpaceX Dragon and returned aboard the Russian Soyuz. The short time interval between experiment selection and the flight rendered preflight experiment verification tests impossible. In addition, published research regarding the viability of the FME in life science experiments was not available. The experiment was therefore structured in such a way as to gather the needed data. Here we report that C. elegans can survive relatively short storage and activation in the FME but cannot produce viable populations for post-flight analysis on extended missions. The FME appears to support short-duration life science experiments, potentially on supply or crew exchange missions, but not on longer ISS expeditions. Additionally, the flown FME was not properly activated, reportedly due to a flaw in training procedures. We suggest that a modified transparent FME could prevent similar failures in future flight experiments. (C) 2013 COSPAR. Published by Elsevier Ltd. All rights reserved. C1 [Warren, Paul] Henry E Lackey High Sch, Indian Head, MD 20640 USA. [Golden, Andy] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Hanover, John] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Love, Dona] NIDDK, Lab Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Shephard, Freya; Szewczyk, Nathaniel J.] Univ Nottingham, Royal Derby Hosp, MRC, Arthrit Res UK Ctr Musculoskeletal Ageing Res, Derby DE22 3DT, England. RP Warren, P (reprint author), Henry E Lackey High Sch, 3000 Chicamuxen Rd, Indian Head, MD 20640 USA. EM pawarren95@gmail.com; nathaniel.szewczyk@nottingham.ac.uk FU Maryland Space Grant Consortium; NIAMS [AR054342]; UK Space Agency [K00123X] FX CeMM was obtained from Liusuo Zhang of Texas A&M University. Modified CeHR was obtained from Tamika Samuel of the University of Maryland, College Park. Participation in the Student Spaceflight Experiments Program International Space Station Mission One was funded by the Maryland Space Grant Consortium and coordinated by Charles County Public Schools. Special thanks to teacher facilitators Lara North and Romulo Gabriel, the administration at Henry E. Lackey High School, the board members of the Charles County Board of Education, and the Science Department at the College of Southern Maryland, La Plata campus for providing extra support. The SSEP on-orbit educational research opportunity is enabled through NanoRacks LLC, which is working in partnership with NASA under a Space Act Agreement as part of the utilization of the International Space Station as a National Laboratory. FS and NJS were supported by a grant from the NIAMS (AR054342) and the UK Space Agency (K00123X). NR 46 TC 0 Z9 0 U1 0 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0273-1177 EI 1879-1948 J9 ADV SPACE RES JI Adv. Space Res. PD JUN 15 PY 2013 VL 51 IS 12 BP 2241 EP 2250 DI 10.1016/j.asr.2013.02.002 PG 10 WC Astronomy & Astrophysics; Geosciences, Multidisciplinary; Meteorology & Atmospheric Sciences SC Astronomy & Astrophysics; Geology; Meteorology & Atmospheric Sciences GA 168DN UT WOS:000320686000006 PM 23794777 ER PT J AU Anantharaman, V Makarova, KS Burroughs, AM Koonin, EV Aravind, L AF Anantharaman, Vivek Makarova, Kira S. Burroughs, A. Maxwell Koonin, Eugene V. Aravind, L. TI Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing SO BIOLOGY DIRECT LA English DT Article ID TOXIN-ANTITOXIN SYSTEMS; MULTIPLE SEQUENCE ALIGNMENT; UNFOLDED PROTEIN RESPONSE; CRISPR-CAS SYSTEMS; RESTRICTION-MODIFICATION SYSTEMS; STREPTOMYCES-COELICOLOR A3(2); MOBILE GENETIC ELEMENTS; ESCHERICHIA-COLI; MESSENGER-RNA; ABORTIVE INFECTION AB Background: The major role of enzymatic toxins that target nucleic acids in biological conflicts at all levels has become increasingly apparent thanks in large part to the advances of comparative genomics. Typically, toxins evolve rapidly hampering the identification of these proteins by sequence analysis. Here we analyze an unexpectedly widespread superfamily of toxin domains most of which possess RNase activity. Results: The HEPN superfamily is comprised of all alpha-helical domains that were first identified as being associated with DNA polymerase beta-type nucleotidyltransferases in prokaryotes and animal Sacsin proteins. Using sensitive sequence and structure comparison methods, we vastly extend the HEPN superfamily by identifying numerous novel families and by detecting diverged HEPN domains in several known protein families. The new HEPN families include the RNase LS and LsoA catalytic domains, KEN domains (e.g. RNaseL and Ire1) and the RNase domains of RloC and PrrC. The majority of HEPN domains contain conserved motifs that constitute a metal-independent endoRNase active site. Some HEPN domains lacking this motif probably function as non-catalytic RNA-binding domains, such as in the case of the mannitol repressor MtlR. Our analysis shows that HEPN domains function as toxins that are shared by numerous systems implicated in intra-genomic, inter-genomic and intra-organismal conflicts across the three domains of cellular life. In prokaryotes HEPN domains are essential components of numerous toxin-antitoxin (TA) and abortive infection (Abi) systems and in addition are tightly associated with many restriction-modification (R-M) and CRISPR-Cas systems, and occasionally with other defense systems such as Pgl and Ter. We present evidence of multiple modes of action of HEPN domains in these systems, which include direct attack on viral RNAs (e.g. LsoA and RNase LS) in conjunction with other RNase domains (e.g. a novel RNase H fold domain, NamA), suicidal or dormancy-inducing attack on self RNAs (RM systems and possibly CRISPR-Cas systems), and suicidal attack coupled with direct interaction with phage components (Abi systems). These findings are compatible with the hypothesis on coupling of pathogen- targeting (immunity) and self-directed (programmed cell death and dormancy induction) responses in the evolution of robust antiviral strategies. We propose that altruistic cell suicide mediated by HEPN domains and other functionally similar RNases was essential for the evolution of kin and group selection and cell cooperation. HEPN domains were repeatedly acquired by eukaryotes and incorporated into several core functions such as endonucleolytic processing of the 5.8S-25S/28S rRNA precursor (Las1), a novel ER membrane-associated RNA degradation system (C6orf70), sensing of unprocessed transcripts at the nuclear periphery (Swt1). Multiple lines of evidence suggest that, similar to prokaryotes, HEPN proteins were recruited to antiviral, antitransposon, apoptotic systems or RNA-level response to unfolded proteins (Sacsin and KEN domains) in several groups of eukaryotes. Conclusions: Extensive sequence and structure comparisons reveal unexpectedly broad presence of the HEPN domain in an enormous variety of defense and stress response systems across the tree of life. In addition, HEPN domains have been recruited to perform essential functions, in particular in eukaryotic rRNA processing. These findings are expected to stimulate experiments that could shed light on diverse cellular processes across the three domains of life. C1 [Anantharaman, Vivek; Makarova, Kira S.; Burroughs, A. Maxwell; Koonin, Eugene V.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU US Department of Health and Human Services (National Library of Medicine, NIH) FX Research by the authors is supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH). NR 159 TC 32 Z9 32 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUN 15 PY 2013 VL 8 AR 15 DI 10.1186/1745-6150-8-15 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 180WJ UT WOS:000321629500001 PM 23768067 ER PT J AU Damiano, DL Wingert, JR Stanley, CJ Curatalo, L AF Damiano, Diane L. Wingert, Jason R. Stanley, Christopher J. Curatalo, Lindsey TI Contribution of hip joint proprioception to static and dynamic balance in cerebral palsy: a case control study SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Static balance; Sensory function; Sroprioception; Hemiplegia; Diplegia ID STANDING BALANCE; POSTURAL CONTROL; CHILDREN; PERFORMANCE; ADAPTATION; HEMIPLEGIA; WALKING AB Background: Balance problems are common in cerebral palsy (CP) but etiology is often uncertain. The classic Romberg test compares ability to maintain standing with eyes open versus closed. Marked instability without vision is a positive test and generally indicates proprioceptive loss. From previous work showing diminished hip joint proprioception in CP, we hypothesized that static and dynamic balance without vision (positive Romberg) would be compromised in CP. Methods: Force plate sway and gait velocity data were collected using 3D motion capture on 52 participants, 19 with diplegic CP, 13 with hemiplegic CP, and 20 without disability. Center of mass (COM) and center or pressure (COP) velocity, excursion, and differences between COM and COP in AP and ML directions were computed from static standing trials with eyes open and closed. Mean gait velocity with and without dribble glasses was compared. Hip joint proprioception was quantified as the root mean square of magnitude of limb positioning errors during a hip rotation task with and without view of the limb. Mixed model repeated measures analysis of variance (ANOVA) was performed with condition as within-subject (EO, EC) and group as between-subject factors (hemiplegia, diplegia, controls). Sway characteristics and gait speed were correlated with proprioception values. Results: Groups with CP had greater sway in standing with eyes open indicating that they had poorer balance than controls, with the deficit relatively greater in the ML compared to AP direction. Contrary to our hypothesis, the decrement with eyes closed did not differ from controls (negative Romberg); however, proprioception error was related to sway parameters particularly for the non-dominant leg. Gait speed was related to proprioception values such that those with worse proprioception tended to walk more slowly. Conclusions: Postural instability is present even in those with mild CP and is yet another manifestation of their motor control disorder, the specific etiology of which may vary across individuals in this heterogeneous diagnostic category. C1 [Damiano, Diane L.; Stanley, Christopher J.; Curatalo, Lindsey] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Wingert, Jason R.] Univ N Carolina, Dept Hlth & Wellness, WHC, Asheville, NC 28804 USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Room 1-1469, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU NIH Clinical Center; Cerebral Palsy International Research Foundation; Foundation for Physical Therapy PODS scholarship; NIH NRSA FX This work was supported in part by the intramural research program at the NIH Clinical Center, the Cerebral Palsy International Research Foundation, the Foundation for Physical Therapy PODS scholarship and NIH NRSA Grant. NR 29 TC 12 Z9 12 U1 1 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD JUN 15 PY 2013 VL 10 AR 57 DI 10.1186/1743-0003-10-57 PG 10 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 171IW UT WOS:000320920400001 PM 23767869 ER PT J AU McQueen, PG Williamson, KC McKenzie, FE AF McQueen, Philip G. Williamson, Kim C. McKenzie, F. Ellis TI Host immune constraints on malaria transmission: insights from population biology of within-host parasites SO MALARIA JOURNAL LA English DT Article ID PLASMODIUM-FALCIPARUM GAMETOCYTES; VIVAX MALARIA; BLOCKING IMMUNITY; SURFACE-ANTIGENS; SEXUAL STAGES; BLOOD-CELLS; IN-VITRO; INFECTIONS; GAMETOCYTOGENESIS; ERYTHROCYTES AB Background: Plasmodium infections trigger complex immune reactions from their hosts against several life stages of the parasite, including gametocytes. These immune responses are highly variable, depending on age, genetics, and exposure history of the host as well as species and strain of parasite. Although the effects of host antibodies that act against gamete stages in the mosquito (due to uptake in the blood meal) are well documented, the effects of host immunity upon within-host gametocytes are not as well understood. This report consists of a theoretical population biology-based analysis to determine constraints that host immunity impose upon gametocyte population growth. The details of the mathematical models used for the analysis were guided by published reports of clinical and animal studies, incorporated plausible modalities of immune reactions to parasites, and were tailored to the life cycles of the two most widespread human malaria pathogens, Plasmodium falciparum and Plasmodium vivax. Results: For the same ability to bind and clear a target, the model simulations suggest that an antibody attacking immature gametocytes would tend to lower the overall density of transmissible mature gametocytes more than an antibody attacking the mature forms directly. Transmission of P. falciparum would be especially vulnerable to complete blocking by antibodies to its immature forms since its gametocytes take much longer to reach maturity than those of P. vivax. On the other hand, antibodies attacking the mature gametocytes directly would reduce the time the mature forms can linger in the host. Simulation results also suggest that varying the standard deviation in the time necessary for individual asexual parasites to develop and produce schizonts can affect the efficiency of production of transmissible gametocytes. Conclusions: If mature gametocyte density determines the probability of transmission, both Plasmodium species, but especially P. falciparum, could bolster this probability through evasion or suppression of host immune responses against the immature gametocytes. However, if the long term lingering of mature gametocytes at low density in the host is also important to ensure transmission, then evasion or suppression of antibodies against the mature stages would bolster probability of transmission as well. C1 [McQueen, Philip G.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. [Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP McQueen, PG (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM mcqueenp@mail.nih.gov FU Intramural Research Program of the NIH, Center for Information Technology; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX 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. PGM was supported by the Intramural Research Program of the NIH, Center for Information Technology. KCW was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 94 TC 5 Z9 5 U1 1 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 15 PY 2013 VL 12 AR 206 DI 10.1186/1475-2875-12-206 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 171QH UT WOS:000320943600001 PM 23767770 ER PT J AU Pilc, A Wieronska, JM Skolnick, P AF Pilc, Andrzej Wieronska, Joanna M. Skolnick, Phil TI Glutamate-Based Antidepressants: Preclinical Psychopharmacology SO BIOLOGICAL PSYCHIATRY LA English DT Review DE AMPA; depression; GLT-1; mGlu2/3; mGlu5; mGlu7; NMDA; x(c)(-) ID METHYL-D-ASPARTATE; MAJOR DEPRESSIVE DISORDER; AMPA RECEPTOR POTENTIATOR; CENTRAL-NERVOUS-SYSTEM; TAIL SUSPENSION TEST; MILD STRESS MODEL; ALLOSTERIC MODULATOR; NMDA ANTAGONIST; MOOD DISORDERS; DOUBLE-BLIND AB Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2). C1 [Pilc, Andrzej; Wieronska, Joanna M.] Polish Acad Sci, Inst Pharmacol, PL-31343 Krakow, Poland. [Skolnick, Phil] NIDA, NIH, Bethesda, MD 20892 USA. RP Pilc, A (reprint author), Polish Acad Sci, Inst Pharmacol, Smetna 12, PL-31343 Krakow, Poland. EM nfpilc@cyf-kr.edu.pl OI Pilc, Andrzej/0000-0002-4045-0597 FU Institute of Pharmacology, Polish Academy of Sciences, Krakow; Task 3.7 [POIG.01.01.0212-004/09-00] FX This work was supported by the Institute of Pharmacology, Polish Academy of Sciences, Krakow, and by Grant POIG.01.01.0212-004/09-00, Task 3.7. The views in this article expressed by PS do not necessarily reflect the views of the National Institute on Drug Abuse, the National Institutes of Health, or the US Department of Health and Human Services. NR 100 TC 62 Z9 63 U1 1 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2013 VL 73 IS 12 BP 1125 EP 1132 DI 10.1016/j.biopsych.2013.01.021 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166VI UT WOS:000320586400006 PM 23453290 ER PT J AU Zarate, CA Mathews, DC Furey, ML AF Zarate, Carlos A., Jr. Mathews, Daniel C. Furey, Maura L. TI Human Biomarkers of Rapid Antidepressant Effects SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Antidepressant; biomarker; cholinergic; depression; glutamate; ketamine; muscarinic; N-methyl-D-aspartate; scopolamine; sleep deprivation ID TOTAL SLEEP-DEPRIVATION; SEROTONIN TRANSPORTER GENE; MAJOR DEPRESSIVE DISORDER; D-ASPARTATE ANTAGONIST; EMISSION COMPUTERIZED-TOMOGRAPHY; MAGNETIC-RESONANCE-SPECTROSCOPY; GLUCOSE METABOLIC-RESPONSE; CEREBRAL-BLOOD-FLOW; HIGH-DENSITY EEG; SLOW-WAVE SLEEP AB Mood disorders such as major depressive disorder and bipolar disorder-and their consequent effects on the individual and society-are among the most disabling and costly of all medical illnesses. Although a number of antidepressant treatments are available in clinical practice, many patients still undergo multiple and lengthy medication trials before experiencing relief of symptoms. Therefore a tremendous need exists to improve current treatment options and to facilitate more rapid, successful treatment in patients suffering from the deleterious neurobiological effects of ongoing depression. Toward that end, ongoing research is exploring the identification of biomarkers that might be involved in prevention, diagnosis, treatment response, severity, or prognosis of depression. Biomarkers evaluating treatment response will be the focus of this review, given the importance of providing relief to patients in a more expedient and systematic manner. A novel approach to developing such biomarkers of response would incorporate interventions with a rapid onset of action-such as sleep deprivation or intravenous drugs (e.g., ketamine or scopolamine). This alternative translational model for new treatments in psychiatry would facilitate shorter studies, improve feasibility, and increase higher compound throughput testing for these devastating disorders. C1 [Zarate, Carlos A., Jr.; Mathews, Daniel C.; Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, NIH, CRC, 10 Ctr Dr,7 Southeast Unit,Room 7-3465, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Furey, Maura/H-5273-2013 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services; (Brain and Behavior Research Foundation) NARSAD Independent Investigator award; Brain and Behavior Mood Disorders Research award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services; a (Brain and Behavior Research Foundation) NARSAD Independent Investigator award to CAZ; and a Brain and Behavior Mood Disorders Research award to CAZ. NR 101 TC 43 Z9 43 U1 11 U2 44 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 JUN 15 PY 2013 VL 73 IS 12 BP 1142 EP 1155 DI 10.1016/j.biopsych.2012.11.031 PG 14 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166VI UT WOS:000320586400008 PM 23374639 ER PT J AU Drevets, WC Zarate, CA Furey, ML AF Drevets, Wayne C. Zarate, Carlos A., Jr. Furey, Maura L. TI Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Antidepressant; bipolar; cholinergic; muscarinic; scopolamine; unipolar ID BEHAVIORAL DESPAIR TEST; LOW-DOSE PHYSOSTIGMINE; REM INDUCTION TEST; MAJOR DEPRESSION; GENDER-DIFFERENCES; AFFECTIVE-DISORDERS; SLEEP-DEPRIVATION; ANTI-DEPRESSANTS; MATCHED CONTROLS; BASAL FOREBRAIN AB The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 mg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism. C1 [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med Dept Psychiat, Tulsa, OK USA. [Zarate, Carlos A., Jr.; Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Furey, ML (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, 15K North Dr,Bldg 15K,Rm 115B, Bethesda, MD 20892 USA. EM mfurey@mail.nih.gov RI Furey, Maura/H-5273-2013 FU Intramural NIH HHS [ZIA MH002813-10] NR 75 TC 42 Z9 43 U1 3 U2 33 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 JUN 15 PY 2013 VL 73 IS 12 BP 1156 EP 1163 DI 10.1016/j.biopsych.2012.09.031 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166VI UT WOS:000320586400009 PM 23200525 ER PT J AU Carlson, PJ Diazgranados, N Nugent, AC Ibrahim, L Luckenbaugh, DA Brutsche, N Herscovitch, P Manji, HK Zarate, CA Drevets, WC AF Carlson, Paul J. Diazgranados, Nancy Nugent, Allison C. Ibrahim, Lobna Luckenbaugh, David A. Brutsche, Nancy Herscovitch, Peter Manji, Husseini K. Zarate, Carlos A., Jr. Drevets, Wayne C. TI Neural Correlates of Rapid Antidepressant Response to Ketamine in Treatment-Resistant Unipolar Depression: A Preliminary Positron Emission Tomography Study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Habenula; insula; major depressive disorder; NMDA receptor antagonist; parahippocampal gyrus; PET imaging ID CEREBRAL-BLOOD-FLOW; BRAIN GLUCOSE-METABOLISM; MEDIAL PREFRONTAL CORTEX; NMDA RECEPTOR BLOCKADE; DORSAL RAPHE NUCLEUS; TRYPTOPHAN DEPLETION; MAJOR DEPRESSION; LATERAL HABENULA; MOOD DISORDERS; LEARNED HELPLESSNESS AB Background: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. Methods: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5 mg/kg intravenous over 40 minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. Results: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. Conclusions: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects. C1 [Carlson, Paul J.] Univ Utah, Sch Med, Salt Lake City Vet Affairs Med, Salt Lake City, UT USA. [Carlson, Paul J.] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT USA. [Diazgranados, Nancy] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Nugent, Allison C.; Ibrahim, Lobna; Luckenbaugh, David A.; Brutsche, Nancy; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD USA. [Herscovitch, Peter] NIH, Ctr Clin, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. [Manji, Husseini K.; Drevets, Wayne C.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Dept Psychiat, Tulsa, OK USA. Univ Oklahoma, Coll Med, Tulsa, OK USA. RP Zarate, CA (reprint author), Natl Inst Mental Hlth, Expt Therapeut & Pathophysiol Branch, Intramural Program, Unit 7SE,CRC, 10 Ctr Dr, Bethesda, MD 20892 USA. OI Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Program of the National Institute of Mental Health; National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. Authors CAZ and WCD are joint senior authors. Ioline Henter provided excellent editorial assistance. Drs. Manji and Zarate are listed as co-inventors on a patent for the use of ketamine in major depression and have assigned their patent rights on ketamine to the US government. Dr. Manji is currently an employee of Johnson & Johnson Pharmaceuticals. Dr. Drevets has consulted for Pfizer Pharmaceuticals; Johnson & Johnson Pharmaceuticals; Eisai, Inc.; and Myriad/Rules Based Medicine, Inc. All other authors report no biomedical financial interests or potential conflicts of interest. NR 83 TC 47 Z9 48 U1 0 U2 24 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 JUN 15 PY 2013 VL 73 IS 12 BP 1213 EP 1221 DI 10.1016/j.biopsych.2013.02.008 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166VI UT WOS:000320586400016 PM 23540908 ER PT J AU Zeng, MC Niciu, MJ Luckenbaugh, DA Ionescu, DF Mathews, DC Richards, EM Franco-Chaves, J Brutsche, NE Zarate, CA AF Zeng, Mary C. Niciu, Mark J. Luckenbaugh, David A. Ionescu, Dawn F. Mathews, Daniel C. Richards, Erica M. Franco-Chaves, Jose Brutsche, Nancy E. Zarate, Carlos A., Jr. TI Acute Stress Symptoms Do Not Worsen in Posttraumatic Stress Disorder and Abuse with a Single Subanesthetic Dose of Ketamine SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID D-ASPARTATE ANTAGONIST; ADD-ON TRIAL; BIPOLAR DEPRESSION; ACCIDENT VICTIMS C1 [Zeng, Mary C.] SUNY, Downstate Med Ctr, Bethesda, MD USA. [Niciu, Mark J.; Luckenbaugh, David A.; Ionescu, Dawn F.; Mathews, Daniel C.; Richards, Erica M.; Brutsche, Nancy E.; Zarate, Carlos A., Jr.] NIMH, NIH, Bethesda, MD 20892 USA. [Franco-Chaves, Jose] VA Caribbean Hlth Care Syst, San Juan, PR USA. RP Zarate, CA (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015 OI Niciu, Mark/0000-0002-5612-3021; NR 9 TC 3 Z9 3 U1 0 U2 3 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 JUN 15 PY 2013 VL 73 IS 12 BP E37 EP E38 DI 10.1016/j.biopsych.2012.10.017 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166VI UT WOS:000320586400003 PM 23245747 ER PT J AU Fowler, CJ Olivier, KN Leung, JM Smith, CC Huth, AG Root, H Kuhns, DB Logun, C Zelazny, A Frein, CA Daub, J Haney, C Shelhamer, JH Bryant, CE Holland, SM AF Fowler, Cedar J. Olivier, Kenneth N. Leung, Janice M. Smith, Caroline C. Huth, Andrea G. Root, Heather Kuhns, Douglas B. Logun, Carolea Zelazny, Adrian Frein, Cathleen A. Daub, Janine Haney, Carissa Shelhamer, James H. Bryant, Clare E. Holland, Steven M. TI Abnormal Nasal Nitric Oxide Production, Ciliary Beat Frequency, and Toll-like Receptor Response in Pulmonary Nontuberculous Mycobacterial Disease Epithelium SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE nontuberculous mycobacteria infections; cilia beat frequency; nasal nitric oxide; Toll-like receptors ID COMPLEX LUNG-DISEASE; AVIUM COMPLEX; CYSTIC-FIBROSIS; INFECTIOUS-DISEASES; SIGNALING PATHWAY; RISK-FACTORS; CELLS; PREVALENCE; DYSKINESIA; PATTERN AB Rationale: Pulmonary nontuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Despite extensive investigation, no consistent immunological abnormalities have been found. Using evidence from diseases such as cystic fibrosis and primary ciliary dyskinesia, in which mucociliary dysfunction predisposes subjects to high rates of nontuberculous mycobacterial disease that increase with age, we investigated correlates of mucociliary function in subjects with PNTM infections and healthy control subjects. Objectives: To define ex vivo characteristics of PNTM disease. Methods: From 2009 to 2012, 58 subjects with PNTM infections and 40 control subjects were recruited. Nasal nitric oxide (nNO) was determined at the time of respiratory epithelial collection. Ciliary beat frequency at rest and in response to Toll-like receptor (TLR) and other agonists was determined using high-speed video microscopy. Measurements and Main Results: We found decreased nNO production, abnormally low resting ciliary beat frequency, and abnormal responses to agonists of TLR2, -3, -5, -7/8, and -9 in subjects with PNTM compared with healthy control subjects. The low ciliary beat frequency in subjects with PNTM was normalized ex vivo by augmentation of the NO-cyclic guanosinemonophosphate pathway without normalization of their TLR agonist responses. Conclusions: Impaired nNO, ciliary beat frequency, and TLR responses in PNTM disease epithelium identify possible underlying susceptibility mechanisms as well as possible avenues for directed investigation and therapy. C1 [Fowler, Cedar J.; Olivier, Kenneth N.; Smith, Caroline C.; Huth, Andrea G.; Root, Heather; Zelazny, Adrian; Frein, Cathleen A.; Daub, Janine; Haney, Carissa; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Leung, Janice M.; Logun, Carolea; Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Bryant, Clare E.] Univ Cambridge, Dept Vet Med, Cambridge, England. RP Holland, SM (reprint author), Lab Clin Infect Dis, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU National Institutes of Health [9U54HL096458-06]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health grant 9U54HL096458-06 and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 50 TC 16 Z9 16 U1 0 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2013 VL 187 IS 12 BP 1374 EP 1381 DI 10.1164/rccm.201212-2197OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 163UO UT WOS:000320362600017 PM 23593951 ER PT J AU Huang, YJ Charlson, ES Collman, RG Colombini-Hatch, S Martinez, FD Senior, RM AF Huang, Yvonne J. Charlson, Emily S. Collman, Ronald G. Colombini-Hatch, Sandra Martinez, Fernando D. Senior, Robert M. TI The Role of the Lung Microbiome in Health and Disease A National Heart, Lung, and Blood Institute Workshop Report SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE microbiome; lung; gut ID OBSTRUCTIVE PULMONARY-DISEASE; CYSTIC-FIBROSIS; GUT MICROBIOTA; AIRWAY MICROBIOTA; DENDRITIC CELLS; DIVERSITY; BACTERIA; COMMUNITIES; ASTHMA; TRACT AB Study of the human lung microbiome in the context of pulmonary health and disease is an area of emerging research interest that is being driven by several contributing factors. These factors include increased recognition of the diversity of human-associated microbiota, their roles in health and in diseases associated with chronic inflammation, and advancements in technologies and tools that have facilitated such discoveries about the microbiota in organ systems outside of the lung. Therefore, the overarching goals of lung microbiome research are: to identify and characterize microbial populations associated with the respiratory tract and lungs; to understand their roles in lung health and disease; and, we hope, to allow the development of improved approaches for diagnosing and treating chronic respiratory diseases in which the microbiome has a role. Recent studies of the lung microbiome have yielded a number of interesting findings but also highlighted questions and challenges for researchers and clinicians. In December 2011, the National Heart, Lung, and Blood Institute convened a workshop to identify key issues and areas for further attention or development to advance research on the lung microbiome. Current knowledge and the state of research on the lung and related areas of human microbiome investigation were reviewed and discussed. C1 [Huang, Yvonne J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Charlson, Emily S.; Collman, Ronald G.] Univ Penn, Dept Internal Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Colombini-Hatch, Sandra] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. [Martinez, Fernando D.] Univ Arizona, Coll Med, Dept Pediat, Arizona Resp Ctr, Tucson, AZ USA. [Senior, Robert M.] Washington Univ, Dept Internal Med, Div Pulm & Crit Care Med, St Louis, MO USA. RP Colombini-Hatch, S (reprint author), NHLBI, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM hatchs@nhlbi.nih.gov RI Huang, Yvonne /A-7360-2015 FU NHLBI NIH HHS [K23 HL105572] NR 50 TC 52 Z9 54 U1 0 U2 47 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2013 VL 187 IS 12 BP 1382 EP 1387 DI 10.1164/rccm.201303-0488WS PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 163UO UT WOS:000320362600018 PM 23614695 ER PT J AU Navarro, A Clot, G Prieto, M Royo, C Vegliante, MC Amador, V Hartmann, E Salaverria, I Bea, S Martin-Subero, JI Rosenwald, A Ott, G Wiestner, A Wilson, WH Campo, E Hernandez, L AF Navarro, Alba Clot, Guillem Prieto, Miriam Royo, Cristina Carmela Vegliante, Maria Amador, Virginia Hartmann, Elena Salaverria, Itziar Bea, Slvia Ignacio Martin-Subero, Jose Rosenwald, Andreas Ott, German Wiestner, Adrian Wilson, Wyndham H. Campo, Elias Hernandez, Luis TI microRNA Expression Profiles Identify Subtypes of Mantle Cell Lymphoma with Different Clinicobiological Characteristics SO CLINICAL CANCER RESEARCH LA English DT Article ID CLASS DISCOVERY; GOOD PROGNOSIS; CANCER-CELLS; DISEASE; IMMUNOGLOBULIN; SUBGROUP; TRACKING; SURVIVAL; FEATURES; NUMBERS AB Purpose: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL). Experimental Design: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs. Results: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene. Conclusion: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. (C)2013 AACR. C1 [Navarro, Alba; Clot, Guillem; Prieto, Miriam; Royo, Cristina; Carmela Vegliante, Maria; Amador, Virginia; Salaverria, Itziar; Bea, Slvia; Campo, Elias; Hernandez, Luis] IDIBAPS, Hosp Clin, Dept Pathol, Barcelona 08036, Spain. [Hartmann, Elena; Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Ignacio Martin-Subero, Jose] Univ Barcelona, Dept Pathol Pharmacol & Microbiol, Barcelona, Spain. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Wiestner, Adrian] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hernandez, L (reprint author), IDIBAPS, Edifici Ctr Esther Koplowitz CEK,Rossello 153, Barcelona 08036, Spain. EM hernan@clinic.ub.es RI Navarro, Alba/H-2611-2015; Royo, Cristina/H-3193-2015; SALAVERRIA, ITZIAR/L-2246-2015; Bea, Silvia/K-7699-2014; OI Navarro, Alba/0000-0002-4041-0974; Royo, Cristina/0000-0002-1214-4656; SALAVERRIA, ITZIAR/0000-0002-2427-9822; Bea, Silvia/0000-0001-7192-2385; Martin-Subero, Jose Ignacio/0000-0001-8809-5195; Campo, elias/0000-0001-9850-9793 FU Instituto de Salud Carlos III (ISCIII); Fondo Investigaciones Sanitarias; European Regional Development Fund (Union Europea. "Una manera de hacer Europa") [PI12/01302, PI08/0077-PI11/01177]; Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/0039, RD12/0036/0036]; Plan Nacional del MINECO [SAF08/03630]; Generalitat de Catalunya [AGAUR 2009-SGR-992]; NHLBI; NCI; FIS; "programa d'estabilitzacio d'investigadors'' of Direccio d'Estrategia i Coordinacio del Departament de Salut (Generalitat de Catalunya) FX This work was supported by the Instituto de Salud Carlos III (ISCIII), Fondo Investigaciones Sanitarias & European Regional Development Fund (Union Europea. "Una manera de hacer Europa"; PI12/01302; to L. Hernandez), (PI08/0077-PI11/01177; S. Bea), and (RD06/0020/0039 and RD12/0036/0036) from Red Tematica de Investigacion Cooperativa en Cancer (RTICC); Plan Nacional del MINECO SAF08/03630, and Generalitat de Catalunya AGAUR 2009-SGR-992. A. Wiestner and W. H. Wilson are supported by the intramural research program of NHLBI and NCI, respectively. The work was carried out at the Centro Esther Koplowitz, Barcelona, Spain. L. Hernandez is supported by FIS and "programa d'estabilitzacio d'investigadors'' of Direccio d'Estrategia i Coordinacio del Departament de Salut (Generalitat de Catalunya). NR 39 TC 15 Z9 16 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2013 VL 19 IS 12 BP 3121 EP 3129 DI 10.1158/1078-0432.CCR-12-3077 PG 9 WC Oncology SC Oncology GA 164AL UT WOS:000320381000003 PM 23640973 ER PT J AU El-Gohary, Y Tulachan, S Guo, P Welsh, C Wiersch, J Prasadan, K Paredes, J Shiota, C Xiao, XW Wada, Y Diaz, M Gittes, G AF El-Gohary, Yousef Tulachan, Sidhartha Guo, Ping Welsh, Carey Wiersch, John Prasadan, Krishna Paredes, Jose Shiota, Chiyo Xiao, Xiangwei Wada, Yoko Diaz, Marilyn Gittes, George TI Smad signaling pathways regulate pancreatic endocrine development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Pancreas; TGF-beta; Smads; Embryonic ID INSULIN-POSITIVE DIFFERENTIATION; EMBRYONIC MOUSE PANCREAS; RECEPTOR-II EXPRESSION; TGF-BETA SIGNAL; TARGETED DISRUPTION; EXOCRINE PANCREAS; DUCTAL CELLS; AR42J CELLS; GROWTH; TRANSDUCTION AB Expansion of the pancreatic endocrine cell population occurs during both embryonic development and during post-natal pancreatic growth and regeneration. Mechanisms of the expansion of endocrine cells during embryonic development are not completely understood, and no clear mechanistic link has been established between growth of the embryonic endocrine pancreas and the islet cell replication that occurs in an adult animal. We found that transforming growth factor-beta (TGF-beta) superfamily signaling, which has been implicated in many developmental processes, plays a key role in regulating pancreatic endocrine maturation and development. Specifically, the intracellular mediators of TGF-beta signaling, smad2 and smad3, along with their inhibitor smad7, appear to mediate this process. Smad2, smad3 and smad7 were all broadly expressed throughout the early embryonic pancreatic epithelium. However, during later stages of development, smad2 and smad3 became strongly localized to the nuclei of the endocrine positive cells, whereas the inhibitory smad7 became absent in the endocrine component. Genetic inactivation of smad2 and smad3 led to a significant expansion of the embryonic endocrine compartment, whereas genetic inactivation of smad7 led to a significant decrease in the endocrine compartment. In vitro antisense studies further corroborated these results and supported the possibility that interplay between the inhibitory smad7 and the intracellular mediators smad2/3 is a control point for pancreatic endocrine development. These results should provide a better understanding of the key control mechanisms for beta-cell development. (c) 2013 Elsevier Inc. All rights reserved. C1 [El-Gohary, Yousef; Guo, Ping; Wiersch, John; Prasadan, Krishna; Paredes, Jose; Shiota, Chiyo; Xiao, Xiangwei; Gittes, George] Childrens Hosp Pittsburgh, Dept Surg, Div Pediat Surg, Pittsburgh, PA 15224 USA. [Tulachan, Sidhartha] St Elizabeth Hlth Ctr, Dept Internal Med, Youngstown, OH 44501 USA. [Welsh, Carey] Childrens Hosp Pittsburgh, Dept Pediat, Div Neonatol, Pittsburgh, PA 15224 USA. [Wiersch, John] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Surg, San Antonio, TX 78229 USA. [Wada, Yoko] Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Chuo Ku, Niigata 9518510, Japan. [Diaz, Marilyn] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Gittes, G (reprint author), Childrens Hosp Pittsburgh, Dept Surg, Div Pediat Surg, 1 Childrens Hosp Dr,4401 Penn Ave, Pittsburgh, PA 15224 USA. EM yousef.gohary@gmail.com; george.gittes@chp.edu RI xiao, xiangwei/K-1218-2012 FU NIH [RO1 DK064952, R01 DK083541-01]; Children's Hospital of Pittsburgh; Division of Intramural Research of the NIH (NIEHS) [Z01 ES101603] FX Special thanks to Lauren Brink, Jessica Thomas, and Sean-Paul Williams for technical assistance in flow cytometry and mouse genotyping. Thanks to Sanjay Mishra, Csaba Galambos, Farzad Esni, Angela Criscimanna, Sohail Shah, Marcus Malek, Nikesh Lath for helpful discussions. Thanks to Christine Kalinyak, Anne L Meiner and Tamara Daviston for administrative assistance. Financial support was from NIH (G.K.G., RO1 DK064952, R01 DK083541-01) and the Children's Hospital of Pittsburgh. M.D. was supported by Project Z01 ES101603 from the Division of Intramural Research of the NIH (NIEHS). NR 43 TC 15 Z9 15 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 15 PY 2013 VL 378 IS 2 BP 83 EP 93 DI 10.1016/j.ydbio.2013.04.003 PG 11 WC Developmental Biology SC Developmental Biology GA 161RF UT WOS:000320210300002 PM 23603491 ER PT J AU Lu, YC Yao, X Li, YF El-Gamil, M Dudley, ME Yang, JC Almeida, JR Douek, DC Samuels, Y Rosenberg, SA Robbins, PF AF Lu, Yong-Chen Yao, Xin Li, Yong F. El-Gamil, Mona Dudley, Mark E. Yang, James C. Almeida, Jorge R. Douek, Daniel C. Samuels, Yardena Rosenberg, Steven A. Robbins, Paul F. TI Mutated PPP1R3B Is Recognized by T Cells Used To Treat a Melanoma Patient Who Experienced a Durable Complete Tumor Regression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROMOTES GLYCOGEN ACCUMULATION; PROTEIN PHOSPHATASE 1; METASTATIC MELANOMA; TARGETING SUBUNIT; CANCER REGRESSION; ADOPTIVE TRANSFER; TRANSFER THERAPY; EXPRESSION; ANTIGEN; BINDING AB Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) represents an effective treatment for patients with metastatic melanoma. However, most of the Ag targets recognized by effective melanoma-reactive TILs remain elusive. In this study, patient 2369 experienced a complete response, including regressions of bulky liver tumor masses, ongoing beyond 7 y following adoptive TIL transfer. The screening of a cDNA library generated from the autologous melanoma cell line resulted in the isolation of a mutated protein phosphatase 1, regulatory (inhibitor) subunit 3B (PPP1R3B) gene product. The mutated PPP1R3B peptide represents the immunodominant epitope recognized by tumor-reactive T cells in TIL 2369. Five years following adoptive transfer, peripheral blood T lymphocytes obtained from patient 2369 recognized the mutated PPP1R3B epitope. These results demonstrate that adoptive T cell therapy targeting a tumor-specific Ag can mediate long-term survival for a patient with metastatic melanoma. This study also provides an impetus to develop personalized immunotherapy targeting tumor-specific, mutated Ags. C1 [Lu, Yong-Chen; Yao, Xin; Li, Yong F.; El-Gamil, Mona; Dudley, Mark E.; Yang, James C.; Rosenberg, Steven A.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Almeida, Jorge R.; Douek, Daniel C.] NIAID, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Lu, YC (reprint author), NIH, Bldg 10 CRC,Room 3W-3832,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM Yong-Chen.Lu@nih.gov; Paul_Robbins@nih.gov RI Lu, Yong-Chen/G-4520-2014; OI Lu, Yong-Chen/0000-0002-0275-9825; Ramos de Almeida, Jorge/0000-0002-5009-8478 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 37 TC 53 Z9 54 U1 0 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 JUN 15 PY 2013 VL 190 IS 12 BP 6034 EP 6042 DI 10.4049/jimmunol.1202830 PG 9 WC Immunology SC Immunology GA 163YE UT WOS:000320373700016 PM 23690473 ER PT J AU Aerbajinai, W Lee, K Chin, K Rodgers, GP AF Aerbajinai, Wulin Lee, Kevin Chin, Kyung Rodgers, Griffin P. TI Glia Maturation Factor-gamma Negatively Modulates TLR4 Signaling by Facilitating TLR4 Endocytic Trafficking in Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; MEDIATED ENDOCYTOSIS; LIPID RAFTS; ACTIN CYTOSKELETON; CELL ACTIVATION; INNATE IMMUNITY; ARP2/3 COMPLEX; TOLL-LIKE-RECEPTOR-4; LIPOPOLYSACCHARIDE; DEGRADATION AB TLR4 signaling must be tightly regulated to provide both effective immune protection and avoid inflammation-induced pathology. Thus, the mechanisms that negatively regulate the TLR4-triggered inflammatory response are of particular importance. Glia maturation factor-gamma (GMFG), a novel actin depolymerization factor/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in mediating neutrophil and T cell migration, but its function in macrophage immune response remains unclear. In the current study, the role of GMFG in the LPS-induced TLR4-signaling pathway was investigated in THP-1 macrophages and human primary macrophages. LPS stimulation of macrophages decreased GMFG mRNA and protein expression. We show that GMFG negatively regulates LPS-induced activation of NF-kappa B-, MAPK-, and IRF3-signaling pathways and subsequent production of proinflammatory cytokines and type I IFN in human macrophages. We found that endogenous GMFG localized within early and late endosomes. GMFG knockdown delayed LPS-induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome, suggesting that TLR4 transport from early to late endosomes is interrupted, which may contribute to enhanced LPS-induced TLR4 signaling. Taken together, our findings suggest that GMFG functions as a negative regulator of TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages. C1 [Aerbajinai, Wulin; Lee, Kevin; Chin, Kyung; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIH, Mol & Clin Hematol Branch, Bldg 10,Room 9N-113A, Bethesda, MD 20892 USA. EM gr5n@nih.gov 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 47 TC 4 Z9 5 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 JUN 15 PY 2013 VL 190 IS 12 BP 6093 EP 6103 DI 10.4049/jimmunol.1203048 PG 11 WC Immunology SC Immunology GA 163YE UT WOS:000320373700022 PM 23677465 ER PT J AU Huang, JP Jochems, C Anderson, AM Talaie, T Jales, A Madan, RA Hodge, JW Tsang, KY Liewehr, DJ Steinberg, SM Gulley, JL Schlom, J AF Huang, Jianping Jochems, Caroline Anderson, Austin M. Talaie, Tara Jales, Alessandra Madan, Ravi A. Hodge, James W. Tsang, Kwong Y. Liewehr, David J. Steinberg, Seth M. Gulley, James L. Schlom, Jeffrey TI Soluble CD27-Pool in Humans May Contribute to T Cell Activation and Tumor Immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESISTANT PROSTATE-CANCER; FACTOR RECEPTOR FAMILY; HUMAN CD40 LIGAND; CD27-CD70 INTERACTIONS; METASTATIC MELANOMA; IN-VIVO; CD27; ANTIGEN; EXPRESSION; MEMBER AB The interaction between CD27 and its ligand, CD70, has been implicated in regulating cellular immune responses to cancer. In this article, we report on the role of soluble CD27 (sCD27) in T cell activation and its elevation in the serum of cancer patients after immunotherapy. In vitro, sCD27 is preferentially derived from activated CD4(+) T cells. Adding sCD27 to stimulated PBMCs increases T cell activation and proliferation, and is associated with the immunologic synapse-related proteins myosin IIA, high mobility group box 1, and the TCR V beta-chain. The pool of serum sCD27 is shown to be greater in healthy donors than in cancer patients. However, metastatic cancer patients treated with immunotherapy showed a significant increase in the serum sCD27-pool posttherapy (p < 0.0005); there was also an increased trend toward an association between enhanced sCD27-pool posttherapy and overall survival (p = 0.022). The identification of sCD27 as an immune modulator associated with enhanced human T cell activation in vitro and in vivo provides a rationale for developing new immunotherapeutic strategies aimed at enhancing sCD27 for treating cancer and potentially other diseases. C1 [Huang, Jianping; Jochems, Caroline; Anderson, Austin M.; Talaie, Tara; Jales, Alessandra; Madan, Ravi A.; Hodge, James W.; Tsang, Kwong Y.; Gulley, James L.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Rockville, MD 20850 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 36 TC 20 Z9 20 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 JUN 15 PY 2013 VL 190 IS 12 BP 6250 EP 6258 DI 10.4049/jimmunol.1300022 PG 9 WC Immunology SC Immunology GA 163YE UT WOS:000320373700038 PM 23677477 ER PT J AU Zhou, QH Haupt, S Prots, I Thummler, K Kremmer, E Lipsky, PE Schulze-Koops, H Skapenko, A AF Zhou, Qihui Haupt, Sonja Prots, Iryna Thuemmler, Katja Kremmer, Elisabeth Lipsky, Peter E. Schulze-Koops, Hendrik Skapenko, Alla TI miR-142-3p Is Involved in CD25(+) CD4 T Cell Proliferation by Targeting the Expression of Glycoprotein A Repetitions Predominant SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; MESSENGER-RNA; GENE-EXPRESSION; MICRORNAS; DICER; DIFFERENTIATION; IDENTIFICATION; CANCER; RECOGNITION; CARCINOMA AB Because of the numerous targets of microRNAs (miRNAs), functional dissection of specific miRNA/mRNA interactions is important to understand the complex miRNA regulatory mechanisms. Glycoprotein A repetitions predominant (GARP) is specifically expressed on regulatory CD25(+) CD4 T cells upon their activation. GARP has a long 39 untranslated region containing five highly conserved regions suggesting miRNA regulation of its expression. Although GARP is physiologically expressed on a cell subset characterized by stringent control of proliferation, amplification of the GARP gene has been found in many tumors characterized by uncontrolled proliferation. In this study, we investigated in detail miRNA regulation of GARP expression, in particular by miR-142-3p, and dissected the functional outcome of miR-142-3p/GARP mRNA interaction. We demonstrate that miR-142-3p binds directly to the 39 untranslated region of GARP and represses GARP protein expression by Argonaute 2-associated degradation of GARP mRNA. Functionally, miR-142-3p-mediated regulation of GARP is involved in the expansion of CD25(+) CD4 T cells in response to stimulation. The data indicate that miR-142-3p regulates GARP expression on CD25(+) CD4 T cells and, as a result, their expansion in response to activation. Our data provide novel insight into the molecular mechanisms controlling regulatory T cell expansion. They may also have implications for understanding tumor cell biology. C1 [Zhou, Qihui; Haupt, Sonja; Prots, Iryna; Thuemmler, Katja; Schulze-Koops, Hendrik; Skapenko, Alla] Univ Munich, Div Rheumatol, Dept Internal Med 4, D-80336 Munich, Germany. [Kremmer, Elisabeth] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Mol Immunol, D-81377 Munich, Germany. [Lipsky, Peter E.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Skapenko, A (reprint author), Univ Munich, Div Rheumatol, Dept Internal Med 4, Pettenkoferstr 8A, D-80336 Munich, Germany. EM alla.skapenko@med.uni-muenchen.de FU Deutsche Forschungsgemeinschaft [SK59/4-1, 786/2-5, 786/8-1]; Sonderforschungsbereich [571]; Verbundantra"ge "ArthroMark'' [OIEC100913]; Impam' [OIEC1008H]; German Federal Ministry of Education and Research FX This work was supported by Deutsche Forschungsgemeinschaft Grants SK59/4-1, Schu 786/2-5, and Schu 786/8-1; by Sonderforschungsbereich Grant 571 (Autoimmunity), project D9; by Deutsche Forschungsgemeinschaft Training Grant GK1202 (Oligonucleotides), project E2; and by the Verbundantra"ge "ArthroMark'' (Projects 1 and 7, Grant OIEC100913) and "Impam'' (Project 10, Grant OIEC1008H) of the German Federal Ministry of Education and Research. NR 35 TC 16 Z9 20 U1 1 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2013 VL 190 IS 12 BP 6579 EP 6588 DI 10.4049/jimmunol.1202993 PG 10 WC Immunology SC Immunology GA 163YE UT WOS:000320373700071 PM 23650616 ER PT J AU Wan, ZP Zhang, SS Fan, YL Liu, K Du, F Davey, AM Zhang, HY Han, WD Xiong, CY Liu, WL AF Wan, Zhengpeng Zhang, Shaosen Fan, Yilin Liu, Kai Du, Feng Davey, Angel M. Zhang, Huiyuan Han, Weidong Xiong, Chunyang Liu, Wanli TI B cell activation is regulated by the stiffness properties of the substrate presenting the antigens (vol 190, pg 4661, 2013) SO JOURNAL OF IMMUNOLOGY LA English DT Correction C1 [Wan, Zhengpeng; Zhang, Shaosen; Fan, Yilin; Zhang, Huiyuan; Liu, Wanli] Tsinghua Univ, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China. [Liu, Kai; Xiong, Chunyang] Peking Univ, Acad Adv Interdisciplinary Studies, Beijing 100871, Peoples R China. [Du, Feng; Xiong, Chunyang] Peking Univ, Coll Engn, Beijing 100871, Peoples R China. [Davey, Angel M.] NIAID, NIH, Bethesda, MD 20892 USA. [Han, Weidong] Chinese Peoples Liberat Army Gen Hosp, Inst Basic Med, Biotherapeut Ctr, Dept Immunol, Beijing 100853, Peoples R China. [Liu, Wanli] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Collaborat Innovat Ctr Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China. RP Wan, ZP (reprint author), Tsinghua Univ, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China. NR 1 TC 0 Z9 0 U1 1 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 JUN 15 PY 2013 VL 190 IS 12 BP 6711 EP 6711 DI 10.4049/jimmunol.1390030 PG 1 WC Immunology SC Immunology GA 163YE UT WOS:000320373700086 ER PT J AU Kwon, DY Dimitriadi, M Terzic, B Cable, C Hart, AC Chitnis, A Fischbeck, KH Burnett, BG AF Kwon, Deborah Y. Dimitriadi, Maria Terzic, Barbara Cable, Casey Hart, Anne C. Chitnis, Ajay Fischbeck, Kenneth H. Burnett, Barrington G. TI The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SPINAL MUSCULAR-ATROPHY; CAENORHABDITIS-ELEGANS; SMN PROTEIN; SINGLE NUCLEOTIDE; DETERMINING GENE; IN-VIVO; NOTCH; ZEBRAFISH; DELTA; INHIBITORS AB Spinal muscular atrophy is an inherited motor neuron disease that results from a deficiency of the survival of motor neuron (SMN) protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition increases SMN protein levels, improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy (SMA) mice. Specific targets in the UPS may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. Also, knocking down the Mib1 orthologue improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for SMA. C1 [Kwon, Deborah Y.; Terzic, Barbara; Cable, Casey; Fischbeck, Kenneth H.; Burnett, Barrington G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Deborah Y.; Dimitriadi, Maria; Hart, Anne C.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Chitnis, Ajay] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Dev, NIH, Bethesda, MD 20892 USA. RP Burnett, BG (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM burnettb@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institutes of Health-National Institute of Neurological Disorders and Stroke [NS066888] FX We thank Liu Yang (University of Arkansas) for the myc-tagged FL-SMN and deletion mutant cDNAs. This work was supported by intramural research funds from the National Institute of Neurological Disorders and Stroke and from National Institutes of Health-National Institute of Neurological Disorders and Stroke (NS066888) to A.C.H. NR 54 TC 14 Z9 15 U1 0 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 15 PY 2013 VL 24 IS 12 BP 1863 EP 1871 DI 10.1091/mbc.E13-01-0042 PG 9 WC Cell Biology SC Cell Biology GA 175AG UT WOS:000321200600005 PM 23615451 ER PT J AU Boeckmann, L Takahashi, Y Au, WC Mishra, PK Choy, JS Dawson, AR Szeto, MY Waybright, TJ Heger, C McAndrew, C Goldsmith, PK Veenstra, TD Baker, RE Basrai, MA AF Boeckmann, Lars Takahashi, Yoshimitsu Au, Wei-Chun Mishra, Prashant K. Choy, John S. Dawson, Anthony R. Szeto, May Y. Waybright, Timothy J. Heger, Christopher McAndrew, Christopher Goldsmith, Paul K. Veenstra, Timothy D. Baker, Richard E. Basrai, Munira A. TI Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in Saccharomyces cerevisiae SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BUDDING YEAST KINETOCHORE; E3 UBIQUITIN LIGASE; CENP-A; PROTEIN-KINASE; AURORA-B; TARGETING DOMAIN; CHECKPOINT; COMPLEX; ARCHITECTURE; EXPRESSION AB The centromeric histone H3 variant (CenH3) is essential for chromosome segregation in eukaryotes. We identify posttranslational modifications of Saccharomyces cerevisiae CenH3, Cse4. Functional characterization of cse4 phosphorylation mutants shows growth and chromosome segregation defects when combined with kinetochore mutants okp1 and ame1. Using a phosphoserine-specific antibody, we show that the association of phosphorylated Cse4 with centromeres increases in response to defective microtubule attachment or reduced cohesion. We determine that evolutionarily conserved Ipl1/Aurora B contributes to phosphorylation of Cse4, as levels of phosphorylated Cse4 are reduced at centromeres in ipl1 strains in vivo, and in vitro assays show phosphorylation of Cse4 by Ipl1. Consistent with these results, we observe that a phosphomimetic cse4-4SD mutant suppresses the temperature-sensitive growth of ipl1-2 and Ipl1 substrate mutants dam1 spc34 and ndc80, which are defective for chromosome biorientation. Furthermore, cell biology approaches using a green fluorescent protein-labeled chromosome show that cse4-4SD suppresses chromosome segregation defects in dam1 spc34 strains. On the basis of these results, we propose that phosphorylation of Cse4 destabilizes defective kinetochores to promote biorientation and ensure faithful chromosome segregation. Taken together, our results provide a detailed analysis, in vivo and in vitro, of Cse4 phosphorylation and its role in promoting faithful chromosome segregation. C1 [Boeckmann, Lars; Takahashi, Yoshimitsu; Au, Wei-Chun; Mishra, Prashant K.; Choy, John S.; Dawson, Anthony R.; Szeto, May Y.; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Heger, Christopher; McAndrew, Christopher; Goldsmith, Paul K.] NCI, Antibody & Prot Purificat Unit, NIH, Bethesda, MD 20892 USA. [Waybright, Timothy J.; Veenstra, Timothy D.] NIH, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Baker, Richard E.] Univ Massachusetts, Dept Microbiol & Physiol Syst, Sch Med, Worcester, MA 01655 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM basraim@nih.gov FU National Cancer Institute, National Institutes of Health FX We are grateful to Trisha N. Davis for purified Ipl1/Sli15, Sue Biggins for strains and advice, Domenic Esposito of the National Cancer Institute for construction of cse4 alleles, and Todd Stukenberg, Tony Hazbun, and Basrai Laboratory members for advice. We thank Katherine McKinnon of the National Cancer Institute Vaccine Branch FACS Core and Tatiana Karpova and Jim McNally of the National Cancer Institute Fluorescence Imaging Group. M. B. is supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 45 TC 10 Z9 10 U1 0 U2 11 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 15 PY 2013 VL 24 IS 12 BP 2034 EP 2044 DI 10.1091/mbc.E12-12-0893 PG 11 WC Cell Biology SC Cell Biology GA 175AG UT WOS:000321200600018 PM 23637466 ER PT J AU Voller, B AF Voller, B. TI Botulinum toxin in rare pain disorders SO TOXICON LA English DT Meeting Abstract CT 7th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (TOXINS) CY OCT 02-05, 2011 CL Santa Fe, NM C1 [Voller, B.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 15 PY 2013 VL 68 BP 64 EP 65 DI 10.1016/j.toxicon.2012.07.030 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159VN UT WOS:000320075500018 ER PT J AU Alter, KE Hallett, M Karp, B Lungu, C AF Alter, K. E. Hallett, M. Karp, B. Lungu, C. TI Advances in toxin therapy: Utilizing ultrasound guidance for botulinum toxin injections SO TOXICON LA English DT Meeting Abstract CT 7th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (TOXINS) CY OCT 02-05, 2011 CL Santa Fe, NM C1 [Alter, K. E.] Mt Washington Pediat Hosp, Baltimore, MD USA. [Alter, K. E.] NICHHD, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 15 PY 2013 VL 68 BP 68 EP 69 DI 10.1016/j.toxicon.2012.07.039 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159VN UT WOS:000320075500027 ER PT J AU Rosen, AR Perlmutter, JS Comella, C Ludlow, C Galpern, W Ferguson, J Yan, L Waliczek, T Harbick, S Jinnah, HA AF Rosen, A. R. Perlmutter, J. S. Comella, C. Ludlow, C. Galpern, W. Ferguson, J. Yan, L. Waliczek, T. Harbick, S. Jinnah, H. A. TI The dystonia coalition: Two years of progress SO TOXICON LA English DT Meeting Abstract CT 7th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (TOXINS) CY OCT 02-05, 2011 CL Santa Fe, NM C1 [Rosen, A. R.; Jinnah, H. A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Perlmutter, J. S.; Yan, L.] Washington Univ, Dept Neurol, St Louis, MO USA. [Comella, C.; Waliczek, T.] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA. [Ludlow, C.; Harbick, S.] James Madison Univ, Dept Commun Sci & Disorders, Harrisonburg, VA 22807 USA. [Galpern, W.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Ferguson, J.] NIH, Off Rare Dis Res, Bethesda, MD 20892 USA. EM hjinnah@emory.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 15 PY 2013 VL 68 BP 80 EP 80 DI 10.1016/j.toxicon.2012.07.067 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159VN UT WOS:000320075500055 ER PT J AU Shoemaker, CB Mukherjee, J Tremblay, JM Leysath, C Bedenice, D Feng, X Ofori, K Baldwin, K Webb, RP Wright, PM Smith, LA Tzipori, S AF Shoemaker, C. B. Mukherjee, J. Tremblay, J. M. Leysath, C. Bedenice, D. Feng, X. Ofori, K. Baldwin, K. Webb, R. P. Wright, P. M. Smith, L. A. Tzipori, S. TI A Strategy for rapid development and simplified production of therapeutic antitoxins tested on botulinum neurotoxin SO TOXICON LA English DT Meeting Abstract CT 7th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (TOXINS) CY OCT 02-05, 2011 CL Santa Fe, NM C1 [Shoemaker, C. B.; Mukherjee, J.; Tremblay, J. M.; Bedenice, D.; Feng, X.; Ofori, K.; Baldwin, K.; Tzipori, S.] Tufts Univ, Cummings Sch Vet Med, Dept Biomed Sci, North Grafton, MA USA. [Leysath, C.] NIH, Lab Bacterial Dis, Bethesda, MD 20892 USA. [Webb, R. P.; Wright, P. M.; Smith, L. A.] USA, Med Res Inst Infect Dis, Frederick, MD USA. EM charles.shoemaker@tufts.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 15 PY 2013 VL 68 BP 97 EP 97 DI 10.1016/j.toxicon.2012.07.107 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159VN UT WOS:000320075500095 ER PT J AU Zuniga, J Hammill, J Drory, O Nuss, J Burnett, J Gussio, R Wipf, P Bavari, S Brunger, AT AF Zuniga, J. Hammill, J. Drory, O. Nuss, J. Burnett, J. Gussio, R. Wipf, P. Bavari, S. Brunger, A. T. TI Structural basis for the inhibition of botulinum neurotoxin serotype A by potent peptidomimetics SO TOXICON LA English DT Meeting Abstract CT 7th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (TOXINS) CY OCT 02-05, 2011 CL Santa Fe, NM C1 [Zuniga, J.; Drory, O.; Brunger, A. T.] Howard Hughes Med Inst, Stanford, CA USA. [Zuniga, J.; Drory, O.; Brunger, A. T.] Stanford Univ, Stanford, CA 94305 USA. [Hammill, J.; Wipf, P.] Univ Pittsburgh, Pittsburgh, PA USA. [Nuss, J.; Bavari, S.] USA, Med Res Inst Infect Dis, Frederick, MD USA. [Burnett, J.] NCI, Frederick, MD 21701 USA. [Gussio, R.] NCI, Dev Therapeut Program, Frederick, MD 21701 USA. EM jzuniga@stanford.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 15 PY 2013 VL 68 BP 103 EP 104 DI 10.1016/j.toxicon.2012.07.122 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159VN UT WOS:000320075500110 ER PT J AU Karami, S Daugherty, SE Schonfeld, SJ Park, Y Hollenbeck, AR Grubb, RL Hofmann, JN Chow, WH Purdue, MP AF Karami, Sara Daugherty, Sarah E. Schonfeld, Sara J. Park, Yikyung Hollenbeck, Albert R. Grubb, Robert L., III Hofmann, Jonathan N. Chow, Wong-Ho Purdue, Mark P. TI Reproductive Factors and Kidney Cancer Risk in 2 US Cohort Studies, 1993-2010 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE hysterectomy; kidney cancer; parity; pooled analysis; reproductive factors ID RENAL-CELL-CARCINOMA; IOWA WOMENS HEALTH; HAMSTER-KIDNEY; UNITED-STATES; ENDOMETRIOSIS; HYSTERECTOMY; PREGNANCY; EPIDEMIOLOGY; ASSOCIATION; DIAGNOSIS AB Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of HealthAARP Diet and Health Study (NIH-AARP), 19952006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 19932010). Cohort-specific and aggregated hazard ratios and 95 confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio 1.28, 95 confidence interval: 1.09, 1.50) and PLCO (hazard ratio 1.41, 95 confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend 0.02) and increasing years of oral contraceptive use (P for trend 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation. C1 [Karami, Sara; Daugherty, Sarah E.; Schonfeld, Sara J.; Park, Yikyung; Hofmann, Jonathan N.; Chow, Wong-Ho; Purdue, Mark P.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Grubb, Robert L., III] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8121, Rockville, MD 20852 USA. EM karamis@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health, National Cancer Institute, US National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, US National Institutes of Health. NR 50 TC 9 Z9 9 U1 2 U2 3 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 JUN 15 PY 2013 VL 177 IS 12 BP 1368 EP 1377 DI 10.1093/aje/kws406 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159RF UT WOS:000320062700006 PM 23624999 ER PT J AU Paredes, SH Melgar, MF Sethupathy, P AF Paredes, Sur Herrera Melgar, Michael F. Sethupathy, Praveen TI Promoter-proximal CCCTC-factor binding is associated with an increase in the transcriptional pausing index SO BIOINFORMATICS LA English DT Article ID HUMAN GENOME; SITES; IDENTIFICATION; EXPRESSION; RELEASE; CELLS AB Motivation: It has been known for more than 2 decades that after RNA polymerase II (RNAPII) initiates transcription, it can enter into a paused or stalled state immediately downstream of the transcription start site before productive elongation. Recent advances in high-throughput genomic technologies facilitated the discovery that RNAPII pausing at promoters is a widespread physiologically regulated phenomenon. The molecular underpinnings of pausing are incompletely understood. The CCCTC-factor (CTCF) is a ubiquitous nuclear factor that has diverse regulatory functions, including a recently discovered role in promoting RNAPII pausing at splice sites. Results: In this study, we analyzed CTCF binding sites and nascent transcriptomic data from three different cell types, and found that promoter-proximal CTCF binding is significantly associated with RNAPII pausing. C1 [Paredes, Sur Herrera] Univ N Carolina, Curriculum Bioinformat & Computat Biol, Chapel Hill, NC 27599 USA. [Paredes, Sur Herrera; Sethupathy, Praveen] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Melgar, Michael F.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Sethupathy, Praveen] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sethupathy, Praveen] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Sethupathy, P (reprint author), Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. EM praveen_sethupathy@med.unc.edu OI Herrera Paredes, Sur/0000-0001-9246-8337 FU National Institutes of Health [DK091318-02] FX This work was supported in part by a National Institutes of Health R00 award (DK091318-02 to P.S). NR 20 TC 10 Z9 10 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2013 VL 29 IS 12 BP 1485 EP 1487 DI 10.1093/bioinformatics/bts596 PG 3 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 159SE UT WOS:000320065400001 PM 23047559 ER PT J AU Hansen, NF Gartner, JJ Mei, L Samuels, Y Mullikin, JC AF Hansen, Nancy F. Gartner, Jared J. Mei, Lan Samuels, Yardena Mullikin, James C. TI Shimmer: detection of genetic alterations in tumors using next-generation sequence data SO BIOINFORMATICS LA English DT Article ID SOMATIC POINT MUTATIONS; HUMAN CANCER; GENOME; DISCOVERY; EVOLUTION; VARIANTS; CATALOG AB Motivation: Extensive DNA sequencing of tumor and matched normal samples using exome and whole-genome sequencing technologies has enabled the discovery of recurrent genetic alterations in cancer cells, but variability in stromal contamination and subclonal heterogeneity still present a severe challenge to available detection algorithms. Results: Here, we describe publicly available software, Shimmer, which accurately detects somatic single-nucleotide variants using statistical hypothesis testing with multiple testing correction. This program produces somatic single-nucleotide variant predictions with significantly higher sensitivity and accuracy than other available software when run on highly contaminated or heterogeneous samples, and it gives comparable sensitivity and accuracy when run on samples of high purity. C1 [Hansen, Nancy F.; Mei, Lan; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Gartner, Jared J.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Hansen, NF (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM nhansen@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 29 TC 13 Z9 13 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2013 VL 29 IS 12 BP 1498 EP 1503 DI 10.1093/bioinformatics/btt183 PG 6 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 159SE UT WOS:000320065400004 PM 23620360 ER PT J AU Barocas, DA Grubb, R Black, A Penson, DF Fowke, JH Andriole, G Crawford, ED AF Barocas, Daniel A. Grubb, Robert, III Black, Amanda Penson, David F. Fowke, Jay H. Andriole, Gerald Crawford, E. David TI Association between race and follow-up diagnostic care after a positive prostate cancer screening test in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial SO CANCER LA English DT Article DE prostate cancer; screening; diagnosis; biopsy; race; health care disparity ID RADICAL PROSTATECTOMY; RACIAL-DIFFERENCES; ANTIGEN; MEN; DISPARITIES; MORTALITY; STAGE; PREVENTION; INSURANCE; BIOPSY AB BACKGROUND Follow-through of a positive screening test is necessary to reap the potential benefits of cancer screening. Racial variation in follow-through diagnostic care may underlie a proportion of the known disparity in prostate cancer mortality. The authors used data from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to determine whether race is associated with the use of follow-up diagnostic testing after a positive initial screening evaluation. METHODS Men who had a prostate-specific antigen (PSA) level >4 ng/mL at any time during the study were included. The proportion of men who underwent follow-up evaluation with a repeat PSA, a prostate biopsy, or either test within 9 months was determined, and the authors tested for differences in follow-through according to race using mixed-effects multivariate models with a random effect for accrual site to account for clustering. Models were stratified according to age (<65 years and 65 years). RESULTS Among 6294 men who had a PSA elevation during the study period, 70% underwent a repeat PSA or prostate biopsy within 9 months. Non-Hispanic black men aged <65 years had 45% lower odds of undergoing a repeat PSA test or prostate biopsy compared with non-Hispanic white men (odds ratio, 0.55; 95% confidence interval, 0.37-0.82), whereas there was no racial difference in follow-through among older men. CONCLUSIONS The current results suggest that limitations in access to care among non-Hispanic black men under the age of Medicare eligibility may underlie the paradoxically low use of follow-through diagnostic care among non-Hispanic black men in the United States. Cancer 2013;119:2223-2229. (c) 2013 American Cancer Society. C1 [Barocas, Daniel A.; Penson, David F.; Fowke, Jay H.] Vanderbilt Univ, Dept Urol Surg, Nashville, TN 37232 USA. [Barocas, Daniel A.; Penson, David F.] Vanderbilt Univ, Ctr Surg Qual & Outcomes Res, Nashville, TN 37232 USA. [Grubb, Robert, III; Andriole, Gerald] Washington Univ, Div Urol Surg, St Louis, MO USA. [Black, Amanda] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Penson, David F.] Tennessee Valley Vet Adm Hlth Syst, Nashville, TN USA. [Fowke, Jay H.] Vanderbilt Univ, Div Epidemiol, Nashville, TN 37232 USA. [Crawford, E. David] Univ Colorado, Div Urol, Aurora, CO USA. RP Barocas, DA (reprint author), Vanderbilt Univ, Med Ctr, Med Ctr North A 1302, Nashville, TN 37232 USA. EM dan.barocas@vanderbilt.edu FU Division of Cancer Prevention, National Cancer Institute; National Institutes of Health, Department of Health and Human Services FX This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, and National Institutes of Health, Department of Health and Human Services. NR 34 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2013 VL 119 IS 12 BP 2223 EP 2229 DI 10.1002/cncr.28042 PG 7 WC Oncology SC Oncology GA 157CA UT WOS:000319871800007 PM 23559420 ER PT J AU Kurdgelashvili, G Dores, GM Srour, SA Chaturvedi, AK Huycke, MM Devesa, SS AF Kurdgelashvili, George Dores, Graca M. Srour, Samer A. Chaturvedi, Anil K. Huycke, Mark M. Devesa, Susan S. TI Incidence of potentially human papillomavirus-related neoplasms in the United States, 1978 to 2007 SO CANCER LA English DT Article DE human papillomavirus-associated neoplasms; preinvasive tumors; cancer incidence; epidemiology; squamous cell neoplasms ID ANAL INTRAEPITHELIAL NEOPLASIA; CANCER INCIDENCE; INCIDENCE TRENDS; INCIDENCE RATES; PENILE CANCER; MEN; INFECTION; VACCINE; LESIONS; BURDEN AB BACKGROUND Population-based studies comprehensively describing incidence patterns of human papillomavirus (HPV)-related preinvasive and invasive neoplasms prior to widespread HPV vaccination are sparse. METHODS Age-adjusted incidence rates (IRs), IR ratios (IRRs), and annual percent changes (APCs) in IRs were calculated for potentially HPV-related tumors diagnosed in the Surveillance, Epidemiology and End Results (SEER) Program during 1978 through 2007. RESULTS Overall IRs for preinvasive tumors were significantly higher than for invasive squamous cell tumors of cervix (IRR=3.42), vulva (IRR=1.87), and vagina (IRR=1.19) and significantly lower for adenomatous cervical tumors (IRR=0.43), and squamous cell tumors of penis (IRR=0.64), anus (males, IRR=0.53; females, IRR=0.14), and head and neck (H&N) (males, IRR=0.01; females, IRR=0.02). Incidence of preinvasive squamous tumors of cervix, vagina, and penis rose rapidly over time and decreased for invasive neoplasms. The most rapid increases occurred for preinvasive (males, APC=16.0; females, APC=7.3) and invasive anal tumors (males, APC=3.6; females, APC=2.3). IR patterns were generally similar among evaluable racial/ethnic groups, with the exception of H&N invasive tumor IRs which increased exclusively among white males. CONCLUSIONS Contrary to the opposing trends of preinvasive and invasive squamous tumors of cervix, vagina, and penis, preinvasive and invasive anal tumor IRs increased significantly over time by sex, age, and racial/ethnic groups. Successful HPV vaccination programs are needed to measurably reduce incidence of HPV-related neoplasms in the future, particularly for cancer sites with rising incidence rates for which effective screening modalities are limited. Cancer 2013;119:2291-2299. (c) 2013 American Cancer Society. C1 [Kurdgelashvili, George; Dores, Graca M.; Srour, Samer A.; Huycke, Mark M.] Dept Vet Affairs Med Ctr, Oklahoma City, OK 73104 USA. [Kurdgelashvili, George; Srour, Samer A.; Huycke, Mark M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Dores, Graca M.; Chaturvedi, Anil K.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kurdgelashvili, G (reprint author), Dept Vet Affairs Med Ctr, 921 NE 13th St,111 C, Oklahoma City, OK 73104 USA. EM george.kurdgelashvili@va.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Department of Veterans Affairs Medical Center; Frances Duffy Endowment, Oklahoma City, Okla; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services in Bethesda, Md FX This work was supported by the Department of Veterans Affairs Medical Center and the Frances Duffy Endowment, Oklahoma City, Okla; and the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services in Bethesda, Md. NR 34 TC 20 Z9 20 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2013 VL 119 IS 12 BP 2291 EP 2299 DI 10.1002/cncr.27989 PG 9 WC Oncology SC Oncology GA 157CA UT WOS:000319871800015 PM 23580435 ER PT J AU Hall, EC Pfeiffer, RM Segev, DL Engels, EA AF Hall, Erin C. Pfeiffer, Ruth M. Segev, Dorry L. Engels, Eric A. TI Cumulative incidence of cancer after solid organ transplantation SO CANCER LA English DT Article DE transplantation; screening; non-Hodgkin lymphoma; absolute risk ID FORCE RECOMMENDATION STATEMENT; EPSTEIN-BARR-VIRUS; LUNG TRANSPLANTATION; SKIN-CANCER; BRONCHOGENIC-CARCINOMA; COLORECTAL-CANCER; COMPETING RISK; UNITED-STATES; RECIPIENTS; KIDNEY AB BACKGROUND Solid organ transplantation recipients have elevated cancer incidence. Estimates of absolute cancer risk after transplantation can inform prevention and screening. METHODS The Transplant Cancer Match Study links the US transplantation registry with 14 state/regional cancer registries. The authors used nonparametric competing risk methods to estimate the cumulative incidence of cancer after transplantation for 2 periods (1987-1999 and 2000-2008). For recipients from 2000 to 2008, the 5-year cumulative incidence, stratified by organ, sex, and age at transplantation, was estimated for 6 preventable or screen-detectable cancers. For comparison, the 5-year cumulative incidence was calculated for the same cancers in the general population at representative ages using Surveillance, Epidemiology, and End Results data. RESULTS Among 164,156 recipients, 8520 incident cancers were identified. The absolute cancer risk was slightly higher for recipients during the period from 2000 to 2008 than during the period from 1987 to 1999 (5-year cumulative incidence: 4.4% vs 4.2%; P=.006); this difference arose from the decreasing risk of competing events (5-year cumulative incidence of death, graft failure, or retransplantation: 26.6% vs 31.9%; P<.001). From 2000 to 2008, the 5-year cumulative incidence of non-Hodgkin lymphoma was highest at extremes of age, especially in thoracic organ recipients (ages 0-34 years: range, 1.74%-3.28%; aged >50 years; range, 0.36%-2.22%). For recipients aged >50 years, the 5-year cumulative incidence was higher for colorectal cancer (range, 0.33%-1.94%) than for the general population at the recommended screening age (aged 50 years: range, 0.25%-0.33%). For recipients aged >50 years, the 5-year cumulative incidence was high for lung cancer among thoracic organ recipients (range, 1.16%-3.87%) and for kidney cancer among kidney recipients (range, 0.53%-0.84%). The 5-year cumulative incidence for prostate cancer and breast cancer was similar or lower in transplantation recipients than at the recommended ages of screening in the general population. CONCLUSIONS Subgroups of transplantation recipients have a high absolute risk of some cancers and may benefit from targeted prevention or screening. Cancer 2013;119:2300-2308. (c) 2013 American Cancer Society. C1 [Hall, Erin C.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Hall, Erin C.; Segev, Dorry L.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7076, Rockville, MD 20852 USA. EM engelse@exchange.nih.gov FU National Cancer Institute; Centers for Disease Control and Prevention: California [1U58 DP000807-01]; Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; Centers for Disease Control and Prevention: Georgia [5U58DP000817-05]; Centers for Disease Control and Prevention: Illinois [5658DP 000805-04]; Centers for Disease Control and Prevention: Michigan [5U58DP000812-03]; Centers for Disease Control and Prevention: New Jersey [5U58/DP000808-05]; Centers for Disease Control and Prevention: New York [15-0351]; Centers for Disease Control and Prevention: North Carolina [U58DP000832]; Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; National Cancer Institute: California [HHSN 261201000036C, HHSN261201000035C, HHSN261201 000034C]; National Cancer Institute: Connecticut [HHSN261201000024C]; National Cancer Institute: Hawaii [HH SN261201000037C, N01-PC-137, N01-PC-35, N01-PC-139]; National Cancer Institute: Iowa [N01-PC-35, N01-PC-143]; National Cancer Institute: New Jersey [HHSN261201000027C N01-PC-2012-00,027]; National Cancer Institute: Seattle-Puget Sound [N01-PC-35, N01-PC-142]; National Cancer Institute: Utah [HHSN261201000026C]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative) [14-2491]; state of Texas; state of Washington; Fred Hutchinson Cancer Research Center in Seattle, Washington; [T32CA126607]; [HHSH234200537009C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute (E. A. Engels) and by training grant T32CA126607 (Clinical and Laboratory Research Training for Surgical Oncologists; to E. C. Hall). During the initial period when registry linkages were performed, the Scientific Registry of Transplant Recipients (SRTR) was managed by Arbor Research Collaborative for Health in Ann Arbor, Michigan (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, Minnesota (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP 000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (15-0351), North Carolina (U58DP000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN 261201000036C, HHSN261201000035C, and HHSN261201 000034C), Connecticut (HHSN261201000024C), Hawaii (HH SN261201000037C, N01-PC-35,137, and N01-PC-35,139), Iowa (N01-PC-35,143), New Jersey (HHSN261201000027C N01-PC-2012-00,027), Seattle-Puget Sound (N01-PC-35,142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, Washington. NR 34 TC 32 Z9 33 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2013 VL 119 IS 12 BP 2300 EP 2308 DI 10.1002/cncr.28043 PG 9 WC Oncology SC Oncology GA 157CA UT WOS:000319871800016 PM 23559438 ER PT J AU Kote-Jarai, Z Saunders, EJ Leongamornlert, DA Tymrakiewicz, M Dadaev, T Jugurnauth-Little, S Ross-Adams, H Al Olama, AA Benlloch, S Halim, S Russel, R Dunning, AM Luccarini, C Dennis, J Neal, DE Hamdy, FC Donovan, JL Muir, K Giles, GG Severi, G Wiklund, F Gronberg, H Haiman, CA Schumacher, F Henderson, BE Le Marchand, L Lindstrom, S Kraft, P Hunter, DJ Gapstur, S Chanock, S Berndt, SI Albanes, D Andriole, G Schleutker, J Weischer, M Canzian, F Riboli, E Key, TJ Travis, RC Campa, D Ingles, SA John, EM Hayes, RB Pharoah, P Khaw, KT Stanford, JL Ostrander, EA Signorello, LB Thibodeau, SN Schaid, D Maier, C Vogel, W Kibel, AS Cybulski, C Lubinski, J Cannon-Albright, L Brenner, H Park, JY Kaneva, R Batra, J Spurdle, A Clements, JA Teixeira, MR Govindasami, K Guy, M Wilkinson, RA Sawyer, EJ Morgan, A Dicks, E Baynes, C Conroy, D Bojesen, SE Kaaks, R Vincent, D Bacot, F Tessier, DC Easton, DF Eeles, RA AF Kote-Jarai, Zsofia Saunders, Edward J. Leongamornlert, Daniel A. Tymrakiewicz, Malgorzata Dadaev, Tokhir Jugurnauth-Little, Sarah Ross-Adams, Helen Al Olama, Ali Amin Benlloch, Sara Halim, Silvia Russel, Roslin Dunning, Alison M. Luccarini, Craig Dennis, Joe Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Ken Giles, Graham G. Severi, Gianluca Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Le Marchand, Loic Lindstrom, Sara Kraft, Peter Hunter, David J. Gapstur, Susan Chanock, Stephen Berndt, Sonja I. Albanes, Demetrius Andriole, Gerald Schleutker, Johanna Weischer, Maren Canzian, Federico Riboli, Elio Key, Tim J. Travis, Ruth C. Campa, Daniele Ingles, Sue A. John, Esther M. Hayes, Richard B. Pharoah, Paul Khaw, Kay-Tee Stanford, Janet L. Ostrander, Elaine A. Signorello, Lisa B. Thibodeau, Stephen N. Schaid, Dan Maier, Christiane Vogel, Walther Kibel, Adam S. Cybulski, Cezary Lubinski, Jan Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y. Kaneva, Radka Batra, Jyotsna Spurdle, Amanda Clements, Judith A. Teixeira, Manuel R. Govindasami, Koveela Guy, Michelle Wilkinson, Rosemary A. Sawyer, Emma J. Morgan, Angela Dicks, Ed Baynes, Caroline Conroy, Don Bojesen, Stig E. Kaaks, Rudolf Vincent, Daniel Bacot, Francois Tessier, Daniel C. Easton, Douglas F. Eeles, Rosalind A. CA COGS-CRUK GWAS-ELLIPSE Part UK Genetic Prostate Canc UK ProtecT Study Collaborators PRACTICAL Consortium TI Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression SO HUMAN MOLECULAR GENETICS LA English DT Article ID TELOMERE LENGTH; TERT-CLPTM1L LOCUS; WIDE ASSOCIATION; BREAST-CANCER; LUNG-CANCER; VARIANTS; HTERT; PROMOTER AB Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease. C1 [Kote-Jarai, Zsofia; Saunders, Edward J.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Jugurnauth-Little, Sarah; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A.; Sawyer, Emma J.; Morgan, Angela; Eeles, Rosalind A.] Inst Canc Res, Oncogenet Team, Sutton SM2 5NG, Surrey, England. [Ross-Adams, Helen; Halim, Silvia; Russel, Roslin] Cambridge Res Inst, Li Ka Shing Ctr, Canc Res UK, Cambridge CB2 0RE, England. [Al Olama, Ali Amin; Benlloch, Sara; Dunning, Alison M.; Luccarini, Craig; Dennis, Joe; Pharoah, Paul; Dicks, Ed; Baynes, Caroline; Conroy, Don; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Lab, Cambridge CB1 8RN, England. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Surg Oncol Uro Oncol S4, Cambridge CB2 2QQ, England. [Neal, David E.] Cambridge Res Inst, Li Ka Shing Ctr, Canc Res UK, Cambridge CB2 2QQ, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, Fac Med Sci, John Radcliffe Hosp, Oxford OX3 9DU, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PS, Avon, England. [Muir, Ken] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Ingles, Sue A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lindstrom, Sara; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Gapstur, Susan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Chanock, Stephen; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Schleutker, Johanna; Campa, Daniele] Univ Turku, Dept Medic Biochem & Genet, Inst Biomed Technol, Turku, Finland. [Schleutker, Johanna; Campa, Daniele] Univ Tampere, BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna; Campa, Daniele] FimLab Labs, Tampere, Finland. [Weischer, Maren; Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-230 Herlev, Denmark. [Canzian, Federico; Kaaks, Rudolf] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Key, Tim J.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Travis, Ruth C.; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Travis, Ruth C.; John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Hayes, Richard B.] NYU, Inst Canc, Langone Med Ctr, Div Epidemiol,Dept Environm Med, New York, NY USA. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Stanford, Janet L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Signorello, Lisa B.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Thibodeau, Stephen N.; Schaid, Dan] Mayo Clin, Rochester, MN USA. [Maier, Christiane; Vogel, Walther] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane; Vogel, Walther] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02245 USA. [Cybulski, Cezary; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Div Genet Epidemiol, Dept Med, Salt Lake City, UT 84132 USA. [Cannon-Albright, Lisa] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Park, Jong Y.] Univ S Florida, H Lee Moffitt Canc Ctr, Div Canc Prevent & Control, Tampa, FL 33682 USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, Sofia 1531, Bulgaria. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, Sofia 1531, Bulgaria. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Australian Prostate Canc Res Ctr Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Spurdle, Amanda] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, P-4100 Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] Ctr Innovat Genome Quebec, Montreal, PQ H3A 0G1, Canada. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] McGill Univ, Montreal, PQ H3A 0G1, Canada. RP Kote-Jarai, Z (reprint author), Inst Canc Res, Oncogenet Team, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM zsofia.kote-jarai@icr.ac.uk RI Batra, Jyotsna/B-4130-2011; Spurdle, Amanda/A-4978-2011; Albanes, Demetrius/B-9749-2015; Teixeira, Manuel/E-4885-2011; Campa, Daniele/K-1617-2016; Brenner, Hermann/B-4627-2017; OI Leongamornlert, Daniel/0000-0002-3486-3168; Hayes, Richard/0000-0002-0918-661X; albright, lisa/0000-0003-2602-3668; Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; Ostrander, Elaine/0000-0001-6075-9738; Saunders, Ed/0000-0003-4343-3570; Eeles, Rosalind/0000-0002-3698-6241; Spurdle, Amanda/0000-0003-1337-7897; Dennis, Joe/0000-0003-4591-1214; Neal, David/0000-0002-6033-5086; Teixeira, Manuel/0000-0002-4896-5982; Campa, Daniele/0000-0003-3220-9944; Brenner, Hermann/0000-0002-6129-1572; Dadaev, Tokhir/0000-0002-8268-0438 FU European Commission [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135]; National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative [1 U19 CA 148537-01]; Institute of Cancer Research and The Everyman Campaign; Prostate Action; Orchid Cancer Appeal; National Cancer Research Network, UK; National Cancer Research Institute (NCRI), UK; NIHR; Royal Marsden NHS Foundation Trust FX This work was supported by European Commission's Seventh Framework Programme grant agreement No. 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). We would like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation (now Prostate Action), Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network, UK and The National Cancer Research Institute (NCRI), UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Funding to pay the Open Access publication charges for this article was provided by European Commission's Seventh Framework Programme grant agreement No. 223175 (HEALTH-F2-2009-223175). NR 25 TC 58 Z9 59 U1 2 U2 26 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 JUN 15 PY 2013 VL 22 IS 12 BP 2520 EP 2528 DI 10.1093/hmg/ddt086 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 151AK UT WOS:000319432800017 PM 23535824 ER PT J AU Chen, Z Tang, H Qayyum, R Schick, UM Nalls, MA Handsaker, R Li, J Lu, YC Yanek, LR Keating, B Meng, Y van Rooij, FJA Okada, Y Kubo, M Rasmussen-Torvik, L Keller, MF Lange, L Evans, M Bottinger, EP Linderman, MD Ruderfer, DM Hakonarson, H Papanicolaou, G Zonderman, AB Gottesman, O Thomson, C Ziv, E Singleton, AB Loos, RJF Sleiman, PMA Ganesh, S McCarroll, S Becker, DM Wilson, JG Lettre, G Reiner, AP AF Chen, Zhao Tang, Hua Qayyum, Rehan Schick, Ursula M. Nalls, Michael A. Handsaker, Robert Li, Jin Lu, Yingchang Yanek, Lisa R. Keating, Brendan Meng, Yan van Rooij, Frank J. A. Okada, Yukinori Kubo, Michiaki Rasmussen-Torvik, Laura Keller, Margaux F. Lange, Leslie Evans, Michele Bottinger, Erwin P. Linderman, Michael D. Ruderfer, Douglas M. Hakonarson, Hakon Papanicolaou, George Zonderman, Alan B. Gottesman, Omri Thomson, Cynthia Ziv, Elad Singleton, Andrew B. Loos, Ruth J. F. Sleiman, Patrick M. A. Ganesh, Santhi McCarroll, Steven Becker, Diane M. Wilson, James G. Lettre, Guillaume Reiner, Alexander P. CA BioBank Japan Project CHARGE Consortium TI Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network SO HUMAN MOLECULAR GENETICS LA English DT Article ID ERYTHROID PROGENITORS; ALPHA-THALASSEMIA; HEMOGLOBIN LEVELS; IRON-DEFICIENCY; DIFFERENTIATION; GENE; HEMOCHROMATOSIS; INDIVIDUALS; CONSORTIUM; EXPRESSION AB Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to 16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P 1E13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P 1E 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs. C1 [Chen, Zhao] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ 85724 USA. [Thomson, Cynthia] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Div Nutr, Tucson, AZ 85724 USA. [Tang, Hua] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Tang, Hua] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Qayyum, Rehan; Becker, Diane M.] Johns Hopkins Sch Med, Div Gen Internal Med, GeneSTAR Res Program, Baltimore, MD 21287 USA. [Schick, Ursula M.; Reiner, Alexander P.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Handsaker, Robert] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02141 USA. [Li, Jin; Hakonarson, Hakon; Sleiman, Patrick M. A.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Hakonarson, Hakon; Sleiman, Patrick M. A.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Lu, Yingchang] Mt Sinai Sch Med, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Bottinger, Erwin P.; Gottesman, Omri] Mt Sinai Sch Med, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Linderman, Michael D.] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Ruderfer, Douglas M.] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Loos, Ruth J. F.] Mt Sinai Sch Med, Genet Obes & Related Metab Traits Program, Inst Child Hlth & Dev, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Yanek, Lisa R.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Keating, Brendan] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Hakonarson, Hakon; Sleiman, Patrick M. A.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Meng, Yan; Okada, Yukinori] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [van Rooij, Frank J. A.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Okada, Yukinori] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Okada, Yukinori] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Kubo, Michiaki] RIKEN, CGM, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Rasmussen-Torvik, Laura] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Keller, Margaux F.; Singleton, Andrew B.] Univ N Carolina, Neurogenet Lab, Chapel Hill, NC 27599 USA. [Lange, Leslie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Evans, Michele] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Papanicolaou, George] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Ziv, Elad] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Ganesh, Santhi] Univ Michigan Hlth Syst, Div Cardiol, Ann Arbor, MI 48109 USA. [McCarroll, Steven] Harvard Univ, Sch Med, Dept Genet, Cambridge, MA 02138 USA. [McCarroll, Steven] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Reiner, AP (reprint author), 1100 N Fairview Ave N M3-A410, Seattle, WA USA. EM apreiner@u.washington.edu RI Singleton, Andrew/C-3010-2009; Ziv, Elad/L-5396-2014; Kubo, Michiaki/N-7947-2015; Ruderfer, Douglas/M-5795-2016; OI Ruderfer, Douglas/0000-0002-2365-386X; Qayyum, Rehan/0000-0003-3086-8014; Zonderman, Alan B/0000-0002-6523-4778 FU NIH [R01 HL71862-06, ARRA N000949304]; US Public Health Service Resource Grant from the National Center for Research Resources [RR03655]; National Cancer Institute [R25CA094880] FX Additional support for this work was provided by NIH (R01 HL71862-06 and ARRA N000949304 to A. P. R.). Some of the results of this paper were obtained by using the program package S. A. G. E., which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Additional support came from the National Cancer Institute (grant R25CA094880 to U.M.S.). NR 35 TC 13 Z9 14 U1 2 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2013 VL 22 IS 12 BP 2529 EP 2538 DI 10.1093/hmg/ddt087 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 151AK UT WOS:000319432800018 PM 23446634 ER PT J AU Zheng, W Zhang, B Cai, QY Sung, H Michailidou, K Shi, JJ Choi, JY Long, JR Dennis, J Humphreys, MK Wang, Q Lu, W Gao, YT Li, C Cai, H Park, SK Yoo, KY Noh, DY Han, W Dunning, AM Benitez, J Vincent, D Bacot, F Tessier, D Kim, SW Lee, MH Lee, JW Lee, JY Xiang, YB Zheng, Y Wang, WJ Ji, BT Matsuo, K Ito, H Iwata, H Tanaka, H Wu, AH Tseng, CC Van den Berg, D Stram, DO Teo, SH Yip, CH Kang, IN Wong, TY Shen, CY Yu, JC Huang, CS Hou, MF Hartman, M Miao, H Lee, SC Putti, TC Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Sangrajrang, S Shen, HB Chen, KX Wu, PE Ren, ZF Haiman, CA Sueta, A Kim, MK Khoo, US Iwasaki, M Pharoah, PDP Wen, WQ Hall, P Shu, XO Easton, DF Kang, D AF Zheng, Wei Zhang, Ben Cai, Qiuyin Sung, Hyuna Michailidou, Kyriaki Shi, Jiajun Choi, Ji-Yeob Long, Jirong Dennis, Joe Humphreys, Manjeet K. Wang, Qin Lu, Wei Gao, Yu-Tang Li, Chun Cai, Hui Park, Sue K. Yoo, Keun-Young Noh, Dong-Young Han, Wonshik Dunning, Alison M. Benitez, Javier Vincent, Daniel Bacot, Francois Tessier, Daniel Kim, Sung-Won Lee, Min Hyuk Lee, Jong Won Lee, Jong-Young Xiang, Yong-Bing Zheng, Ying Wang, Wenjin Ji, Bu-Tian Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tanaka, Hideo Wu, Anna H. Tseng, Chiu-chen Van den Berg, David Stram, Daniel O. Teo, Soo Hwang Yip, Cheng Har Kang, In Nee Wong, Tien Y. Shen, Chen-Yang Yu, Jyh-Cherng Huang, Chiun-Sheng Hou, Ming-Feng Hartman, Mikael Miao, Hui Lee, Soo Chin Putti, Thomas Choudary Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Sangrajrang, Suleeporn Shen, Hongbing Chen, Kexin Wu, Pei-Ei Ren, Zefang Haiman, Christopher A. Sueta, Aiko Kim, Mi Kyung Khoo, Ui Soon Iwasaki, Motoki Pharoah, Paul D. P. Wen, Wanqing Hall, Per Shu, Xiao-Ou Easton, Douglas F. Kang, Daehee TI Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BASE-LINE CHARACTERISTICS; SUSCEPTIBILITY LOCI; CHINESE WOMEN; CONFER SUSCEPTIBILITY; STROBE STATEMENT; VARIANTS; POLYMORPHISMS; METAANALYSIS; ANCESTRY AB In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of 0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain 10 of excess familial risk of breast cancer in Asian populations. C1 [Zheng, Wei; Zhang, Ben; Cai, Qiuyin; Shi, Jiajun; Long, Jirong; Cai, Hui; Wen, Wanqing; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr,Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. [Sung, Hyuna; Choi, Ji-Yeob; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Han, Wonshik; Kang, Daehee] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Park, Sue K.; Yoo, Keun-Young; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Noh, Dong-Young; Han, Wonshik] Seoul Natl Univ, Coll Med, Dept Surg, Seoul, South Korea. [Michailidou, Kyriaki; Dennis, Joe; Humphreys, Manjeet K.; Wang, Qin; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Dunning, Alison M.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Lu, Wei; Zheng, Ying; Wang, Wenjin] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel] McGill Univ, Montreal, PQ, Canada. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Kim, Sung-Won] Seoul Natl Univ, Coll Med, Bundang Hosp, Dept Surg, Songnam, South Korea. [Lee, Min Hyuk] Soon Chunh Yang Univ Hosp, Dept Surg, Seoul, South Korea. [Lee, Jong Won] Univ Ulsan, Coll Med, Dept Surg, Seoul, South Korea. [Lee, Jong Won] Asan Med Ctr, Seoul, South Korea. [Lee, Jong-Young] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Matsuo, Keitaro; Ito, Hidemi; Tanaka, Hideo; Sueta, Aiko] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Iwata, Hiroji] Aichi Canc Ctr Cent Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Wu, Anna H.; Tseng, Chiu-chen; Van den Berg, David; Stram, Daniel O.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Teo, Soo Hwang; Kang, In Nee] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Canc Res Inst, Med Ctr, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Hartman, Mikael] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Lee, Soo Chin] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Putti, Thomas Choudary] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pathol, Singapore 117595, Singapore. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Huang, Chiun-Sheng] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Lee, Soo Chin] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Nonthaburi, Thailand. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Shen, Hongbing] Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Chen, Kexin] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin, Peoples R China. [Wu, Pei-Ei] Taiwan Biobank, Inst Biomed Sci, Taipei, Taiwan. [Wu, Pei-Ei] China Med Univ, Coll Publ Hlth, Taichung, Taiwan. [Ren, Zefang] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou 510275, Guangdong, Peoples R China. [Khoo, Ui Soon] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Iwasaki, Motoki] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Div, Tokyo 104, Japan. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Tanaka, Hideo/A-8145-2016; Han, Wonshik/B-3699-2008; Khoo, Ui Soon/C-1345-2014; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Noh, Dong-Young/G-5531-2011; Yip, Cheng-Har/B-1909-2010 OI Huang, Chiun-Sheng/0000-0002-6557-211X; Khoo, Ui Soon/0000-0003-2200-7505; Dennis, Joe/0000-0003-4591-1214; Dunning, Alison Margaret/0000-0001-6651-7166; Matsuo, Keitaro/0000-0003-1761-6314; FU US NIH [R01CA124558, R01CA148667, R01CA64277, R37CA070867, U19 CA148065, R01CA118229, R01CA0 92585, R01CA122756, R01 CA137013, R01CA63464, R01CA54281, CA132839]; Ingram Professorship funds; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A10710]; European Community [223175 (HEALTH-F2-2009-223175)]; European Union COST program [BM0606]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; Vanderbilt-Ingram Cancer Center [P30 CA68485]; US Department of Defense Breast Cancer Research Program [BC011118, BC050791]; National Research Foundation; Ministry of Education, Science and Technology; National Biobank of Korea and National R&D Program of the Republic of Korea [2011-0001564, 1020350, 0620410-1, 2012-0000347, KOBB-2011-03]; National Natural Science Foundation of China [09KJA330001, 30771844, 81072383]; Taiwan Biobank [DOH97-01]; Hong Kong Research Grant Council [7520/05M, 76730M]; Japanese Ministry of Health, Labor and Welfare and Ministry of Education [17015049, 221S0001, 17015052, H20-002]; Marit and Hans Rausings Initiative Against Breast Cancer; Cancer Risk Prediction Center, a Linneus Centre [70867902]; Swedish Research Council FX The work for this project at Vanderbilt was supported primarily by US NIH grants R01CA124558, R01CA148667, R01CA64277, R37CA070867 and U19 CA148065, as well as Ingram Professorship funds. The BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). BCAC meetings have been funded by the European Union COST program (BM0606). Genotyping of the COGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program (J.S. and D. F. E.) and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701) (J.S., D. F. E. and P. H). Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by Vanderbilt-Ingram Cancer Center (P30 CA68485). Funding for the constituent studies was provided by US NIH grants (R01CA124558, R01CA148667, R01CA64277, R37CA070867, R01CA118229, R01CA0 92585, R01CA122756, R01 CA137013, R01CA63464, R01CA54281 and CA132839), US Department of Defense Breast Cancer Research Program (BC011118 and BC050791), National Research Foundation, Ministry of Education, Science and Technology, National Biobank of Korea and National R&D Program of the Republic of Korea (2011-0001564, 1020350, 0620410-1, 2012-0000347 and KOBB-2011-03), National Natural Science Foundation of China (09KJA330001, 30771844 and 81072383), Taiwan Biobank (DOH97-01), Hong Kong Research Grant Council (7520/05M and 76730M) and the Japanese Ministry of Health, Labor and Welfare and Ministry of Education (17015049, 221S0001, 17015052 and H20-002). The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer and Cancer Risk Prediction Center, a Linneus Centre (contract 70867902) financed by the Swedish Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The sponsors of this study had no role in study design, data collection, data analyses, data interpretation or writing the final report. The corresponding author had full access to all the data used in this study and had final responsibility for the decision to submit for publication. NR 46 TC 35 Z9 36 U1 1 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2013 VL 22 IS 12 BP 2539 EP 2550 DI 10.1093/hmg/ddt089 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 151AK UT WOS:000319432800019 PM 23535825 ER PT J AU Williamson, PR AF Williamson, Peter R. TI Advancing Translational Immunology in HIV-Associated Cryptococcal Meningitis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE Cryptococcus neoformans; immunology; fungus; HIV; AIDS; meningitis; Africa ID MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; HUMAN-IMMUNODEFICIENCY-VIRUS; EARLY FUNGICIDAL ACTIVITY; CELL-MEDIATED-IMMUNITY; ANTIRETROVIRAL THERAPY; NEOFORMANS INFECTION; AMPHOTERICIN-B; TUBERCULOSIS; TRIAL; FLUCYTOSINE C1 [Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Williamson, Peter R.] Univ Illinois, Chicago Coll Med, Dept Med, Infect Dis Sect, Chicago, IL 60680 USA. RP Williamson, PR (reprint author), 9000 Rockville Pike,Bldg 10,Rm 11N222,MSC 1888, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU Intramural NIH HHS NR 29 TC 0 Z9 0 U1 0 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 JUN 15 PY 2013 VL 207 IS 12 BP 1793 EP 1795 DI 10.1093/infdis/jit102 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200003 PM 23493727 ER PT J AU Jarvis, JN Casazza, JP Stone, HH Meintjes, G Lawn, SD Levitz, SM Harrison, TS Koup, RA AF Jarvis, Joseph N. Casazza, Joseph P. Stone, Hunter H. Meintjes, Graeme Lawn, Stephen D. Levitz, Stuart M. Harrison, Thomas S. Koup, Richard A. TI The Phenotype of the Cryptococcus-Specific CD4(+) Memory T-Cell Response Is Associated With Disease Severity and Outcome in HIV-Associated Cryptococcal Meningitis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; cryptococcus neoformans; TB; CMV; memory T cells; flow cytometry ID PROTECTIVE TH1 RESPONSE; NECROSIS-FACTOR-ALPHA; NEOFORMANS INFECTION; INTERFERON-GAMMA; PULMONARY CRYPTOCOCCOSIS; IFN-GAMMA; VIRULENCE FACTORS; IMMUNE-RESPONSES; AFFERENT PHASE; MICE AB Background. Correlates of immune protection in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis are poorly defined. A clearer understanding of these immune responses is essential to inform rational development of immunotherapies. Methods. Cryptococcal-specific peripheral CD4(+) T-cell responses were measured in 44 patients with HIV-associated cryptococcal meningitis at baseline and during follow-up. Responses were assessed following ex vivo cryptococcal mannoprotein stimulation, using 13-color flow-cytometry. The relationships between cryptococcal-specific CD4(+) T-cell responses, clinical parameters at presentation, and outcome were investigated. Results. Cryptococcal-specific CD4(+) T-cell responses were characterized by the production of macrophage inflammatory protein 1 alpha, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Conversely, minimal interleukin 4 and interleukin 17 production was detected. Patients surviving to 2 weeks had significantly different functional CD4(+) T-cell responses as compared to those who died. Patients with a response predominantly consisting of IFN-gamma or TNF-alpha production had a 2-week mortality of 0% (0/20), compared with 25% (6/24) in those without this response (P = .025). Such patients also had lower fungal burdens (10 400 vs 390 000 colony-forming units/mL; P < .001), higher cerebrospinal fluid lymphocyte counts (122 vs 8 cells/mu L; P < .001), and a trend toward faster rates of clearance of infection. Conclusions. The phenotype of the peripheral CD4(+) T-cell response to Cryptococcus was associated with disease severity and outcome in HIV-associated cryptococcal meningitis. IFN-gamma/TNF-alpha-predominant responses were associated with survival. C1 [Jarvis, Joseph N.; Harrison, Thomas S.] St Georges Univ London, Div Clin Sci, Res Ctr Infect & Immun, London, England. [Jarvis, Joseph N.; Lawn, Stephen D.] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London WC1E 7HT, England. Univ London Imperial Coll Sci Technol & Med, Dept Med, London SW7 2AZ, England. [Jarvis, Joseph N.] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa. [Jarvis, Joseph N.; Meintjes, Graeme] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7700 Rondebosch, South Africa. [Meintjes, Graeme] Univ Cape Town, Dept Med, ZA-7700 Rondebosch, South Africa. [Casazza, Joseph P.; Stone, Hunter H.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Levitz, Stuart M.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. RP Jarvis, JN (reprint author), Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, Keppel St, London WC1E 7HT, England. EM joejarvis@doctors.net.uk OI Jarvis, Joseph/0000-0003-1459-5554 FU Wellcome Trust [WT081794, 088590]; National Institutes of Health [RO1 AI025780]; Intramural Research Program of the Vaccine Research Center, National Institutes of Allergy and Infectious Disease, National Institutes of Health FX This work was supported by the Wellcome Trust (training fellowship WT081794 to J. N. J.) and the National Institutes of Health (grant RO1 AI025780 to S. M. L.). Flow cytometry was supported by funding from the Intramural Research Program of the Vaccine Research Center, National Institutes of Allergy and Infectious Disease, National Institutes of Health. S. D. L. is funded by the Wellcome Trust (grant 088590). NR 50 TC 32 Z9 36 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2013 VL 207 IS 12 BP 1817 EP 1828 DI 10.1093/infdis/jit099 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200007 PM 23493728 ER PT J AU Casazza, JP Bowman, KA Adzaku, S Smith, EC Enama, ME Bailer, RT Price, DA Gostick, E Gordon, IJ Ambrozak, DR Nason, MC Roederer, M Andrews, CA Maldarelli, FM Wiegand, A Kearney, MF Persaud, D Ziemniak, C Gottardo, R Ledgerwood, JE Graham, BS Koup, RA AF Casazza, Joseph P. Bowman, Kathryn A. Adzaku, Selorm Smith, Emily C. Enama, Mary E. Bailer, Robert T. Price, David A. Gostick, Emma Gordon, Ingelise J. Ambrozak, David R. Nason, Martha C. Roederer, Mario Andrews, Charla A. Maldarelli, Frank M. Wiegand, Ann Kearney, Mary F. Persaud, Deborah Ziemniak, Carrie Gottardo, Raphael Ledgerwood, Julie E. Graham, Barney S. Koup, Richard A. CA VRC 101 Study Team TI Therapeutic Vaccination Expands and Improves the Function of the HIV-Specific Memory T-Cell Repertoire SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; vaccination; therapy; cytotoxic T lymphocytes; humoral immunity; viral latency ID ACTIVE ANTIRETROVIRAL THERAPY; DNA CANDIDATE VACCINE; VIRAL REPLICATION; IMMUNOGENICITY EVALUATION; PHASE-1 SAFETY; INFECTION; IMMUNIZATION; RESPONSES; VIREMIA; INTERRUPTION AB Background. The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. Methods. In this double-blind study, 17 HIV-infected individuals with viral loads of < 50 copies/mL and CD4(+) T-cell counts of > 350 cells/mu L were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. Results. Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. Conclusions. Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. Clinical Trials Registration. NCT00270465. C1 [Casazza, Joseph P.; Bowman, Kathryn A.; Adzaku, Selorm; Smith, Emily C.; Enama, Mary E.; Bailer, Robert T.; Price, David A.; Gordon, Ingelise J.; Ambrozak, David R.; Roederer, Mario; Andrews, Charla A.; Ledgerwood, Julie E.; Graham, Barney S.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Maldarelli, Frank M.; Wiegand, Ann; Kearney, Mary F.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Persaud, Deborah; Ziemniak, Carrie] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Price, David A.; Gostick, Emma] Cardiff Univ, Sch Med, Dept Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. RP Koup, RA (reprint author), 40 Convent Dr,Bldg 40,Rm 3502, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Bench-to-Bedside Program, National Institutes of Health (NIH); Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH; NIAID, NIH [R01 AI062446-01A2]; UK Medical Research Council (MRC) [G0501963]; Bill and Melinda Gates Foundation [OPP1032317] FX This work was supported by the Bench-to-Bedside Program, National Institutes of Health (NIH), and by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Latent HIV reservoir studies were funded by the NIAID, NIH (R01 AI062446-01A2 to D. P.). Tetramer studies were funded by the UK Medical Research Council (MRC; G0501963 to D. A. P.); D. A. P. is a MRC senior clinical fellow. Single-copy viral load measurements were supported by the Intramural Research Program of the HIV Drug Resistance Program, National Cancer Institute, NIH (to F. M. M.). Antibody specificity studies were supported by the Bill and Melinda Gates Foundation (OPP1032317 to R. G.). NR 50 TC 21 Z9 21 U1 2 U2 13 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 JUN 15 PY 2013 VL 207 IS 12 BP 1829 EP 1840 DI 10.1093/infdis/jit098 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200008 PM 23482645 ER PT J AU Smith, SA de Alwis, R Kose, N Durbin, AP Whitehead, SS de Silva, AM Crowe, JE AF Smith, Scott A. de Alwis, Ruklanthi Kose, Nurgun Durbin, Anna P. Whitehead, Stephen S. de Silva, Aravinda M. Crowe, James E., Jr. TI Human Monoclonal Antibodies Derived From Memory B Cells Following Live Attenuated Dengue Virus Vaccination or Natural Infection Exhibit Similar Characteristics SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human; B cells; hybridomas; dengue virus; antibodies; antibody-dependent enhancement; neutralization ID HEALTHY ADULT VOLUNTEERS; 3'-UNTRANSLATED REGION; CANDIDATE; IMMUNOGENICITY; RDEN1-DELTA-30; VACCINES; DELETION; MONKEYS; SAFE AB The immunopathogenesis of severe dengue is poorly understood, but there is concern that induction of cross-reactive nonneutralizing antibodies by infection or vaccination may increase the likelihood of severe disease during a subsequent infection. We generated a total of 63 new human monoclonal antibodies to compare the B-cell response of subjects who received the National Institutes of Health live attenuated dengue vaccine rDEN1 delta 30 to that of subjects following symptomatic primary infection with DENV1. Both infection and vaccination induced serum neutralizing antibodies and DENV1-reactive peripheral blood B cells, but the magnitude of induction was lower in vaccinated individuals. Serotype cross-reactive weakly neutralizing antibodies dominated the response in both vaccinated and naturally infected subjects. Antigen specificities were very similar, with a slightly greater percentage of antibodies targeting E protein domain I/II than domain III. These data shed light on the similarity of human B-cell response to live attenuated DENV vaccine or natural infection. C1 [Smith, Scott A.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Smith, Scott A.; Kose, Nurgun; Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN USA. [de Alwis, Ruklanthi; de Silva, Aravinda M.] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Crowe, JE (reprint author), 2213 Garland Ave MRBIV 11475, Nashville, TN 37232 USA. EM james.crowe@vanderbilt.edu RI Crowe, James/B-5549-2009 OI Crowe, James/0000-0002-0049-1079 FU NIH [HHSN272200900042C, K08 AI103038]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH (Southeastern Regional Center of Excellence for Emerging Infections and Biodefense) [U54 AI057157] FX This work was supported by the NIH (grant U54 AI057157- the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense; contract HHSN272200900042C to Alessandro Sette); grant K08 AI103038 to S. A. S.), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 24 TC 30 Z9 30 U1 1 U2 10 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 JUN 15 PY 2013 VL 207 IS 12 BP 1898 EP 1908 DI 10.1093/infdis/jit119 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200015 PM 23526830 ER PT J AU Zivcec, M Safronetz, D Scott, D Robertson, S Ebihara, H Feldmann, H AF Zivcec, Marko Safronetz, David Scott, Dana Robertson, Shelly Ebihara, Hideki Feldmann, Heinz TI Lethal Crimean-Congo Hemorrhagic Fever Virus Infection in Interferon alpha/beta Receptor Knockout Mice Is Associated With High Viral Loads, Proinflammatory Responses, and Coagulopathy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE CCHFV; interferon alpha; beta receptor knockout mice; coagulopathy; thrombocytopenia; pathology; proinflammatory response ID DISSEMINATED INTRAVASCULAR COAGULATION; CCHF VIRUS; PATHOGENESIS; AFRICAN; TRANSMISSION; REPLICATION; PREDICTOR; CELLS; MODEL AB Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed viral hemorrhagic fever characterized by rapid onset of flu-like symptoms often followed by hemorrhagic manifestations. CCHF virus (CCHFV), a bunyavirus in the Nairovirus genus, is capable of infecting a wide range of mammalian hosts in nature but so far only causes disease in humans. Recently, immunocompromised mice have been reported as CCHF disease models, but detailed characterization is lacking. Here, we closely followed infection and disease progression in CCHFV-infected interferon alpha/beta receptor knockout (IFNAR(-/-)) mice and age-matched wild-type (WT) mice. WT mice quickly clear CCHFV without developing any disease signs. In contrast, CCHFV infected IFNAR(-/-) mice develop an acute fulminant disease with high viral loads leading to organ pathology (liver and lymphoid tissues), marked proinflammatory host responses, severe thrombocytopenia, coagulopathy, and death. Disease progression closely mimics hallmarks of human CCHF disease, making IFNAR(-/-) mice an excellent choice to assess medical countermeasures. C1 [Zivcec, Marko; Safronetz, David; Robertson, Shelly; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. [Scott, Dana] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Zivcec, Marko; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI Zivcec, Marko/0000-0003-4337-8487 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 41 TC 19 Z9 19 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2013 VL 207 IS 12 BP 1909 EP 1921 DI 10.1093/infdis/jit061 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200016 PM 23417661 ER PT J AU Henriet, SSV Jans, J Simonetti, E Kwon-Chung, KJ Rijs, AJMM Hermans, PWM Holland, SM de Jonge, MI Warris, A AF Henriet, Stefanie S. V. Jans, Jop Simonetti, Elles Kwon-Chung, Kyung J. Rijs, Antonius J. M. M. Hermans, Peter W. M. Holland, Steve M. de Jonge, Marien I. Warris, Adilia TI Chloroquine Modulates the Fungal Immune Response in Phagocytic Cells From Patients With Chronic Granulomatous Disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE chronic granulomatous disease; Aspergillus spp; pathogenesis; chloroquine; polymorphonuclear cells; mononuclear cells; inflammation; antifungal activity; cytokines ID CRYPTOCOCCUS-NEOFORMANS; ASPERGILLUS-FUMIGATUS; MONONUCLEAR PHAGOCYTES; HISTOPLASMA-CAPSULATUM; INDEPENDENT ACTIVATION; PLASMODIUM-FALCIPARUM; ANTIMALARIAL AGENTS; INTRACELLULAR IRON; HUMAN-NEUTROPHILS; CYTOKINE RELEASE AB Invasive aspergillosis is a major threat to patients with chronic granulomatous disease (CGD). Fungal pathogenesis is the result of a diminished antifungal capacity and dysregulated inflammation. A deficient NADPH-oxidase complex results in defective phagolysosomal alkalization. To investigate the contribution of defective pH regulation in phagocytes among patients with CGD during fungal pathogenesis, we evaluated the effect of the acidotropic, antimalarial drug chloroquine (CQ) on the antifungal capacity of polymorphonuclear cells (PMNs) and on the inflammatory response of peripheral blood mononuclear cells (PBMCs). Chloroquine exerted a direct pH-dependent antifungal effect on Aspergillus fumigatus and Aspergillus nidulans; it increased the antifungal activity of PMNs from patients with CGD at a significantly lower concentration, compared with the concentration for PMNs from healthy individuals; and decreased the hyperinflammatory state of PBMCs from patients with CGD, as observed by decreased tumor necrosis factor alpha and interleukin 1 beta release. Chloroquine targets both limbs of fungal pathogenesis and might be of great value in the clearance of invasive aspergillosis in patients with CGD. C1 [Henriet, Stefanie S. V.; Jans, Jop; Simonetti, Elles; Hermans, Peter W. M.; de Jonge, Marien I.; Warris, Adilia] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6500 HB Nijmegen, Netherlands. [Henriet, Stefanie S. V.; Jans, Jop; Simonetti, Elles; Hermans, Peter W. M.; de Jonge, Marien I.; Warris, Adilia] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun, NL-6500 HB Nijmegen, Netherlands. [Rijs, Antonius J. M. M.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands. [Kwon-Chung, Kyung J.; Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Henriet, SSV (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Pediat, Subdiv Pediat Infect Dis & Immunol, POB 9101,Internal Mail 804, NL-6500 HB Nijmegen, Netherlands. EM s.henriet@cukz.umcn.nl RI Hermans, Peter/H-8042-2014; Warris, A./L-4745-2015; de Jonge, Marien/P-5869-2015; Jans, Jop/G-5066-2016; Simonetti, Elles/N-2966-2016 OI de Jonge, Marien/0000-0003-2812-5895; NR 37 TC 7 Z9 7 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2013 VL 207 IS 12 BP 1932 EP 1939 DI 10.1093/infdis/jit103 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 151PI UT WOS:000319472200018 PM 23482646 ER PT J AU Das, S Kumar, A Seth, RK Tokar, EJ Kadiiska, MB Waalkes, MP Mason, RP Chatterjee, S AF Das, Suvarthi Kumar, Ashutosh Seth, Ratanesh Kumar Tokar, Erik J. Kadiiska, Maria B. Waalkes, Michael P. Mason, Ronald P. Chatterjee, Saurabh TI Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Adipocytokines; Kupffer cell; Oxidative stress; Lipid peroxidation; Tyrosine nitration; Necrosis; Tumor necrosis factor; OB/OB mice ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; ALPHA PRODUCTION; KUPFFER CELLS; HEPATOTOXICITY; INFLAMMATION; METABOLISM; ACTIVATION; CHLOROFORM; RESISTANCE AB Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-alpha levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. (C) 2013 Elsevier Inc. All rights reserved. C1 [Das, Suvarthi; Seth, Ratanesh Kumar; Chatterjee, Saurabh] Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Kumar, Ashutosh; Kadiiska, Maria B.; Mason, Ronald P.] Free Radical Metab Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Chatterjee, S (reprint author), Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. EM schatt@mailbox.sc.edu RI Seth, Ratanesh/M-3700-2016; OI Seth, Ratanesh/0000-0002-7078-0052 FU NIH [4R00ES019875-02]; National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES050139-13] FX This work has been supported by the NIH Pathway to Independence Award (4R00ES019875-02 to Saurabh Chatterjee) and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences (Z01 ES050139-13 to Ronald P. Mason). NR 39 TC 16 Z9 17 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2013 VL 269 IS 3 BP 297 EP 306 DI 10.1016/j.taap.2013.02.003 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 150EN UT WOS:000319373100011 PM 23438451 ER PT J AU Ahrens, K AF Ahrens, Katherine TI MARGINAL STRUCTURAL MODELS FOR CONTINUOUS EXPOSURES IN THE LONGITUDINAL SETTING: AN APPLICATION TO REPRODUCTIVE EPIDEMIOLOGY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Ahrens, Katherine] Eunice Kennedy Shriver Natl Inst Child & Human De, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S179 EP S179 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300706 ER PT J AU Bao, W Bowers, K Tobias, DK Hu, FB Olsen, S Chavarro, J Vaag, A Zhang, CL AF Bao, Wei Bowers, Katherine Tobias, Deirdre K. Hu, Frank B. Olsen, Sjurdur Chavarro, Jorge Vaag, Allan Zhang, Cuilin TI PREPREGNANCY LOW-CARBOHYDRATE DIET SCORES AND THE RISK OF GESTATIONAL DIABETES MELLITUS: A PROSPECTIVE COHORT STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Bao, Wei; Bowers, Katherine; Tobias, Deirdre K.; Hu, Frank B.; Olsen, Sjurdur; Chavarro, Jorge; Vaag, Allan; Zhang, Cuilin] Kennedy Shriver Natl Inst Child Hlth & Human Dev, Epidemiol Branch, NIH, Rockville, MD 20852 USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 0 Z9 0 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S79 EP S79 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300309 ER PT J AU Bao, W Bowers, K Tobias, DK Hu, FB Zhang, CL AF Bao, Wei Bowers, Katherine Tobias, Deirdre K. Hu, Frank B. Zhang, Cuilin TI HIGHER IRON INTAKE IN RELATION TO AN INCREASED RISK OF PROGRESSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES AFTER THE INDEX PREGNANCY: FINDINGS FROM THE DIABETES & WOMEN'S HEALTH STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Bao, Wei; Bowers, Katherine; Tobias, Deirdre K.; Hu, Frank B.; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Rockville, MD 20852 USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 0 Z9 0 U1 0 U2 8 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 JUN 15 PY 2013 VL 177 SU 11 BP S78 EP S78 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300308 ER PT J AU Boghossian, N Yeung, E Mendola, P Laughon, SK Hinkle, S Zhang, CL Albert, P AF Boghossian, Nansi Yeung, Edwina Mendola, Pauline Laughon, S. Katherine Hinkle, Stephanie Zhang, Cuilin Albert, Paul TI RECURRENCE OF GESTATIONAL HYPERTENSIVE DISORDERS AND IMPACT ON NEWBORN OUTCOMES. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Boghossian, Nansi; Yeung, Edwina; Mendola, Pauline; Laughon, S. Katherine; Hinkle, Stephanie; Zhang, Cuilin; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S20 EP S20 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300077 ER PT J AU Braganza, M de Gonzalez, AB Brenner, AV Kitahara, CM AF Braganza, Melissa de Gonzalez, Amy Berrington Brenner, Alina V. Kitahara, Cari M. TI REPRODUCTIVE AND HORMONAL FACTORS, BENIGN BREAST AND REPRODUCTIVE CONDITIONS, AND THYROID CANCER RISK. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Braganza, Melissa; de Gonzalez, Amy Berrington; Brenner, Alina V.; Kitahara, Cari M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Kitahara, Cari/R-8267-2016 NR 0 TC 0 Z9 0 U1 0 U2 5 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 JUN 15 PY 2013 VL 177 SU 11 BP S125 EP S125 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300494 ER PT J AU Cahoon, E Inskip, P Gridley, G Brenner, A AF Cahoon, Elizabeth Inskip, Peter Gridley, Gloria Brenner, Alina TI IMMUNE-RELATED CONDITIONS AND SUBSEQUENT RISK OF BRAIN CANCER IN A COHORT OF MALE UNITED STATES VETERANS SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Cahoon, Elizabeth; Inskip, Peter; Gridley, Gloria; Brenner, Alina] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S58 EP S58 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300232 ER PT J AU Etemadi, A Abnet, C Kamangar, F Islami, F Poustchi, H Wacholder, S Brennan, P Boffetta, P Malekzadeh, R Dawsey, S AF Etemadi, Arash Abnet, Christian Kamangar, Farin Islami, Farhad Poustchi, Hossein Wacholder, Sholom Brennan, Paul Boffetta, Paolo Malekzadeh, Reza Dawsey, Sanford TI THE IMPACT OF BODY SIZE AND PHYSICAL ACTIVITY DURING ADOLESCENCE AND ADULT LIFE ON OVERALL AND CAUSE-EPECIFIC MORTALITY IN A LARGE COHORT FROM A MIDDLE-INCOME COUNTRY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Etemadi, Arash; Abnet, Christian; Kamangar, Farin; Islami, Farhad; Poustchi, Hossein; Wacholder, Sholom; Brennan, Paul; Boffetta, Paolo; Malekzadeh, Reza; Dawsey, Sanford] NCI, Bethesda, MD 20852 USA. RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S10 EP S10 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300039 ER PT J AU Harmon, Q Baird, D AF Harmon, Quaker Baird, Donna TI SELF REPORTED HISTORY OF KELOIDS IS NOT ASSOCIATED WITH PREVALENT FIBROIDS IN YOUNG AFRICAN AMERICAN WOMEN SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Harmon, Quaker; Baird, Donna] NIEHS, Res Triangle Pk, NC 27709 USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S87 EP S87 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300341 ER PT J AU Hinkle, S Laughon, SK Sjaarda, L Mendola, P Boghossian, N Yeung, E Albert, P AF Hinkle, Stefanie Laughon, S. Katherine Sjaarda, Lindsey Mendola, Pauline Boghossian, Nansi Yeung, Edwina Albert, Paul TI THE ASSOCIATION BETWEEN PARITY AND BIRTHWEIGHT IN A LONGITUDINAL CONSECUTIVE PREGNANCY COHORT. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Hinkle, Stefanie; Laughon, S. Katherine; Sjaarda, Lindsey; Mendola, Pauline; Boghossian, Nansi; Yeung, Edwina; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S24 EP S24 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300096 ER PT J AU Hoffman, HJ Li, CM Losonczy, KG Sklare, DA Cohen, HS Della Santina, CC AF Hoffman, Howard J. Li, Chuan-Ming Losonczy, Katalin G. Sklare, Daniel A. Cohen, Helen S. Della Santina, Charley C. TI CHARACTERISTICS OF US ADULTS WHO FALL FREQUENTLY: THE BALANCE AND DIZZINESS SUPPLEMENT TO THE 2008 NATIONAL HEALTH INTERVIEW SURVEY (NHIS). SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Hoffman, Howard J.; Li, Chuan-Ming; Losonczy, Katalin G.; Sklare, Daniel A.; Cohen, Helen S.; Della Santina, Charley C.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S70 EP S70 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300276 ER PT J AU Jensen, E Longnecker, M AF Jensen, Elizabeth Longnecker, Matthew TI PHARMACOLOGIC SEX HORMONES IN EARLY PREGNANCY AND OFFSPRING OBESITY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Jensen, Elizabeth; Longnecker, Matthew] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27599 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S8 EP S8 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300032 ER PT J AU Jones, R Yu, CL Nuckols, JR Cerhan, JR Ross, JA Robien, K Ward, MH AF Jones, Rena Yu, Chu-Ling Nuckols, John R. Cerhan, James R. Ross, Julie A. Robien, Kim Ward, Mary H. TI FARM RESIDENCE AND LYMPHOHEMATOPOIETIC CANCERS IN A COHORT OF OLDER WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Jones, Rena; Yu, Chu-Ling; Nuckols, John R.; Cerhan, James R.; Ross, Julie A.; Robien, Kim; Ward, Mary H.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S65 EP S65 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300256 ER PT J AU Jukic, AM Weinberg, C Hoppin, J Longnecker, M Baird, D Wilcox, A AF Jukic, Anne Marie Weinberg, Clarice Hoppin, Jane Longnecker, Mattew Baird, Donna Wilcox, Allen TI CYCLE-SPECIFIC PHTHALATE MEASURES, EARLY PREGNANCY LOSS AND TIME TO PREGNANCY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Jukic, Anne Marie; Weinberg, Clarice; Hoppin, Jane; Longnecker, Mattew; Baird, Donna; Wilcox, Allen] NIEHS, Durham, NC 27709 USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 NR 0 TC 0 Z9 0 U1 0 U2 6 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 JUN 15 PY 2013 VL 177 SU 11 BP S116 EP S116 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300457 ER PT J AU Khodr, Z Sherman, M Pfeiffer, R Gierach, G Brinton, L Falk, R Patel, D Visscher, D Mies, C Hewitt, S Clare, S Storniolo, AM Figueroa, J AF Khodr, Zeina Sherman, Mark Pfeiffer, Ruth Gierach, Gretchen Brinton, Louise Falk, Roni Patel, Deesha Visscher, Daniel Mies, Carolyn Hewitt, Stephen Clare, Susan Storniolo, Anna Maria Figueroa, Jonine TI ASSOCIATIONS BETWEEN ENDOGENOUS HORMONE LEVELS AND LOBULAR INVOLUTION IN THE NORMAL BREAST AMONG PREMENOPAUSAL WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Khodr, Zeina; Sherman, Mark; Pfeiffer, Ruth; Gierach, Gretchen; Brinton, Louise; Falk, Roni; Patel, Deesha; Visscher, Daniel; Mies, Carolyn; Hewitt, Stephen; Clare, Susan; Storniolo, Anna Maria; Figueroa, Jonine] NCI, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016 OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S124 EP S124 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300488 ER PT J AU Kim, C Chapman, R Hu, W He, XZ Hosgood, HD Liu, L Lai, H Chen, W Silverman, D Tian, LW Bassig, B Shen, M Zhang, YW Ma, SG Rothman, N Lan, Q AF Kim, Christopher Chapman, Robert Hu, Wei He, Xingzhou Hosgood, H. Dean Liu, Larry Lai, Hong Chen, Wei Silverman, Debra Tian, Linwei Bassig, Bryan Shen, Min Zhang, Yawei Ma, Shuangge Rothman, Nathaniel Lan, Qing TI INDOOR COAL SMOKE EXPOSURE, TOBACCO USE, AND LUNG CANCER RISK IN XUANWEI, CHINA. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Kim, Christopher; Chapman, Robert; Hu, Wei; He, Xingzhou; Hosgood, H. Dean; Liu, Larry; Lai, Hong; Chen, Wei; Silverman, Debra; Tian, Linwei; Bassig, Bryan; Shen, Min; Zhang, Yawei; Ma, Shuangge; Rothman, Nathaniel; Lan, Qing] NCI, Rockville, MD 20892 USA. RI Hu, Wei/M-3524-2013; Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 NR 0 TC 0 Z9 0 U1 0 U2 7 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 JUN 15 PY 2013 VL 177 SU 11 BP S120 EP S120 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300474 ER PT J AU Kissell, K Danaher, M Schisterman, E Perkins, N Schliep, K Ahrens, K Sjaarda, L Wactawski-Wende, J Mumford, S AF Kissell, Kerri Danaher, Michelle Schisterman, Enrique Perkins, Neil Schliep, Karen Ahrens, Katherine Sjaarda, Lindsey Wactawski-Wende, Jean Mumford, Sunni TI THE IMPACT OF SERUM ANTI-MULLERIAN HORMONE ON FOLLICULAR PHASE LENGTH IN PREMENOPAUSAL WOMEN SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Kissell, Kerri; Danaher, Michelle; Schisterman, Enrique; Perkins, Neil; Schliep, Karen; Ahrens, Katherine; Sjaarda, Lindsey; Wactawski-Wende, Jean; Mumford, Sunni] NICHD, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S149 EP S149 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300586 ER PT J AU Laughon, SK AF Laughon, S. Katherine TI INNOVATIVE DESIGN AND ANALYSIS ISSUES IN FETAL GROWTH STUDIES. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Laughon, S. Katherine] NICHD, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S56 EP S56 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300222 ER PT J AU Li, WQ Park, Y Wu, J Goldstein, A Taylor, P Hollenbeck, A Freedman, N Abnet, C AF Li, Wen-Qing Park, Yikyung Wu, Jennifer Goldstein, Alisa Taylor, Philip Hollenbeck, Albert Freedman, Neal Abnet, Christian TI INDEX-BASED DIETARY PATTERNS AND RISK OF HEAD AND NECK CANCER IN THE NIH-AARP DIET AND HEALTH STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Li, Wen-Qing; Park, Yikyung; Wu, Jennifer; Goldstein, Alisa; Taylor, Philip; Hollenbeck, Albert; Freedman, Neal; Abnet, Christian] NCI, Dept Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S142 EP S142 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300560 ER PT J AU Li, WQ Zhang, L Ma, JL Brown, L Li, JY Shen, L Pan, KF Liu, WD Hu, YR Han, ZX Crystal-Mansour, S Pee, D Blot, W Fraumeni, J You, WC Gail, M AF Li, Wen-Qing Zhang, Lian Ma, Jun-Ling Brown, Linda Li, Ji-You Shen, Lin Pan, Kai-Feng Liu, Wei-Dong Hu, Yuanreng Han, Zhong-Xiang Crystal-Mansour, Susan Pee, David Blot, William Fraumeni, Joseph, Jr. You, Wei-Cheng Gail, Mitchell TI FIFTEEN-YEAR EFFECTS OF HELICOBACTER PYLORI TREATMENT ON GASTRIC CANCER INCIDENCE AND MORTALITY AMONG PARTICIPANTS WITH DIFFERENT BASELINE GASTRIC LESIONS AND AGES SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Li, Wen-Qing; Zhang, Lian; Ma, Jun-Ling; Brown, Linda; Li, Ji-You; Shen, Lin; Pan, Kai-Feng; Liu, Wei-Dong; Hu, Yuanreng; Han, Zhong-Xiang; Crystal-Mansour, Susan; Pee, David; Blot, William; Fraumeni, Joseph, Jr.; You, Wei-Cheng; Gail, Mitchell] NCI, Dept Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 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 JUN 15 PY 2013 VL 177 SU 11 BP S61 EP S61 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300242 ER PT J AU Mannisto, T Mendola, P Leishear, K Liu, DP Sundaram, R AF Maennistoe, Tuija Mendola, Pauline Leishear, Kira Liu, Danping Sundaram, Rajeshwari TI ACUTE AIR POLLUTANT EXPOSURE AND BLOOD PRESSURE AT LABOR/DELIVERY ADMISSION SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Maennistoe, Tuija; Mendola, Pauline; Leishear, Kira; Liu, Danping; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S42 EP S42 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300167 ER PT J AU Marpuri, I Bottinger, EP Brilliant, MH Carey, D Chisholm, RL Chute, CG Haines, JL Hakonarson, H Harley, J Jarvik, GP Kohane, I Kullo, I Larson, EB McCarty, C Roden, D Smith, M Williams, MS Li, RL AF Marpuri, Ian Bottinger, Erwin P. Brilliant, Murray H. Carey, David Chisholm, Rex L. Chute, Christopher G. Haines, Jonathan L. Hakonarson, Hakon Harley, John Jarvik, Gail P. Kohane, Isaac Kullo, Iftikhar Larson, Eric B. McCarty, Catherine Roden, Dan Smith, Maureen Williams, Marc S. Li, Rongling TI ELECTRONIC MEDICAL RECORDS AND GENOMICS NETWORK - FROM GWAS TO IMPLEMENTATION. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Marpuri, Ian; Bottinger, Erwin P.; Brilliant, Murray H.; Carey, David; Chisholm, Rex L.; Chute, Christopher G.; Haines, Jonathan L.; Hakonarson, Hakon; Harley, John; Jarvik, Gail P.; Kohane, Isaac; Kullo, Iftikhar; Larson, Eric B.; McCarty, Catherine; Roden, Dan; Smith, Maureen; Williams, Marc S.; Li, Rongling] NHGRI, NIH, Bethesda, MD 20892 USA. RI Jarvik, Gail/N-6476-2014 OI Jarvik, Gail/0000-0002-6710-8708 NR 0 TC 0 Z9 0 U1 0 U2 5 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 JUN 15 PY 2013 VL 177 SU 11 BP S99 EP S99 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300389 ER PT J AU Mendola, P Mannisto, TI Leishear, K Reddy, UM Chen, Z Laughon, SK AF Mendola, Pauline Mannisto, Tuija I. Leishear, Kira Reddy, Uma M. Chen, Zhen Laughon, S. Katherine TI NEONATAL HEALTH OF INFANTS BORN TO MOTHERS WITH ASTHMA. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Mendola, Pauline; Mannisto, Tuija I.; Leishear, Kira; Reddy, Uma M.; Chen, Zhen; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S22 EP S22 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300088 ER PT J AU Perkins, N Mumford, S Schisterman, E AF Perkins, Neil Mumford, Sunni Schisterman, Enrique TI CONSIDERATIONS IN POOLING BIOMARKER CALIBRATION INFORMATION. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Perkins, Neil; Mumford, Sunni; Schisterman, Enrique] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S101 EP S101 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300397 ER PT J AU Pollack, A Sjaarda, L Ahrens, K Mumford, S Browne, R Perkins, N Wactawski-Wende, J Schisterman, E AF Pollack, Anna Sjaarda, Lindsey Ahrens, Katherine Mumford, Sunni Browne, Rick Perkins, Neil Wactawski-Wende, Jean Schisterman, Enrique TI CADMIUM, LEAD AND MERCURY EXPOSURE AND PARAOXONASE 1 (PON1) ACTIVITY IN WOMEN SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Pollack, Anna; Sjaarda, Lindsey; Ahrens, Katherine; Mumford, Sunni; Browne, Rick; Perkins, Neil; Wactawski-Wende, Jean; Schisterman, Enrique] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S88 EP S88 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300346 ER PT J AU Reyes-Guzman, C Caporaso, N AF Reyes-Guzman, Carolyn Caporaso, Neil TI REDEFINING LIGHT AND INTERMITTENT SMOKERS USING US NATIONAL HEALTH SURVEY DATA. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Reyes-Guzman, Carolyn; Caporaso, Neil] NCI, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 JUN 15 PY 2013 VL 177 SU 11 BP S37 EP S37 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300146 ER PT J AU Robbins, H Pfeiffer, RM Shiels, M Engels, E AF Robbins, Hilary Pfeiffer, Ruth M. Shiels, Meredith Engels, Eric TI CONTRIBUTIONS TO CHANGING CANCER INCIDENCE IN THE US HIV POPULATION, 1996-2008 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Robbins, Hilary; Pfeiffer, Ruth M.; Shiels, Meredith; Engels, Eric] NCI, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S47 EP S47 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300185 ER PT J AU Robledo, C Stoner, J Carabin, H Cowan, L Peck, JD AF Robledo, Candace Stoner, Julie Carabin, Helene Cowan, Linda Peck, Jennifer D. TI AUTOMATED VARIABLE SELECTION PROCEDURES TO IDENTIFY STATISTICAL INTERACTION BETWEEN CORRELATED ENVIRONMENTAL EXPOSURES: THE CASE OF PHTHALATE METABOLITES AND BODY MASS INDEX. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Robledo, Candace; Stoner, Julie; Carabin, Helene; Cowan, Linda; Peck, Jennifer D.] NICHD, Rockville, MD 20892 USA. RI Carabin, Helene/B-7600-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S181 EP S181 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300713 ER PT J AU Robledo, C Mendola, P Yeung, E Sundaram, R Liu, DP Ying, Q Sherman, S Lipsky, L Katherine, L AF Robledo, Candace Mendola, Pauline Yeung, Edwina Sundaram, Rajeshwari Liu, Danping Ying, Qi Sherman, Seth Lipsky, Leah Katherine, Laughon TI PRECONCEPTION AIR POLLUTION EXPOSURES INCREASE THE RISK OF GESTATIONAL DIABETES MELLITUS SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Robledo, Candace; Mendola, Pauline; Yeung, Edwina; Sundaram, Rajeshwari; Liu, Danping; Ying, Qi; Sherman, Seth; Lipsky, Leah; Katherine, Laughon] NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RI Ying, Qi/D-1985-2012 NR 0 TC 0 Z9 0 U1 0 U2 7 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 JUN 15 PY 2013 VL 177 SU 11 BP S43 EP S43 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300172 ER PT J AU Schisterman, E Silver, R Lesher, L Faraggi, D Wactawski-Wende, J Townsend, J Lynch, A Perkins, N Mumford, S Galai, N AF Schisterman, Enrique Silver, Robert Lesher, Laurie Faraggi, David Wactawski-Wende, Jean Townsend, Janet Lynch, Anne Perkins, Neil Mumford, Sunni Galai, Noya TI .6RANDOMIZED CLINICAL TRIAL OF PRECONCEPTION LOW DOSE ASPIRIN USE TO IMPROVE PREGNANCY OUTCOMES: EAGER (EFFECTS OF ASPIRIN IN GESTATION AND REPRODUCTION) TRIAL. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Schisterman, Enrique; Silver, Robert; Lesher, Laurie; Faraggi, David; Wactawski-Wende, Jean; Townsend, Janet; Lynch, Anne; Perkins, Neil; Mumford, Sunni; Galai, Noya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S115 EP S115 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300455 ER PT J AU Schliep, K Mumford, S Albert, P Yeung, E Ye, A Schisterman, E AF Schliep, K. Mumford, S. Albert, P. Yeung, E. Ye, A. Schisterman, E. TI APPLICATION OF NONLINEAR MIXED MODELS WITH HARMONIC TERMS FOR ANALYZING LONGITUDINAL DATA. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Schliep, K.; Mumford, S.; Albert, P.; Yeung, E.; Ye, A.; Schisterman, E.] NICHD, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S181 EP S181 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300716 ER PT J AU Shi, M DeRoo, L Sandler, D Weinberg, C AF Shi, Min DeRoo, Lisa Sandler, Dale Weinberg, Clarice TI MIGRAINE AS A RISK FACTOR FOR BREAST CANCER: IS THERE ETIOLOGIC HETEROGENEITY? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Shi, Min; DeRoo, Lisa; Sandler, Dale; Weinberg, Clarice] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S174 EP S174 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300688 ER PT J AU Shiels, M Koritzinsky, E Clarke, C Morton, L Engels, E AF Shiels, Meredith Koritzinsky, Erik Clarke, Christina Morton, Lindsay Engels, Eric TI IMPACT OF HIV INFECTION ON HODGKIN LYMPHOMA CASES IN THE UNITED STATES SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Shiels, Meredith; Koritzinsky, Erik; Clarke, Christina; Morton, Lindsay; Engels, Eric] NCI, Rockville, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S46 EP S46 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300184 ER PT J AU Sjaarda, L Mumford, S Laughon, SK Kissell, K Wactawski-Wende, J Schisterman, E AF Sjaarda, Lindsey Mumford, Sunni Laughon, S. Katherine Kissell, Kerri Wactawski-Wende, Jean Schisterman, Enrique TI PERTURBATIONS IN TESTOSTERONE ARE ASSOCIATED WITH SPORADIC ANOVULATION IN NORMALLY MENSTRUATING WOMEN. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Sjaarda, Lindsey; Mumford, Sunni; Laughon, S. Katherine; Kissell, Kerri; Wactawski-Wende, Jean; Schisterman, Enrique] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S80 EP S80 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300315 ER PT J AU Taylor, K Hoffman, K Thayer, K Daniels, J AF Taylor, Kyla Hoffman, Kate Thayer, Kristina Daniels, Julie TI POLYFLUOROALKYL CHEMICALS AND NATURAL MENOPAUSE AMONG WOMEN AGES 18-65 FROM NHANES 1999-2000, 2003-2004, 2005-2006, 2007-2008, AND 2009-2010 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Univ N Carolina, Chapel Hill, NC USA. NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 6 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 JUN 15 PY 2013 VL 177 SU 11 BP S41 EP S41 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300164 ER PT J AU Thompson, F Dixit-Joshi, S Potischman, N Kirkpatrick, S Alexander, G Coleman, L Kushi, L Groesbeck, M Sundaram, M Clancy, H Douglass, D Mittl, B George, S Subar, A AF Thompson, Frances Dixit-Joshi, Sujata Potischman, Nancy Kirkpatrick, Sharon Alexander, Gwen Coleman, Laura Kushi, Lawrence Groesbeck, Michelle Sundaram, Maria Clancy, Heather Douglass, Deirdre Mittl, Beth George, Stephanie Subar, Amy TI FEASIBILITY AND PERFORMANCE OF NCI'S AUTOMATED SELF-ADMINISTERED 24 HOUR RECALL (ASA24) SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Thompson, Frances; Dixit-Joshi, Sujata; Potischman, Nancy; Kirkpatrick, Sharon; Alexander, Gwen; Coleman, Laura; Kushi, Lawrence; Groesbeck, Michelle; Sundaram, Maria; Clancy, Heather; Douglass, Deirdre; Mittl, Beth; George, Stephanie; Subar, Amy] US Natl Canc Inst, Rockville, MD 20850 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S109 EP S109 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300431 ER PT J AU Trabert, B Wentzensen, N Yang, HP Brinton, LA AF Trabert, Britton Wentzensen, Nicolas Yang, Hannah P. Brinton, Louise A. TI METABOLIC SYNDROME AND OVARIAN CANCER IN THE UNITED STATES: A STUDY IN THE SEER-MEDICARE LINKED DATABASE SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Trabert, Britton; Wentzensen, Nicolas; Yang, Hannah P.; Brinton, Louise A.] NCI, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 1 PU 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 JUN 15 PY 2013 VL 177 SU 11 BP S57 EP S57 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300227 ER PT J AU Wang, JB Abnet, C Chen, W Dawsey, S Fan, JH Yin, LY Yin, J Major, J Taylor, P Qiao, YL Freedman, N AF Wang, Jianbing Abnet, Christian Chen, Wen Dawsey, Sanford Fan, Jinhu Yin, Liangyu Yin, Jian Major, Jacqueline Taylor, Philip Qiao, Youlin Freedman, Neal TI ASSOCIATION BETWEEN SERUM 25(OH) VITAMIN D, INCIDENT LIVER CANCER AND CHRONIC LIVER DISEASE MORTALITY IN THE LINXIAN NUTRITION INTERVENTION TRIALS: A NESTED CASE-CONTROL STUDY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Wang, Jianbing; Abnet, Christian; Chen, Wen; Dawsey, Sanford; Fan, Jinhu; Yin, Liangyu; Yin, Jian; Major, Jacqueline; Taylor, Philip; Qiao, Youlin; Freedman, Neal] NCI, Rockville, MD 20852 USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 0 TC 0 Z9 0 U1 0 U2 4 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 JUN 15 PY 2013 VL 177 SU 11 BP S110 EP S110 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300433 ER PT J AU Wang, Y Rogan, W Chen, PC Lien, GW Chen, HY Longnecker, M Wang, SL AF Wang, Yan Rogan, Walter Chen, Pau-Chung Lien, Guang-Wen Chen, Hsiao-Yen Longnecker, Matthew Wang, Shu-Li TI MATERNAL SERUM PERFLUOROALKYL SUBSTANCES AND MATERNAL AND NEONATAL THYROID FUNCTION. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Wang, Yan; Rogan, Walter; Chen, Pau-Chung; Lien, Guang-Wen; Chen, Hsiao-Yen; Longnecker, Matthew; Wang, Shu-Li] NIEHS, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 0 TC 0 Z9 0 U1 1 U2 3 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 JUN 15 PY 2013 VL 177 SU 11 BP S54 EP S54 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300215 ER PT J AU Weinberg, C Shi, M Deroo, L Taylor, J Sandler, D Umbach, D AF Weinberg, Clarice Shi, Min Deroo, Lisa Taylor, Jack Sandler, Dale Umbach, David TI USING ASYMMETRY IN FAMILY HISTORY TO PROBE GENETIC MECHANISMS: APPLICATION TO THE GENETICS OF BREAST CANCER. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Weinberg, Clarice; Shi, Min; Deroo, Lisa; Taylor, Jack; Sandler, Dale; Umbach, David] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 JUN 15 PY 2013 VL 177 SU 11 BP S174 EP S174 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300686 ER PT J AU Xiao, Q Park, Y Kitahara, C AF Xiao, Qian Park, Yikyung Kitahara, Cari TI INTAKES OF DIETARY FLAVONOIDS AND THYROID CANCER RISK IN A LARGE PROSPECTIVE STUDY. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 [Xiao, Qian; Park, Yikyung; Kitahara, Cari] NCI, North Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2013 VL 177 SU 11 BP S140 EP S140 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 157BL UT WOS:000319870300552 ER PT J AU Reingewertz, TH Britan-Rosich, E Rotem-Bamberger, S Viard, M Jacobs, A Miller, A Lee, JY Hwang, J Blumenthal, R Kotler, M Friedler, A AF Reingewertz, Tali H. Britan-Rosich, Elena Rotem-Bamberger, Shahar Viard, Mathias Jacobs, Amy Miller, Abigail Lee, Ji Youn Hwang, Jeeseong Blumenthal, Robert Kotler, Moshe Friedler, Assaf TI Mapping the Vif-A3G interaction using peptide arrays: A basis for anti-HIV lead peptides SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE A3G; Apobec-3G; HIV-1; Peptide arrays; Protein-protein interactions; Vif ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 VIF PROTEIN; VIRION INFECTIVITY FACTOR; C-TERMINAL DOMAIN; HUMAN APOBEC3G; VIRAL INFECTIVITY; CYTIDINE DEAMINASE; MESSENGER-RNA; RESTRICTION FACTORS; ANTIVIRAL ACTIVITY AB Human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3G (A3G) is a cytidine deaminase that restricts retroviruses, endogenous retro-elements and DNA viruses. A3G plays a key role in the anti-HIV-1 innate cellular immunity. The HIV-1 Vif protein counteracts A3G mainly by leading A3G towards the proteosomal machinery and by direct inhibition of its enzymatic activity. Both activities involve direct interaction between Vif and A3G. Disrupting the interaction between A3G and Vif may rescue A3G antiviral activity and inhibit HIV-1 propagation. Here, mapping the interaction sites between A3G and Vif by peptide array screening revealed distinct regions in Vif important for A3G binding, including the N-terminal domain (NTD), C-terminal domain (CTD) and residues 83-99. The Vif-binding sites in A3G included 12 different peptides that showed strong binding to either full-length Vif, Vif CTD or both. Sequence similarity was found between Vif-binding peptides from the A3G CTD and NTD. A3G peptides were synthesized and tested for their ability to counteract Vif action. A3G 211-225 inhibited HIV-1 replication in cell culture and impaired Vif dependent A3G degradation. In vivo co-localization of full-length Vif with A3G 211-225 was demonstrated by use of FRET. This peptide has the potential to serve as an anti-HIV-1 lead compound. Our results suggest a complex interaction between Vif and A3G that is mediated by discontinuous binding regions with different affinities. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Reingewertz, Tali H.; Rotem-Bamberger, Shahar; Friedler, Assaf] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Reingewertz, Tali H.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Britan-Rosich, Elena; Kotler, Moshe] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91120 Jerusalem, Israel. [Britan-Rosich, Elena; Kotler, Moshe] Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel. [Viard, Mathias; Blumenthal, Robert] NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. [Viard, Mathias] SAIC Frederick Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Jacobs, Amy] SUNY Buffalo, Sch Med & Biomed Sci, Dept Microbiol & Immunol, Buffalo, NY 14260 USA. [Miller, Abigail; Lee, Ji Youn; Hwang, Jeeseong] NIST, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Miller, Abigail] American Univ, Dept Chem, Washington, DC 20016 USA. [Lee, Ji Youn] Korea Res Inst Stand & Sci, Ctr Bioanal, Div Metrol Qual Life, Taejon 305340, South Korea. RP Friedler, A (reprint author), Hebrew Univ Jerusalem, Inst Chem, Safra Campus, IL-91904 Jerusalem, Israel. EM assaf.friedler@mail.huji.ac.il FU US-Israel Binational Science Foundation (BSF); National Institutes of Health [P01 GM091743]; Fulbright Foundation; ISEF Foundation; NIST Innovation in Measurement Science program on "Optical Medical Imaging for Clinical Applications"; NIH (NIBIB)/NIST; National Institute for Biomedical Imaging and Bioengineering of the NIH; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research, Frederick National Lab; NIH Intramural AIDS Targeted Antiviral Program (IATAP); NIAID Intramural Biodefense Research Program FX This work was supported by the US-Israel Binational Science Foundation (BSF) and by Grants from the National Institutes of Health (P01 GM091743 to R. S. H. with a subaward to M. K.).; T.H.R. was partly supported by the Fulbright Foundation and the ISEF Foundation.; J.H. was supported by NIST Innovation in Measurement Science program on "Optical Medical Imaging for Clinical Applications." J.L. held National Research Council Research Associateship supported by NIH (NIBIB)/NIST. Funding for these awards was provided by and the intramural program of the National Institute for Biomedical Imaging and Bioengineering of the NIH.; The pcDNA-HVif plasmid was provided by the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH 78; This project is funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Frederick National Lab. Further funding was provided by grants from the NIH Intramural AIDS Targeted Antiviral Program (IATAP) and the NIAID Intramural Biodefense Research Program. NR 87 TC 7 Z9 7 U1 1 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN 15 PY 2013 VL 21 IS 12 BP 3523 EP 3532 DI 10.1016/j.bmc.2013.03.001 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 152AW UT WOS:000319502800018 PM 23545135 ER PT J AU Coombs, TC Tanega, C Shen, M Wang, JL Auld, DS Gerritz, SW Schoenen, FJ Thomas, CJ Aube, J AF Coombs, Thomas C. Tanega, Cordelle Shen, Min Wang, Jenna L. Auld, Douglas S. Gerritz, Samuel W. Schoenen, Frank J. Thomas, Craig J. Aube, Jeffrey TI Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Clk; Dyrk; Kinase inhibitor; Splicing; Pyrimidine ID PROTEIN-KINASES; DOWN-SYNDROME; NEURONAL DIFFERENTIATION; SUBSTRATE-SPECIFICITY; GENE-EXPRESSION; CELL-SURVIVAL; FAMILY; OVEREXPRESSION; COMBINATION; ACTIVATION AB Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Coombs, Thomas C.; Wang, Jenna L.; Schoenen, Frank J.; Aube, Jeffrey] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA. [Tanega, Cordelle; Shen, Min; Auld, Douglas S.; Thomas, Craig J.] NIH, NIH Chem Genom Ctr, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Gerritz, Samuel W.] Bristol Myers Squibb Res, Wallingford, CT 06492 USA. [Aube, Jeffrey] Univ Kansas, Dept Med Chem, Lawrence, KS 66047 USA. RP Aube, J (reprint author), Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA. EM jaube@ku.edu OI Aube, Jeffrey/0000-0003-1049-5767 FU National Institutes of Health [U54 HG005031, RO3 MH084827-01, U54 MH084681-01]; Division of Preclinical Innovation, National Center for Advancing Translational Sciences of the National Institutes of Health FX This work was supported by National Institutes of Health (grants U54 HG005031, RO3 MH084827-01, and U54 MH084681-01) and the Division of Preclinical Innovation, National Center for Advancing Translational Sciences of the National Institutes of Health. The dendrograms depicting kinase binding selectivity were generated using the online tool at: http://tripod.nih.gov/?p=226. We thank Benjamin Neuenswander and Patrick Porubsky for compound purification and curation. We thank Arianna Mangravita-Novo and Layton H. Smith of the Sanford-Burnham Medical Research Institute at Lake Nona for solubility and PK profiling measurements. NR 46 TC 18 Z9 18 U1 3 U2 27 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 JUN 15 PY 2013 VL 23 IS 12 BP 3654 EP 3661 DI 10.1016/j.bmcl.2013.02.096 PG 8 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 148ST UT WOS:000319268500036 PM 23642479 ER PT J AU Dossou, KSS Devkota, KP Kavanagh, PV Beutler, JA Egan, JM Moaddel, R AF Dossou, K. S. S. Devkota, K. P. Kavanagh, P. V. Beutler, J. A. Egan, J. M. Moaddel, R. TI Development and preliminary validation of a plate-based CB1/CB2 receptor functional assay SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Plate-based assay; Zanthoxylum; Isosteviol; CB1 antagonists; CB2 antagonists ID GREEN-FLUORESCENT-PROTEIN; CB1 CANNABINOID RECEPTOR; LIGANDS; EXPRESSION; IDENTIFICATION; ISOSTEVIOL; OBESITY; CELLS AB Cannabinoid (CB) receptors are being targeted therapeutically for the treatment of anxiety, obesity, movement disorders, glaucoma, and pain. More recently, cannabinoid agonists have displayed antiproliferative activity against breast-cancer and prostate cancer in animal models. To study cannabinoid receptor ligands, we have developed a novel plate-based assay that measures internalization of CB1/CB2 receptors by determining the change in the intracellular levels of the radiolabeled agonists: [H-3]Win55-212-2 for CB1 and [H-3]CP55-940 for CB2. The developed plate-based assay was validated by determining IC50 values for known antagonists: AM251, AM281, AM630, and AM6545. The data obtained were consistent with previously reported values, thereby confirming that the assay can be used to determine the functional binding activities (IC50) of antagonists for the CB1 and CB2 receptors. In addition, we demonstrated that the plate-based assay may be used for screening against complex matrices. Specifically, we demonstrated that the plate-based assay was able to identify which extracts of several species of the genus Zanthoxylum had activity at the CB1/CB2 receptors. Published by Elsevier Inc. C1 [Dossou, K. S. S.; Egan, J. M.; Moaddel, R.] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Devkota, K. P.; Beutler, J. A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Kavanagh, P. V.] Trinity Coll Dublin, Sch Med, Dept Pharmacol & Therapeut, Dublin 2, Ireland. RP Moaddel, R (reprint author), NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU National Institute of Aging; National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIH Office of Dietary Supplements [OD-Y2-OD-1557-01] FX This research was supported in part by the Intramural Research Program of the National Institute of Aging and in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. We thank Chun-Tao Che of the University of Illinois at Chicago for arranging the Chinese collections of Zanthoxylum, and we thank each of the plant collectors. We thank Cynthia Morton of the Carnegie Museum of Natural History for the ITS sequencing. We thank John McElroy (Jenrin Pharmaceutics) for JD2000, JD5000, and JD6000 series. This work was supported in part by funds from the NIH Office of Dietary Supplements (OD-Y2-OD-1557-01). NR 35 TC 6 Z9 6 U1 13 U2 43 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 JUN 15 PY 2013 VL 437 IS 2 BP 138 EP 143 DI 10.1016/j.ab.2013.02.025 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 141RK UT WOS:000318744000008 PM 23481912 ER PT J AU Tang, LL Liu, AY Chen, Z Schisterman, EF Zhang, B Miao, Z AF Tang, Liansheng Larry Liu, Aiyi Chen, Zhen Schisterman, Enrique F. Zhang, Bo Miao, Zhuang TI Nonparametric ROC summary statistics for correlated diagnostic marker data SO STATISTICS IN MEDICINE LA English DT Article DE ROC curve; optimal weights; Wilcoxon statistics; correlated data ID OPERATING CHARACTERISTIC CURVES; COMBINING DEPENDENT TESTS; CLUSTERED DATA; AREAS; ENDOMETRIOSIS; TRIALS; CANCER AB We propose efficient nonparametric statistics to compare medical imaging modalities in multi-reader multi-test data and to compare markers in longitudinal ROC data. The proposed methods are based on the weighted area under the ROC curve, which includes the area under the curve and the partial area under the curve as special cases. The methods maximize the local power for detecting the difference between imaging modalities. We develop the asymptotic results of the proposed methods under a complex correlation structure. Our simulation studies show that the proposed statistics result in much better powers than existing statistics. We apply the proposed statistics to an endometriosis diagnosis study. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Tang, Liansheng Larry; Miao, Zhuang] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Liu, Aiyi; Chen, Zhen; Schisterman, Enrique F.] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Zhang, Bo] Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Biol & Populat Hlth Sci, Biostat Core, Corvallis, OR 97331 USA. RP Tang, LL (reprint author), George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. EM ltang1@gmu.edu OI Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU National Cancer Institute [R15CA150698]; National Security Agency [H98230-11-1-0196]; American Chemistry Council; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors would like to thank an associate editor and two referees for their constructive comments and suggestions. The project described here was supported in part by Award Number R15CA150698 from the National Cancer Institute under the American Recovery and Reinvestment Act of 2009 and by Award Number H98230-11-1-0196 from the National Security Agency. The work was also supported in part with funding from the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 23 TC 2 Z9 2 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2013 VL 32 IS 13 BP 2209 EP 2220 DI 10.1002/sim.5654 PG 12 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 141YR UT WOS:000318763100004 PM 23055248 ER PT J AU Ning, J Qin, J Asgharian, M Shen, Y AF Ning, J. Qin, J. Asgharian, M. Shen, Y. TI Empirical likelihood-based confidence intervals for length-biased data SO STATISTICS IN MEDICINE LA English DT Article DE confidence interval; length-biased data; empirical likelihood ratio test; mean; median; quantile; survival function ID PREVALENT COHORT; SURVIVAL-DATA; CENSORED-DATA; NONPARAMETRIC-ESTIMATION; RATIO; STATIONARITY; INFERENCE; AIDS AB Logistic or other constraints often preclude the possibility of conducting incident cohort studies. A feasible alternative in such cases is to conduct a cross-sectional prevalent cohort study for which we recruit prevalent cases, that is, subjects who have already experienced the initiating event, say the onset of a disease. When the interest lies in estimating the lifespan between the initiating event and a terminating event, say death for instance, such subjects may be followed prospectively until the terminating event or loss to follow-up, whichever happens first. It is well known that prevalent cases have, on average, longer lifespans. As such, they do not constitute a representative random sample from the target population; they comprise a biased sample. If the initiating events are generated from a stationary Poisson process, the so-called stationarity assumption, this bias is called length bias. The current literature on length-biased sampling lacks a simple method for estimating the margin of errors of commonly used summary statistics. We fill this gap by using the empirical likelihood-based confidence intervals by adapting this method to right-censored length-biased survival data. Both large and small sample behaviors of these confidence intervals are studied. We illustrate our method by using a set of data on survival with dementia, collected as part of the Canadian Study of Health and Aging. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Ning, J.; Shen, Y.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, J.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Asgharian, M.] McGill Univ, Dept Math & Stat, Montreal, PQ H3A 2K6, Canada. RP Ning, J (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. EM jning@mdanderson.org OI Shen, Yu/0000-0002-3899-7868 FU Seniors Independence Research Program through the National Health Research and Development Program of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council-Pharmaceutical Manufacturers Association of Canada Health Activity Program; National Health Research and Development Program [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38 (93-2), 34 (96-1)]; National Institute of Health [CA079466, CA016672]; Natural Sciences and Engineering Research Council of Canada FX The data reported in this article were collected as part of the Canadian Study of Health and Aging. The core study was funded by the Seniors Independence Research Program, through the National Health Research and Development Program of Health Canada (Project no. 6606-3954-MC(S)). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council-Pharmaceutical Manufacturers Association of Canada Health Activity Program, National Health Research and Development Program (Project no. 6603-1417-302(R)), Bayer Incorporated, and the British Columbia Health Research Foundation (Projects no. 38 (93-2) and no. 34 (96-1)). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. This work was supported in part by grants from the National Institute of Health (CA079466 and CA016672) and Natural Sciences and Engineering Research Council of Canada. NR 31 TC 2 Z9 2 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2013 VL 32 IS 13 BP 2278 EP 2291 DI 10.1002/sim.5637 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 141YR UT WOS:000318763100009 PM 23027662 ER PT J AU Etemadi, A Islami, F Phillips, DH Godschalk, R Golozar, A Kamangar, F Malekshah, AFT Pourshams, A Elahi, S Ghojaghi, F Strickland, PT Taylor, PR Boffetta, P Abnet, CC Dawsey, SM Malekzadeh, R van Schooten, FJ AF Etemadi, Arash Islami, Farhad Phillips, David H. Godschalk, Roger Golozar, Asieh Kamangar, Farin Malekshah, Akbar Fazel-Tabar Pourshams, Akram Elahi, Seerat Ghojaghi, Farhad Strickland, Paul T. Taylor, Philip R. Boffetta, Paolo Abnet, Christian C. Dawsey, Sanford M. Malekzadeh, Reza van Schooten, Frederik J. TI Variation in PAH-related DNA adduct levels among non-smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotype SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE polycyclic aromatic hydrocarbons; DNA adducts; nucleotide excision repair; polymorphism ID POLYCYCLIC AROMATIC-HYDROCARBONS; 1-HYDROXYPYRENE GLUCURONIDE CONCENTRATIONS; PULMONARY EPITHELIAL-CELLS; WHITE BLOOD-CELLS; GRANDE-DO-SUL; ESOPHAGEAL CANCER; HEALTHY-SUBJECTS; TOBACCO-SMOKE; HIGH-RISK; EXPOSURE AB Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 108 nucleotides (mean: 5.8 +/- 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity. C1 [Etemadi, Arash; Golozar, Asieh; Kamangar, Farin; Taylor, Philip R.; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Etemadi, Arash; Islami, Farhad; Golozar, Asieh; Malekshah, Akbar Fazel-Tabar; Pourshams, Akram; Elahi, Seerat; Ghojaghi, Farhad; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Islami, Farhad] Int Agcy Res Canc, F-69372 Lyon, France. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Phillips, David H.] Kings Coll London, Analyt & Environm Sci Div, London WC2R 2LS, England. [Godschalk, Roger; van Schooten, Frederik J.] Maastricht Univ, Dept Toxicol, Sch Nutr Toxicol & Metab NUTRIM, Maastricht, Netherlands. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Strickland, Paul T.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Etemadi, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Malekzadeh, Reza/0000-0003-1043-3814; Phillips, David/0000-0001-8509-3485 FU Digestive Disease Research Center, Tehran University of Medical Sciences [88-04-37-10130]; Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS), a network of excellence operating within the European Union 6th Framework Program [Priority 5: "Food Quality and Safety"] [513943]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Grant sponsor: Digestive Disease Research Center, Tehran University of Medical Sciences; Grant number: 88-04-37-10130; Grant sponsor: Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS), a network of excellence operating within the European Union 6th Framework Program [Priority 5: "Food Quality and Safety"]; Grant number: 513943; Grant sponsor: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Intramural Research Program). NR 51 TC 6 Z9 6 U1 0 U2 44 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2013 VL 132 IS 12 BP 2738 EP 2747 DI 10.1002/ijc.27953 PG 10 WC Oncology SC Oncology GA 126DV UT WOS:000317593100003 PM 23175176 ER PT J AU Zhao, YQ Schetter, AJ Yang, GB Nguyen, G Mathe, EA Li, P Cai, H Yu, L Liu, FF Hang, D Yang, HJ Wang, XW Ke, Y Harris, CC AF Zhao, Yiqiang Schetter, Aaron J. Yang, Geoffrey B. Giang Nguyen Mathe, Ewy A. Li, Peng Cai, Hong Yu, Lei Liu, Fangfang Hang, Dong Yang, Haijun Wang, Xin Wei Ke, Yang Harris, Curtis C. TI microRNA and inflammatory gene expression as prognostic marker for overall survival in esophageal squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE esophageal squamous cell carcinoma; microRNA; prognostic classifier; inflammations ID ENDOTHELIAL GROWTH-FACTOR; LYMPH-NODE METASTASIS; TUMOR-SUPPRESSOR GENE; LUNG-CANCER; CLINICAL-SIGNIFICANCE; COLORECTAL-CANCER; POOR-PROGNOSIS; RISK-FACTORS; ADENOCARCINOMA; ANGIOGENESIS AB MicroRNAs (miRNAs) and inflammatory genes have a role in the initiation and development of esophageal squamous cell carcinoma (ESCC). In our study, we examined the potential of using miRNA and inflammatory gene expression patterns as prognostic classifiers for ESCC. Five miRNAs and 25 inflammatory-related genes were measured by quantitative reverse transcriptase PCR in tumor tissues and adjacent noncancerous tissues from 178 Chinese patients with ESCC. The expression levels of miR-21 (p = 0.027), miR-181b (p = 0.002) and miR-146b (p = 0.021) in tumor tissue and miR-21 (p = 0.003) in noncancerous tissue were associated with overall survival of patients. These data were combined to generate a miRNA risk score that was significantly associated with worse prognosis (p = 0.0001), suggesting that these miRNAs may be useful prognostic classifiers for ESCC. To construct an inflammatory gene prognostic classifier, we divided the population into training (n = 124) and test cohorts (n = 54). The expression levels of CRY61, CTGF and IL-18 in tumor tissue and VEGF in adjacent noncancerous tissue were modestly associated with prognosis in the training cohort |Z-score| > 1.5 and were subsequently used to construct a Cox regression-based inflammatory risk score (IRS). IRS was significantly associated with survival in both the training cohort (p = 0.002) and the test cohort (p = 0.005). Furthermore, Cox regression models combining both miRNA risk score and IRS performed significantly better than models with either alone (p < 0.001 likelihood ratio test). Therefore, miRNA and inflammatory gene expression patterns, alone or in combination, have potential as prognostic classifiers for ESCC and may help to guide therapeutic decisions. C1 [Zhao, Yiqiang; Schetter, Aaron J.; Yang, Geoffrey B.; Giang Nguyen; Mathe, Ewy A.; Yu, Lei; Wang, Xin Wei; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Yang, Geoffrey B.; Giang Nguyen] Howard Hughes Med Inst, Chevy Chase, MD USA. [Li, Peng] NIH, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Peng] Capital Normal Univ, Sch Math Sci, Beijing, Peoples R China. [Cai, Hong; Liu, Fangfang; Hang, Dong; Ke, Yang] Peking Univ, Sch Oncol, Beijing Canc Hosp & Inst, Beijing 100871, Peoples R China. [Yu, Lei] Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Shanghai 200433, Peoples R China. RP Ke, Y (reprint author), Peking Univ, Sch Oncol, Beijing Canc Hosp & Inst, Beijing 100871, Peoples R China. EM keyang@bjmu.edu.cn; curtis_harris@nih.gov RI Wang, Xin/B-6162-2009 FU National Cancer Institute, Center for Cancer Research at the National Institutes of Health; Natural Science Foundation of China [30872937, 30930102]; National Ministry of Science and Technology (973 Project) [2011CB504301]; Natural Science Foundation of Beijing [7100001] FX Grant sponsor: National Cancer Institute, Center for Cancer Research at the National Institutes of Health; Grant sponsor: Natural Science Foundation of China; Grant numbers: 30872937, 30930102; Grant sponsor: National Ministry of Science and Technology (973 Project); Grant number: 2011CB504301; Grant sponsor: Natural Science Foundation of Beijing; Grant number: 7100001 NR 72 TC 25 Z9 27 U1 0 U2 45 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 JUN 15 PY 2013 VL 132 IS 12 BP 2901 EP 2909 DI 10.1002/ijc.27954 PG 9 WC Oncology SC Oncology GA 126DV UT WOS:000317593100020 PM 23175214 ER PT J AU Weinstein, SJ Mondul, AM Kopp, W Rager, H Virtamo, J Albanes, D AF Weinstein, Stephanie J. Mondul, Alison M. Kopp, William Rager, Helen Virtamo, Jarmo Albanes, Demetrius TI Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE vitamin D-binding protein; 25-hydroxyvitamin D; prostate cancer; serum biomarkers; prospective study ID MACROPHAGE-ACTIVATING FACTOR; GENOME-WIDE ASSOCIATION; D METABOLITES; GC-GLOBULIN; SERUM; PLASMA; REPRODUCIBILITY; COHORT; MEGALIN; TRIAL AB We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D-binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and statistical tests were two sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR = 1.81, 95% CI: 1.182.79 for highest vs. lowest quintile, p-trend = 0.001) compared to those with DBP below the median (OR = 1.22, 95% CI: 0.811.84, p-trend 0.97; p-interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR = 0.96, 95% CI: 0.701.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower ( 98% sequence similarity) and an additional 32% could be assigned to a higher taxonomic level using Bayesian assignment. Conclusions: The molecular analysis of gut contents targeting the 313 COI fragment using the newly designed mlCOIintF primer in combination with the jgHCO2198 primer offers enormous promise for metazoan metabarcoding studies. We believe that this primer set will be a valuable asset for a range of applications from large-scale biodiversity assessments to food web studies. C1 [Leray, Matthieu; Mills, Suzanne C.] Univ Perpignan, Lab Excellence CORAIL, USR CRIOBE CNRS EPHE 3278, F-66860 Perpignan, France. [Leray, Matthieu; Meyer, Christopher P.; Agudelo, Natalia] Smithsonian Inst, Dept Invertebrate Zool, Natl Museum Nat Hist, Washington, DC 20013 USA. [Yang, Joy Y.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ranwez, Vincent] Montpellier SupAgro, UMR AGAP, Montpellier, France. [Boehm, Joel T.] CUNY City Coll, Dept Biol, New York, NY 10031 USA. [Boehm, Joel T.] CUNY, Grad Ctr, New York, NY 10016 USA. [Machida, Ryuji J.] Acad Sinica, Biodivers Res Ctr, Taipei 115, Taiwan. RP Leray, M (reprint author), Univ Perpignan, Lab Excellence CORAIL, USR CRIOBE CNRS EPHE 3278, F-66860 Perpignan, France. EM leray.upmc@gmail.com RI Mills, Suzanne/K-5538-2012 FU Gordon and Betty Moore Foundation; Smithsonian Institution; France American Cultural Exchange program (FACE - Partner University Fund); Live and Let Die [ANR-11-JSV7-012-01] FX We thank Gustav Paulay, Arthur Anker and the BIOCODE teams who collected and identified marine and terrestrial specimens, the "Centre de Recherche Insulaire et Observatoire de l'Environnement (CRIOBE) de Moorea" and the Richard B. Gump field station in Moorea for logistical support. We also greatly acknowledge the Gordon and Betty Moore Foundation, Smithsonian Institution Fellowship Program, France American Cultural Exchange program (FACE - Partner University Fund) and ANR-11-JSV7-012-01 Live and Let Die for financial support. Ehsan Kayal and Yvonne Linton provided constructive comments on an early draft of the manuscript. We are also grateful for insightful comments provided by Nancy Knowlton. This study was part of M. Leray PhD research program at Universite Pierre et Marie Curie (Paris VI) and Ecole Pratique des Hautes Etudes (EPHE) under the supervision of S.C. Mills. NR 68 TC 59 Z9 61 U1 21 U2 184 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-9994 J9 FRONT ZOOL JI Front. Zool. PD JUN 14 PY 2013 VL 10 AR UNSP 34 DI 10.1186/1742-9994-10-34 PG 14 WC Zoology SC Zoology GA 167FK UT WOS:000320616500001 PM 23767809 ER PT J AU Suh, YH Park, JY Park, S Jou, I Roche, PA Roche, KW AF Suh, Young Ho Park, Ji-Young Park, Sangwook Jou, Ilo Roche, Paul A. Roche, Katherine W. TI Regulation of Metabotropic Glutamate Receptor 7 (mGluR7) Internalization and Surface Expression by Ser/Thr Protein Phosphatase 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERINE/THREONINE PHOSPHATASES; INTERACTING PROTEINS; SYNAPTIC PLASTICITY; PKC PHOSPHORYLATION; CATALYTIC SUBUNIT; NERVOUS-SYSTEM; OKADAIC ACID; CALYCULIN-A; S6 KINASE; 2A AB The metabotropic glutamate receptor type 7 (mGluR7) is the predominant group III mGluR in the presynaptic active zone, where it serves as an autoreceptor to inhibit neurotransmitter release. Our previous studies show that PKC phosphorylation of mGluR7 on Ser-862 is a key mechanism controlling constitutive and activity-dependent surface expression of mGluR7 by regulating a competitive interaction of calmodulin and protein interacting with C kinase (PICK1). As receptor phosphorylation and dephosphorylation are tightly coordinated through the precise action of protein kinases and phosphatases, dephosphorylation by phosphatases is likely to play an active role in governing the activity-dependent or agonist-induced changes in mGluR7 receptor surface expression. In the present study, we find that the serine/threonine protein phosphatase 1 (PP1) has a crucial role in the constitutive and agonist-induced dephosphorylation of Ser-862 on mGluR7. Treatment of neurons with PP1 inhibitors leads to a robust increase in Ser-862 phosphorylation and increased surface expression of mGluR7. In addition, Ser-862 phosphorylation of both mGluR7a and mGluR7b is a target of PP1. Interestingly, agonist-induced dephosphorylation of mGluR7 is regulated by PP1, whereas NMDA-mediated activity-induced dephosphorylation is not, illustrating there are multiple signaling pathways that affect receptor phosphorylation and trafficking. Importantly, PP1 gamma 1 regulates agonist-dependent Ser-862 dephosphorylation and surface expression of mGluR7. C1 [Suh, Young Ho; Park, Ji-Young; Park, Sangwook; Jou, Ilo] Ajou Univ, Sch Med, Dept Pharmacol, Suwon 443721, South Korea. [Suh, Young Ho; Park, Ji-Young; Park, Sangwook; Jou, Ilo] Ajou Univ, Sch Med, Chron Inflammatory Dis Res Ctr, Suwon 443721, South Korea. [Suh, Young Ho; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Suh, Young Ho; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), NINDS, Receptor Biol Sect, NIH, Porter Neurosci Res Ctr, Bldg 35,Rm 2C903, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU NINDS, National Institutes of Health, Intramural Research Program; NCI, National Institutes of Health, Intramural Research Program; Ajou University School of Medicine; Basic Science Research Program through the National Research Foundation of Korea [2011-0011694]; Medical Research Center Program through the National Research Foundation of Korea [NRF-2012R1A5A048183] FX This work was supported by the NINDS, National Institutes of Health, Intramural Research Program (to K. W. R.), the NCI, National Institutes of Health, Intramural Research Program (to P. A. R.), the new faculty research fund of the Ajou University School of Medicine, and the Basic Science Research Program (2011-0011694) and Medical Research Center Program (NRF-2012R1A5A048183) through the National Research Foundation of Korea. NR 42 TC 8 Z9 8 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 14 PY 2013 VL 288 IS 24 BP 17544 EP 17551 DI 10.1074/jbc.M112.439513 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164AH UT WOS:000320380600045 PM 23612982 ER PT J AU Varkey, J Mizuno, N Hegde, BG Cheng, NQ Steven, AC Langen, R AF Varkey, Jobin Mizuno, Naoko Hegde, Balachandra G. Cheng, Naiqian Steven, Alasdair C. Langen, Ralf TI alpha-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEINS; APOLIPOPROTEIN-A-I; FAMILIAL PARKINSONS-DISEASE; PULSED ESR MEASUREMENTS; FATTY-ACIDS; TRANSGENIC MICE; MEMBRANE INTERACTIONS; UNILAMELLAR VESICLES; HIPPOCAMPAL-NEURONS; SECONDARY STRUCTURE AB alpha-Synuclein (alpha S) is a membrane-binding protein with sequence similarity to apolipoproteins and other lipid-carrying proteins, which are capable of forming lipid-containing nanoparticles, sometimes referred to as "discs." Previously, it has been unclear whether alpha S also possesses this property. Using cryo-electron microscopy and light scattering, we found that alpha S can remodel phosphatidylglycerol vesicles into nanoparticles whose shape (ellipsoidal) and dimensions (in the 7-10-nm range) resemble those formed by apolipoproteins. The molar ratio of alpha S to lipid in nanoparticles is similar to 1:20, and alpha S is oligomeric (including trimers and tetramers). Similar nanoparticles form when alpha S is added to vesicles of mitochondrial lipids. This observation suggests a mechanism for the previously reported disruption of mitochondrial membranes by alpha S. Circular dichroism and four-pulse double electron electron resonance experiments revealed that in nanoparticles alpha S assumes a broken helical conformation distinct from the extended helical conformation adopted when alpha S is bound to intact vesicles or membrane tubules. We also observed alpha S-dependent tubule and nanoparticle formation in the presence of oleic acid, implying that alpha S can interact with fatty acids and lipids in a similar manner. alpha S-related nanoparticles might play a role in lipid and fatty acid transport functions previously attributed to this protein. C1 [Varkey, Jobin; Langen, Ralf] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Mizuno, Naoko] Max Planck Inst Biochem, Dept Struct Cell Biol, D-82152 Martinsried, Germany. [Hegde, Balachandra G.] PES Inst Technol, Bangalore, Karnataka, India. [Mizuno, Naoko; Cheng, Naiqian; Steven, Alasdair C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih; langen@usc.edu FU National Institutes of Health [2 R01 M063915]; Intramural Research Program of the NIAMS FX This work was supported, in whole or in part, by National Institutes of Health Grant 2 R01 M063915 (to R. L.) and by the Intramural Research Program of the NIAMS. NR 90 TC 26 Z9 26 U1 3 U2 30 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 JUN 14 PY 2013 VL 288 IS 24 BP 17620 EP 17630 DI 10.1074/jbc.M113.476697 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164AH UT WOS:000320380600053 PM 23609437 ER PT J AU Leidgens, S Bullough, KZ Shi, HF Li, FM Shakoury-Elizeh, M Yabe, T Subramanian, P Hsu, E Natarajan, N Nandal, A Stemmler, TL Philpott, CC AF Leidgens, Sebastien Bullough, Kimberly Z. Shi, Haifeng Li, Fengmin Shakoury-Elizeh, Minoo Yabe, Toshiki Subramanian, Poorna Hsu, Emory Natarajan, Navin Nandal, Anjali Stemmler, Timothy L. Philpott, Caroline C. TI Each Member of the Poly-r(C)-binding Protein 1 (PCBP) Family Exhibits Iron Chaperone Activity toward Ferritin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA STABILITY; BINDING-PROTEIN; SACCHAROMYCES-CEREVISIAE; HOMEOSTASIS; GENE; HYDROXYLASE; PATHWAY; YEAST AB The mechanisms through which iron-dependent enzymes receive their metal cofactors are largely unknown. Poly r(C)-binding protein 1 (PCBP1) is an iron chaperone for ferritin; both PCBP1 and its paralog PCBP2 are required for iron delivery to the prolyl hydroxylase that regulates HIF1. Here we show that PCBP2 is also an iron chaperone for ferritin. Co-expression of PCBP2 and human ferritins in yeast activated the iron deficiency response and increased iron deposition into ferritin. Depletion of PCBP2 in Huh7 cells diminished iron incorporation into ferritin. Both PCBP1 and PCBP2 were co-immunoprecipitated with ferritin in HEK293 cells, and expression of both PCBPs was required for ferritin complex formation in cells. PCBP1 and -2 exhibited high affinity binding to ferritin in vitro. Mammalian genomes encode 4 PCBPs, including the minimally expressed PCBPs 3 and 4. Expression of PCBP3 and -4 in yeast activated the iron deficiency response, but only PCBP3 exhibited strong interactions with ferritin. Expression of PCBP1 and ferritin in an iron-sensitive, ccc1 yeast strain intensified the toxic effects of iron, whereas expression of PCBP4 protected the cells from iron toxicity. Thus, PCBP1 and -2 form a complex for iron delivery to ferritin, and all PCBPs may share iron chaperone activity. C1 [Leidgens, Sebastien; Bullough, Kimberly Z.; Shi, Haifeng; Li, Fengmin; Shakoury-Elizeh, Minoo; Yabe, Toshiki; Hsu, Emory; Natarajan, Navin; Nandal, Anjali; Philpott, Caroline C.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Subramanian, Poorna; Stemmler, Timothy L.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. [Hsu, Emory] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. RP Philpott, CC (reprint author), NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov RI Li, Fengmin/J-5721-2013; Nandal, Anjali/A-5376-2013; Yabe-Wada, Toshiki/L-9942-2016 OI Yabe-Wada, Toshiki/0000-0002-6208-0590 FU Intramural Research Program of the NIDDK, National Institutes of Health; National Institutes of Health [DK068139] FX This work was supported in part by the Intramural Research Program of the NIDDK, National Institutes of Health.; Supported by the National Institutes of Health Grant DK068139. NR 28 TC 36 Z9 39 U1 0 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 14 PY 2013 VL 288 IS 24 BP 17791 EP 17802 DI 10.1074/jbc.M113.460253 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164AH UT WOS:000320380600068 PM 23640898 ER PT J AU Oguariri, RM Dai, L Adelsberger, JW Rupert, A Stevens, R Yang, J Huang, DW Lempicki, RA Zhou, M Baseler, MW Lane, HC Imamichi, T AF Oguariri, Raphael M. Dai, Lue Adelsberger, Joseph W. Rupert, Adam Stevens, Randy Yang, Jun Huang, Dawei Lempicki, Richard A. Zhou, Ming Baseler, Michael W. Lane, H. Clifford Imamichi, Tomozumi TI Interleukin-2 Inhibits HIV-1 Replication in Some Human T Cell Lymphotrophic Virus-1-infected Cell Lines via the Induction and Incorporation of APOBEC3G into the Virion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NECROSIS FACTOR-ALPHA; GAMMA-CHAIN; ANTIVIRAL ACTIVITY; IN-VIVO; FUNCTIONAL COMPONENT; CYTIDINE DEAMINATION; HUMAN MACROPHAGES; CUTTING EDGE; VIF PROTEIN AB IL-2 has been used in culture of primary T cells to maintain cell proliferation. We have previously reported that IL-27 inhibits HIV-1 replication in primary T cells in the presence of IL-2. To gain a better understanding of the mechanisms involved in this inhibitory effect, we attempted to investigate in detail the effects of IL-27 and IL-2 using several cell lines. Unexpectedly, IL-27 did not inhibit HIV-1 in T cell lines, whereas IL-2 inhibited HIV-1 replication in the human T cell lymphotrophic virus (HTLV)- 1-transformed T cell lines, MT-2, MT-4, SLB-1, and ATL-2. No effects were seen in HTLV-1-negative cell lines. Utilizing MT-2 cells, we demonstrated that IL-2 treatment inhibited HIV-1 syncytia-inducing ability and dose-dependently decreased supernatant p24 antigen levels by >90%. Using real time PCR and Western blot analysis, we observed that IL-2 treatment induced the host restriction factor, APOBEC3G with accumulation into the lower molecular mass active form as characterized by FPLC. Further analysis revealed that the virus recovered from IL-2-treated MT-2 cells had impaired replication competency. This was found to be due to incorporation of APOBEC3G into the virion despite the presence of Vif. These findings demonstrate a novel role for IL-2 in regulating production of infectious HIV-1 virions in HTLV-1-infected cells through the induction of APOBEC3G. C1 [Oguariri, Raphael M.; Dai, Lue; Imamichi, Tomozumi] Frederick Natl Lab Canc Res, Lab Human Retrovirol, Frederick, MD 21702 USA. [Adelsberger, Joseph W.; Rupert, Adam; Stevens, Randy; Baseler, Michael W.] Frederick Natl Lab Canc Res, AIDS Monitoring Lab, Frederick, MD 21702 USA. [Yang, Jun; Huang, Dawei; Lempicki, Richard A.] Frederick Natl Lab Canc Res, Lab Immunopathogenesis & Bioinformat, Frederick, MD 21702 USA. [Oguariri, Raphael M.; Dai, Lue; Adelsberger, Joseph W.; Rupert, Adam; Stevens, Randy; Yang, Jun; Huang, Dawei; Lempicki, Richard A.; Baseler, Michael W.; Imamichi, Tomozumi] Frederick Natl Lab Canc Res, Clin Serv Program, Appl & Dev Directorate, Frederick, MD 21702 USA. [Zhou, Ming] Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Adv Technol Program Directorate, Sci Applicat Int Corp,Frederick Inc, Frederick, MD 21702 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), Frederick Natl Lab Canc Res, Lab Human Retrovirol, Appl & Dev Directorate, Sci Applicat Int Corp,Frederick Inc, Bldg 550,Rm 126,1050 Boyles St, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This work was supported, in whole or in part, by a National Institutes of Health Grant under Contract HHSN261200800001E. This work was also supported in part by the National Institute of Allergy and Infectious Diseases. NR 67 TC 6 Z9 6 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 JUN 14 PY 2013 VL 288 IS 24 BP 17812 EP 17822 DI 10.1074/jbc.M113.468975 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164AH UT WOS:000320380600070 PM 23640893 ER PT J AU Gao, SJ Damaj, MB Park, JW Beyene, G Buenrostro-Nava, MT Molina, J Wang, XF Ciomperlik, JJ Manabayeva, SA Alvarado, VY Rathore, KS Scholthof, HB Mirkov, TE AF Gao, San-Ji Damaj, Mona B. Park, Jong-Won Beyene, Getu Buenrostro-Nava, Marco T. Molina, Joe Wang, Xiaofeng Ciomperlik, Jessica J. Manabayeva, Shuga A. Alvarado, Veria Y. Rathore, Keerti S. Scholthof, Herman B. Mirkov, T. Erik TI Enhanced Transgene Expression in Sugarcane by Co-Expression of Virus-Encoded RNA Silencing Suppressors SO PLOS ONE LA English DT Article ID TRANSIENT GENE-EXPRESSION; DOUBLE-STRANDED-RNA; VIRAL SUPPRESSORS; MICROPROJECTILE BOMBARDMENT; GFP EXPRESSION; NICOTIANA-BENTHAMIANA; PARTICLE BOMBARDMENT; SUSPENSION-CULTURES; BETA-GLUCURONIDASE; PROTOPLAST SYSTEM AB Post-transcriptional gene silencing is commonly observed in polyploid species and often poses a major limitation to plant improvement via biotechnology. Five plant viral suppressors of RNA silencing were evaluated for their ability to counteract gene silencing and enhance the expression of the Enhanced Yellow Fluorescent Protein (EYFP) or the beta-glucuronidase (GUS) reporter gene in sugarcane, a major sugar and biomass producing polyploid. Functionality of these suppressors was first verified in Nicotiana benthamiana and onion epidermal cells, and later tested by transient expression in sugarcane young leaf segments and protoplasts. In young leaf segments co-expressing a suppressor, EYFP reached its maximum expression at 48-96 h post-DNA introduction and maintained its peak expression for a longer time compared with that in the absence of a suppressor. Among the five suppressors, Tomato bushy stunt virus-encoded P19 and Barley stripe mosaic virus-encoded gamma b were the most efficient. Co-expression with P19 and gamma b enhanced EYFP expression 4.6-fold and 3.6-fold in young leaf segments, and GUS activity 2.3-fold and 2.4-fold in protoplasts compared with those in the absence of a suppressor, respectively. In transgenic sugarcane, co-expression of GUS and P19 suppressor showed the highest accumulation of GUS levels with an average of 2.7-fold more than when GUS was expressed alone, with no detrimental phenotypic effects. The two established transient expression assays, based on young leaf segments and protoplasts, and confirmed by stable transgene expression, offer a rapid versatile system to verify the efficiency of RNA silencing suppressors that proved to be valuable in enhancing and stabilizing transgene expression in sugarcane. C1 [Gao, San-Ji] Fujian Agr & Forestry Univ, Minist Agr, Key Lab Sugarcane Biol & Genet Breeding, Fuzhou, Fujian, Peoples R China. [Damaj, Mona B.; Park, Jong-Won; Molina, Joe; Mirkov, T. Erik] Texas A&M AgriLife Res, Dept Plant Pathol & Microbiol, Weslaco, TX USA. [Beyene, Getu] Donald Danforth Plant Sci Ctr, Inst Int Crop Improvement, St Louis, MO USA. [Buenrostro-Nava, Marco T.] Univ Colima, FCBA Lab Biotecnol, Tecoman, Colima, Mexico. [Wang, Xiaofeng] VirginiaTech Univ, Dept Plant Pathol Physiol & Weed Sci, Blacksburg, VA USA. [Ciomperlik, Jessica J.; Scholthof, Herman B.] Texas A&M Univ, Dept Plant Pathol & Microbiol, College Stn, TX 77843 USA. [Manabayeva, Shuga A.] Natl Ctr Biotechnol Republ Kazakhstan, Astana, Kazakhstan. [Alvarado, Veria Y.] Texas A&M Univ, Stoller Enterprises Inc, Norman E Borlaug Ctr Southern Crop Improvement, College Stn, TX USA. [Rathore, Keerti S.] Texas A&M Univ, Inst Plant Genom & Biotechnol, Norman E Borlaug Ctr Southern Crop Improvement, Lab Crop Transformat, College Stn, TX USA. RP Mirkov, TE (reprint author), Texas A&M AgriLife Res, Dept Plant Pathol & Microbiol, Weslaco, TX USA. EM e-mirkov@tamu.edu RI Park, Jong-Won/O-5097-2014; Wang, Xiaofeng/E-9940-2016; Manabayeva, Shuga/A-2529-2015 OI Park, Jong-Won/0000-0002-1936-8230; Wang, Xiaofeng/0000-0002-3850-3274; Manabayeva, Shuga/0000-0001-7884-1713 FU Texas AgriLife Bioenergy grant [0809] FX This work was supported by a Texas AgriLife Bioenergy grant 0809. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 3 Z9 4 U1 1 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2013 VL 8 IS 6 AR e66046 DI 10.1371/journal.pone.0066046 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UV UT WOS:000320363300060 PM 23799071 ER PT J AU Nishi, H Tyagi, M Teng, SL Shoemaker, BA Hashimoto, K Alexov, E Wuchty, S Panchenko, AR AF Nishi, Hafumi Tyagi, Manoj Teng, Shaolei Shoemaker, Benjamin A. Hashimoto, Kosuke Alexov, Emil Wuchty, Stefan Panchenko, Anna R. TI Cancer Missense Mutations Alter Binding Properties of Proteins and Their Interaction Networks SO PLOS ONE LA English DT Article ID HUMAN GENETIC-DISEASE; HOT-SPOTS; PHOSPHORYLATION SITES; SIGNALING PATHWAYS; CRYSTAL-STRUCTURE; DRIVER MUTATIONS; CORE PATHWAYS; PREDICTION; STABILITY; COMPLEXES AB Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical properties than mutations occurring outside the interfaces. Analysis of glioblastoma mutations on interfaces allowed us to stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers, including those specific to functions of the nervous system. Such an analysis also offered insight into the molecular mechanism of the phenotypic outcomes of mutations, including effects on complex stability, activity, binding and turnover rate. As a result of mutated protein and gene network analysis, we observed that interactions of proteins with mutations mapped on interfaces had higher bottleneck properties compared to interactions with mutations elsewhere on the protein or unaffected interactions. Such observations suggest that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks. C1 [Nishi, Hafumi; Shoemaker, Benjamin A.; Wuchty, Stefan; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Tyagi, Manoj] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Teng, Shaolei; Alexov, Emil] Clemson Univ, Dept Phys, Clemson, SC USA. [Hashimoto, Kosuke] RIKEN, Omics Sci Ctr, Yokohama, Kanagawa, Japan. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM panch@ncbi.nlm.nih.gov RI Tyagi, Manoj/K-8438-2014; OI Nishi, Hafumi/0000-0002-0846-0330 FU National Library of Medicine at the U.S. National Institutes of Health; JSPS Research Fellowship from the Japan Society for the Promotion of Science; National Institutes of Health, National Institute of General Medical Sciences [R01GM093937] FX This work was supported by the Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health. K. H. in part was supported by a JSPS Research Fellowship from the Japan Society for the Promotion of Science. EA was supported in part by National Institutes of Health, National Institute of General Medical Sciences, grant number R01GM093937. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 27 Z9 27 U1 0 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2013 VL 8 IS 6 AR e66273 DI 10.1371/journal.pone.0066273 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UV UT WOS:000320363300071 PM 23799087 ER PT J AU Vaughan, L Espeland, MA Snively, B Shumaker, SA Rapp, SR Shupe, J Robinson, JG Sarto, GE Resnick, SM AF Vaughan, Leslie Espeland, Mark A. Snively, Beverly Shumaker, Sally A. Rapp, Stephen R. Shupe, Jill Robinson, Jennifer G. Sarto, Gloria E. Resnick, Susan M. CA Women's Hlth Initiative Memory Stu TI The rationale, design, and baseline characteristics of the Women's Health Initiative Memory Study of Younger Women (WHIMS-Y) SO BRAIN RESEARCH LA English DT Article DE Postmenopausal hormone therapy; Cognitive function; Aging ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; CONJUGATED EQUINE ESTROGENS; MILD COGNITIVE IMPAIRMENT; POSTMENOPAUSAL WOMEN; DEMENTIA QUESTIONNAIRE; ALZHEIMER-DISEASE; VALIDATION; TELEPHONE; THERAPY AB The Women's Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women's Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-55 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-55 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites. This article is part of a Special Issue entitled Hormone Therapy. (C) 2013 Elsevier B.V. All rights reserved. C1 [Vaughan, Leslie; Espeland, Mark A.; Snively, Beverly; Shumaker, Sally A.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Rapp, Stephen R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Psychiat, Winston Salem, NC 27157 USA. [Shupe, Jill] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Div Cardiol, Iowa City, IA 52242 USA. [Sarto, Gloria E.] Univ Wisconsin, Ctr Womens Hlth Res, Madison, WI 53715 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Vaughan, L (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM alvaugha@wakehealth.edu; mespelan@wakehealth.edu; bmellen@wakehealth.edu; sshumake@wakehealth.edu; srapp@wakehealth.edu; jshupe@whi.org; jennifer-g-robinson@uiowa.edu; gsarto@wisc.edu; susan.resnick@nih.gov RI Scharre, Douglas/E-4030-2011 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services [HHSN-271-2011-00004C]; National Heart, Lung, and Blood Institute, National Institutes of Health [N01-WH-4-4221]; National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services FX WHIMS-Y has been funded in whole or in part with Federal funds from the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, under Contract no. HHSN-271-2011-00004C, and the National Heart, Lung, and Blood Institute, National Institutes of Health, under Contract no. N01-WH-4-4221. The WHI program is funded by the National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services. NR 28 TC 4 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 13 PY 2013 VL 1514 SI SI BP 3 EP 11 DI 10.1016/j.brainres.2013.03.047 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 180KV UT WOS:000321595000002 PM 23578696 ER PT J AU Davis, BJ Risinger, JI Chandramouli, GVR Bushel, PR Baird, DD Peddada, SD AF Davis, Barbara J. Risinger, John I. Chandramouli, Gadisetti V. R. Bushel, Pierre R. Baird, Donna Day Peddada, Shyamal D. TI Gene Expression in Uterine Leiomyoma from Tumors Likely to Be Growing (from Black Women over 35) and Tumors Likely to Be Non-Growing (from White Women over 35) SO PLOS ONE LA English DT Article ID ORDER-RESTRICTED INFERENCE; SUPPRESSOR PROTEIN; GROWTH; PREGNANCY; FIBROIDS; PVHL; DIFFERENTIATION; PATHOGENESIS; ADHESIONS; INSIGHTS AB The study of uterine leiomyomata (fibroids) provides a unique opportunity to investigate the physiological and molecular determinants of hormone dependent tumor growth and spontaneous tumor regression. We conducted a longitudinal clinical study of premenopausal women with leiomyoma that showed significantly different growth rates between white and black women depending on their age. Growth rates for leiomyoma were on average much higher from older black women than for older white women, and we now report gene expression pattern differences in tumors from these two groups of study participants. Total RNA from 52 leiomyoma and 8 myometrial samples were analyzed using Affymetrix Gene Chip expression arrays. Gene expression data was first compared between all leiomyoma and normal myometrium and then between leiomyoma from older black women (age 35 or older) and from older white women. Genes that were found significant in pairwise comparisons were further analyzed for canonical pathways, networks and biological functions using the Ingenuity Pathway Analysis (IPA) software. Whereas our comparison of leiomyoma to myometrium produced a very large list of genes highly similar to numerous previous studies, distinct sets of genes and signaling pathways were identified in comparisons of older black and white women whose tumors were likely to be growing and non-growing, respectively. Key among these were genes associated with regulation of apoptosis. To our knowledge, this is the first study to compare two groups of tumors that are likely to have different growth rates in order to reveal molecular signals likely to be influential in tumor growth. C1 [Davis, Barbara J.] Tufts Univ, Cummings Sch Vet Med, North Grafton, MA USA. [Risinger, John I.; Chandramouli, Gadisetti V. R.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. [Bushel, Pierre R.; Peddada, Shyamal D.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Baird, Donna Day] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Peddada, SD (reprint author), NIEHS, Biostat Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM Peddada@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural Research Program of the NIEHS, National Institutes of Health [Z01ES 101663-05, Z01 ES102345-04]; National Center on Minority Health and Health Disparities Grant [MO1RR00046]; NIEHS [N01-ES-95446, 273-01-C-0157]; Integrated Laboratory Systems in RT-PCR assays FX This project was supported by Intramural Research Program of the NIEHS, National Institutes of Health (Grant Z01ES 101663-05 and Z01 ES102345-04), with partial funding from the National Center on Minority Health and Health Disparities Grant MO1RR00046 and NIEHS Contracts N01-ES-95446 and 273-01-C-0157. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors thank the study participants; the contributions of Dr. Pamela Blackshear and support of Integrated Laboratory Systems in RT-PCR assays; and Dr. Kissling (NIEHS), Dr. Leppert (Duke University) for careful reading of an earlier version of the manuscript. NR 43 TC 10 Z9 10 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2013 VL 8 IS 6 AR e63909 DI 10.1371/journal.pone.0063909 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 172XB UT WOS:000321038800121 PM 23785396 ER PT J AU Gottesman, MM AF Gottesman, Michael M. TI The Role of the NIH in Nurturing Clinician-Scientists SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 OD999999] NR 5 TC 8 Z9 8 U1 0 U2 4 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 JUN 13 PY 2013 VL 368 IS 24 BP 2249 EP 2251 DI 10.1056/NEJMp1302969 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 161YN UT WOS:000320230500015 PM 23675642 ER PT J AU Marquardt, JU Thorgeirsson, SS AF Marquardt, Jens U. Thorgeirsson, Snorri S. TI Sall4 in "Stemness"-Driven Hepatocarcinogenesis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ADVANCED HEPATOCELLULAR-CARCINOMA; CELLS; SORAFENIB C1 [Marquardt, Jens U.; Thorgeirsson, Snorri S.] NCI, NIH, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Dept Med 1, D-55122 Mainz, Germany. RP Marquardt, JU (reprint author), NCI, NIH, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 12 TC 7 Z9 7 U1 0 U2 9 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 JUN 13 PY 2013 VL 368 IS 24 BP 2316 EP 2318 DI 10.1056/NEJMe1303026 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 161YN UT WOS:000320230500010 PM 23758237 ER PT J AU Zaidi, S Choi, M Wakimoto, H Ma, LJ Jiang, JM Overton, JD Romano-Adesman, A Bjornson, RD Breitbart, RE Brown, KK Carriero, NJ Cheung, YH Deanfield, J DePalma, S Fakhro, KA Glessner, J Hakonarson, H Italia, MJ Kaltman, JR Kaski, J Kim, R Kline, JK Lee, T Leipzig, J Lopez, A Mane, SM Mitchell, LE Newburger, JW Parfenov, M Pe'er, I Porter, G Roberts, AE Sachidanandam, R Sanders, SJ Seiden, HS State, MW Subramanian, S Tikhonova, IR Wang, W Warburton, D White, PS Williams, IA Zhao, HY Seidman, JG Brueckner, M Chung, WK Gelb, BD Goldmuntz, E Seidman, CE Lifton, RP AF Zaidi, Samir Choi, Murim Wakimoto, Hiroko Ma, Lijiang Jiang, Jianming Overton, John D. Romano-Adesman, Angela Bjornson, Robert D. Breitbart, Roger E. Brown, Kerry K. Carriero, Nicholas J. Cheung, Yee Him Deanfield, John DePalma, Steve Fakhro, Khalid A. Glessner, Joseph Hakonarson, Hakon Italia, Michael J. Kaltman, Jonathan R. Kaski, Juan Kim, Richard Kline, Jennie K. Lee, Teresa Leipzig, Jeremy Lopez, Alexander Mane, Shrikant M. Mitchell, Laura E. Newburger, Jane W. Parfenov, Michael Pe'er, Itsik Porter, George Roberts, Amy E. Sachidanandam, Ravi Sanders, Stephan J. Seiden, Howard S. State, Mathew W. Subramanian, Sailakshmi Tikhonova, Irina R. Wang, Wei Warburton, Dorothy White, Peter S. Williams, Ismee A. Zhao, Hongyu Seidman, Jonathan G. Brueckner, Martina Chung, Wendy K. Gelb, Bruce D. Goldmuntz, Elizabeth Seidman, Christine E. Lifton, Richard P. TI De novo mutations in histone-modifying genes in congenital heart disease SO NATURE LA English DT Article ID AUTISM SPECTRUM DISORDERS; COPY-NUMBER VARIANTS; EMBRYONIC STEM-CELLS; RISK; DELETION; NETWORK; FAMILY AB Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births(1). Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation(2-4). There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer(5). The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes(6). These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD. C1 [Zaidi, Samir; Choi, Murim; Overton, John D.; Fakhro, Khalid A.; Lopez, Alexander; Mane, Shrikant M.; Sanders, Stephan J.; State, Mathew W.; Tikhonova, Irina R.; Zhao, Hongyu; Brueckner, Martina; Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06504 USA. [Zaidi, Samir; Choi, Murim; Fakhro, Khalid A.; Lifton, Richard P.] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Wakimoto, Hiroko; Jiang, Jianming; Brown, Kerry K.; DePalma, Steve; Parfenov, Michael; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ma, Lijiang; Lee, Teresa; Warburton, Dorothy; Williams, Ismee A.; Chung, Wendy K.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Jiang, Jianming; Seidman, Christine E.] Harvard Univ, Howard Hughes Med Inst, Boston, MA 02115 USA. [Overton, John D.; Lopez, Alexander; Mane, Shrikant M.; Tikhonova, Irina R.; Lifton, Richard P.] Yale Ctr Mendelian Genom, New Haven, CT 06510 USA. [Overton, John D.; Bjornson, Robert D.; Carriero, Nicholas J.; Lopez, Alexander; Mane, Shrikant M.; Tikhonova, Irina R.; Lifton, Richard P.] Yale Univ, Yale Ctr Genome Anal, New Haven, CT 06511 USA. [Romano-Adesman, Angela] Steven & Alexandra Cohen Childrens Med Ctr New Yo, New Hyde Pk, NY 11040 USA. [Bjornson, Robert D.; Carriero, Nicholas J.] Yale Univ, Dept Comp Sci, New Haven, CT 06511 USA. [Breitbart, Roger E.; Newburger, Jane W.; Roberts, Amy E.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Cheung, Yee Him] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Deanfield, John; Kaski, Juan] Great Ormond St Hosp Sick Children, Univ Coll London, Dept Cardiol, London WC1N 3JH, England. [Glessner, Joseph; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Hakonarson, Hakon; White, Peter S.; Goldmuntz, Elizabeth] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Italia, Michael J.; Leipzig, Jeremy; Wang, Wei; White, Peter S.] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Kaltman, Jonathan R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kim, Richard] Univ So Calif, Keck Sch Med, Sect Cardiothorac Surg, Los Angeles, CA 90089 USA. [Kline, Jennie K.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Mitchell, Laura E.] Univ Texas Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10032 USA. [Porter, George] Univ Rochester, Sch Med & Dent, Med Ctr, Dept Pediat, Rochester, NY 14611 USA. [Sachidanandam, Ravi; Subramanian, Sailakshmi; Gelb, Bruce D.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Sanders, Stephan J.; State, Mathew W.] Yale Univ, Dept Psychiat, Ctr Child Study, Program Neurogenet, New Haven, CT 06510 USA. [Seiden, Howard S.; Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Wang, Wei] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Warburton, Dorothy] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Zhao, Hongyu] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06510 USA. [Brueckner, Martina] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Chung, Wendy K.] Columbia Univ, Med Ctr, Dept Med, New York, NY 10032 USA. [Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Goldmuntz, Elizabeth] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Seidman, Christine E.] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. RP Brueckner, M (reprint author), Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06504 USA. EM martina.brueckner@yale.edu; wkc15@cumc.columbia.edu; bruce.gelb@mssm.edu; goldmuntz@email.chop.edu; csediman@genetics.med.harvard.edu; richard.lifton@yale.edu RI Porter, George/E-7315-2013; jiang, jianming/B-3421-2012; OI Porter, George/0000-0003-0726-9988; Kaski, Juan Pablo/0000-0002-0014-9927; Subramanian, Sai Lakshmi/0000-0003-1384-0722; Leipzig, Jeremy/0000-0001-7224-9620; Sanders, Stephan/0000-0001-9112-5148 FU National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Pediatric Cardiac Genomics Consortium [U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162]; Simons Foundation for Autism Research; NIH Centers for Mendelian Genomics [5U54HG006504] FX The authors are grateful to the patients and families who participated in this research. We thank the following team members for contributions to patient recruitment: D. Awad, K. Celia, D. Etwaru, R. Korsin, A. Lanz, E. Marquez, J. K. Sond, A. Wilpers, R. Yee (Columbia Medical School); K. Boardman, J. Geva, J. Gorham, B. McDonough, A. Monafo, J. Stryker (Harvard Medical School); N. Cross (Yale School of Medicine); S. M. Edman, J. L. Garbarini, J. E. Tusi, S. H. Woyciechowski (Children's Hospital of Philadelphia); J. Ellashek and N. Tran (Children's Hospital of Los Angeles); K. Flack (University College London); D. Gruber, N. Stellato (Steve and Alexandra Cohen Children's Medical Center of New York); D. Guevara, A. Julian, M. Mac Neal, C. Mintz (Icahn School of Medicine at Mount Sinai); and E. Taillie (University of Rochester School of Medicine and Dentistry). We also thank V. Spotlow, P. Candrea, K. Pavlik and M. Sotiropoulos for their expert production of exome sequences. We thank B. Bernstein and R. Ryan (Massachusetts General Hospital) and B. Bruneau (Gladstone Institute and University of California, San Francisco) for discussions. This work was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Pediatric Cardiac Genomics Consortium (U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162) and in part by the Simons Foundation for Autism Research and the NIH Centers for Mendelian Genomics (5U54HG006504). NR 30 TC 228 Z9 232 U1 4 U2 57 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 13 PY 2013 VL 498 IS 7453 BP 220 EP + DI 10.1038/nature12141 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 162RR UT WOS:000320283400046 PM 23665959 ER PT J AU Cruz-Garcia, D Ortega-Bellido, M Scarpa, M Villeneuve, J Jovic, M Porzner, M Balla, T Seufferlein, T Malhotra, V AF Cruz-Garcia, David Ortega-Bellido, Maria Scarpa, Margherita Villeneuve, Julien Jovic, Marko Porzner, Marc Balla, Tamas Seufferlein, Thomas Malhotra, Vivek TI Recruitment of arfaptins to the trans-Golgi network by PI(4)P and their involvement in cargo export SO EMBO JOURNAL LA English DT Article DE amphipathic helix; arfaptins; PI(4)P; PKD; protein secretion ID PROTEIN-KINASE-D; BIN/AMPHIPHYSIN/RVS BAR DOMAIN; D-MEDIATED PHOSPHORYLATION; ADP-RIBOSYLATION FACTOR; BINDING PROTEIN; CELL-SURFACE; MEMBRANE FISSION; PHOSPHOLIPASE-D; COMPLEX; ARF AB The BAR (Bin/Amphiphysin/Rvs) domain proteins arfaptin1 and arfaptin2 are localized to the trans-Golgi network (TGN) and, by virtue of their ability to sense and/or generate membrane curvature, could play an important role in the biogenesis of transport carriers. We report that arfaptins contain an amphipathic helix (AH) preceding the BAR domain, which is essential for their binding to phosphatidylinositol 4-phosphate (PI(4)P)-containing liposomes and the TGN of mammalian cells. The binding of arfaptin1, but not arfaptin2, to PI(4)P is regulated by protein kinase D (PKD) mediated phosphorylation at Ser100 within the AH. We also found that only arfaptin1 is required for the PKD-dependent trafficking of chromogranin A by the regulated secretory pathway. Altogether, these findings reveal the importance of PI(4)P and PKD in the recruitment of arfaptins at the TGN and their requirement in the events leading to the biogenesis of secretory storage granules. C1 [Cruz-Garcia, David; Ortega-Bellido, Maria; Scarpa, Margherita; Villeneuve, Julien; Malhotra, Vivek] Ctr Genom Regulat, Barcelona, Spain. [Cruz-Garcia, David; Ortega-Bellido, Maria; Scarpa, Margherita; Villeneuve, Julien; Malhotra, Vivek] Univ Pompeu Fabra, Barcelona, Spain. [Jovic, Marko; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD USA. [Porzner, Marc; Seufferlein, Thomas] Univ Ulm, Dept Internal Med 1, D-89069 Ulm, Germany. [Malhotra, Vivek] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. RP Malhotra, V (reprint author), CRG Ctr Regulacio Genom, PRBB Bldg,Dr Aiguader 88, Barcelona 08003, Spain. EM vivek.malhotra@crg.eu RI Malhotra, Vivek/O-9811-2014; Ortega Bellido, Maria/N-4594-2015; Scarpa, Margherita/N-5233-2015; OI Malhotra, Vivek/0000-0001-6198-7943; Ortega Bellido, Maria/0000-0003-0845-2610; Scarpa, Margherita/0000-0001-5758-6346; Balla, Tamas/0000-0002-9077-3335 FU Plan Nacional [BFU2008-00414]; Consolider [CSD2009-00016]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) Grups de Recerca Emergents [SGR2009-1488]; European Research Council [268692]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; EMBO postdoctoral fellowship FX We thank members of the Malhotra Lab for helpful discussion. We also thank M Tagaya and M Olayioye for kindly providing reagents used in this study. We especially thank Dr Romeo Ricci for disclosing their findings on the PKD-dependent phosphorylation of arfaptin1 prior to publication. V Malhotra is an Institucio Catalana de Recerca i Estudis Avancats (ICREA) professor at the Center for Genomic Regulation, and the work in his laboratory is funded by grants from Plan Nacional (BFU2008-00414), Consolider (CSD2009-00016), Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) Grups de Recerca Emergents (SGR2009-1488; AGAUR-Catalan Government), and European Research Council (268692). The research of M Jovic and T Balla was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. J Villeneuve is funded by a long-term EMBO postdoctoral fellowship. NR 49 TC 10 Z9 10 U1 0 U2 7 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 JUN 12 PY 2013 VL 32 IS 12 BP 1717 EP 1729 DI 10.1038/emboj.2013.116 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 161YO UT WOS:000320230600009 PM 23695357 ER PT J AU Lenoir, M Tang, JS Woods, AS Kiyatkin, EA AF Lenoir, Magalie Tang, Jeremy S. Woods, Amina S. Kiyatkin, Eugene A. TI Rapid Sensitization of Physiological, Neuronal, and Locomotor Effects of Nicotine: Critical Role of Peripheral Drug Actions SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SENSORY NERVE-ENDINGS; BODY-TEMPERATURE; INTRAVENOUS COCAINE; NUCLEUS-ACCUMBENS; MOTOR-ACTIVITY; RATS; ADDICTION; DOPAMINE; BRAIN; HEXAMETHONIUM AB Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs' reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 mu g/kg) induced sensitization of the drug's effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotine(PM), 30 mu g/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotine(PM) injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drug's peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization. C1 [Lenoir, Magalie; Tang, Jeremy S.; Woods, Amina S.; Kiyatkin, Eugene A.] NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU National Institute on Drug Abuse-Intramural Research Program FX This work was supported by the National Institute on Drug Abuse-Intramural Research Program. We thank Drs. Y. Shaham, S. Ahmed, C. Mejias-Aponte, K. Guillem, C. Lupica, P. Redgrave, E. Gardner, and K. Wakabayashi for helpful suggestions regarding this manuscript; Dr. S. Jackson for assistance in nicotine measurement experiment; and postbaccalaureate trainees S. Schwarzchild and S. Myal for technical assistance. NR 66 TC 9 Z9 9 U1 3 U2 10 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 JUN 12 PY 2013 VL 33 IS 24 BP 9937 EP 9949 DI 10.1523/JNEUROSCI.4940-12.2013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 162AB UT WOS:000320235300009 PM 23761889 ER PT J AU Je, HS Yang, F Ji, YY Potluri, S Fu, XQ Luo, ZG Nagappan, G Chan, JP Hempstead, B Son, YJ Lu, B AF Je, H. Shawn Yang, Feng Ji, Yuanyuan Potluri, Srilatha Fu, Xiu-Qing Luo, Zhen-Ge Nagappan, Guhan Chan, Jia Pei Hempstead, Barbara Son, Young-Jin Lu, Bai TI ProBDNF and Mature BDNF as Punishment and Reward Signals for Synapse Elimination at Mouse Neuromuscular Junctions SO JOURNAL OF NEUROSCIENCE LA English DT Article ID OCULAR DOMINANCE COLUMNS; NEUROTROPHIC FACTOR; MOTOR-NEURONS; SORTILIN; RECEPTOR; DEFICITS; MUSCLE; ROLES; P75(NTR); INJURY AB During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo. C1 [Je, H. Shawn; Yang, Feng; Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Je, H. Shawn; Yang, Feng; Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Je, H. Shawn; Chan, Jia Pei] DUKE NUS Grad Med Sch, Program Neurosci & Behav Disorders, Singapore 169857, Singapore. [Je, H. Shawn] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore. [Yang, Feng] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] GlaxoSmithKline, R&D China, Shanghai 201203, Peoples R China. [Potluri, Srilatha; Son, Young-Jin] Temple Univ, Sch Med, Shriners Hosp, Pediat Res Ctr, Philadelphia, PA 19140 USA. [Potluri, Srilatha; Son, Young-Jin] Temple Univ, Sch Med, Dept Anat & Cell Biol, Philadelphia, PA 19140 USA. [Fu, Xiu-Qing; Luo, Zhen-Ge] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China. [Fu, Xiu-Qing; Luo, Zhen-Ge] Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Neurosci, Shanghai 200031, Peoples R China. [Hempstead, Barbara] Cornell Univ, Weill Med Coll, Dept Med, Div Hematol, New York, NY 10021 USA. RP Lu, B (reprint author), GlaxoSmithKline, R&D China, Shanghai 201203, Peoples R China. EM shawn.je@duke-nus.edu.sg; yson@temple.edu; Bai.b.lu@gsk.com FU NIMH intramural research program; NICHD intramural research program; NIH grant; MDA grant; Shriners Hospitals grant; Singapore National Medical Research Council; Singapore Ministry of Education FX The study was supported by NIMH and NICHD intramural research programs (B.L.), NIH, MDA, and Shriners Hospitals grants (B.L.H. and Y.-J.S.), and by grants from the Singapore National Medical Research Council and the Singapore Ministry of Education (H.S.J.). We thank Drs Eugene Zaitsev, Phillip Nelson, Neil Shneider, Keri Martinowitch, Jay Chang, Newton Woo, and Albert Chen for their thoughtful comments and suggestions, and Regeneron Pharmaceuticals for providing recombinant BDNF. We express our gratitude to Drs Bruce Carter, Mark Bothwell, Moses Chao, and Phil Barker for antibodies to p75NTR, and Louis Reichardt and Moses Chao for antibodies to TrkB. We are particularly grateful to Dr David Ginty and Xi Chen, who provided us the TrkBF616A knock-in mice and also helped with the injection of 1NMPP1. We thank Dr Peder Madsen for the construct to express sortilin propeptide. NR 30 TC 16 Z9 19 U1 1 U2 9 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 JUN 12 PY 2013 VL 33 IS 24 BP 9957 EP 9962 DI 10.1523/JNEUROSCI.0163-13.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 162AB UT WOS:000320235300011 PM 23761891 ER PT J AU Moeller, SJ Parvaz, MA Shumay, E Beebe-Wang, N Konova, AB Alia-Klein, N Volkow, ND Goldstein, RZ AF Moeller, Scott J. Parvaz, Muhammad A. Shumay, Elena Beebe-Wang, Nicasia Konova, Anna B. Alia-Klein, Nelly Volkow, Nora D. Goldstein, Rita Z. TI Gene X Abstinence Effects on Drug Cue Reactivity in Addiction: Multimodal Evidence SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DOPAMINE TRANSPORTER GENE; EXON-III POLYMORPHISM; COCAINE ADDICTION; NOVELTY SEEKING; ALCOHOL DEPENDENCE; REWARD; ASSOCIATION; SMOKING; SENSITIVITY; SEVERITY AB Functional polymorphisms in the dopamine transporter gene (DAT1 or SLC6A3) modulate responsiveness to salient stimuli, such that carriers of one 9R-allele of DAT1 (compared with homozygote carriers of the 10R-allele) show heightened reactivity to drug-related reinforcement in addiction. Here, using multimodal neuroimaging and behavioral dependent variables in 73 human cocaine-addicted individuals and 47 healthy controls, we hypothesized and found that cocaine-addicted carriers of a 9R-allele exhibited higher responses to drug cues, but only among individuals who had used cocaine within 72 h of the study as verified by positive cocaine urine screens (a state characterized by intense craving). Importantly, this responsiveness to drug cues was reliably preserved across multimodal imaging and behavioral probes: psychophysiological event-related potentials, self-report, simulated cocaine choice, and fMRI. Because drug cues contribute to relapse, our results identify the DAT1R 9R-allele as a vulnerability allele for relapse especially during early abstinence (e.g., detoxification). C1 [Moeller, Scott J.; Parvaz, Muhammad A.; Beebe-Wang, Nicasia; Konova, Anna B.; Alia-Klein, Nelly; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Moeller, Scott J.; Parvaz, Muhammad A.; Beebe-Wang, Nicasia; Konova, Anna B.; Alia-Klein, Nelly; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Shumay, Elena] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Konova, Anna B.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM rita.goldstein@mssm.edu RI Moeller, Scott/L-5549-2016 OI Moeller, Scott/0000-0002-4449-0844 FU National Institute on Drug Abuse [1R01DA023579, 1F32DA030017-01, 1F32DA033088] FX This work was supported by National Institute on Drug Abuse Grant 1R01DA023579 to R.Z.G., Grant 1F32DA030017-01 to S.J.M., and Grant 1F32DA033088 to M.A.P. We thank Michail Misyrlis, Thomas Maloney, Patricia A. Woicik, Dardo Tomasi, Ruiliang Wang, and Gene-Jack Wang for assistance. NR 68 TC 13 Z9 14 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 JUN 12 PY 2013 VL 33 IS 24 BP 10027 EP 10036 DI 10.1523/JNEUROSCI.0695-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 162AB UT WOS:000320235300018 PM 23761898 ER PT J AU Thorsell, A Tapocik, JD Liu, K Zook, M Bell, L Flanigan, M Patnaik, S Marugan, J Damadzic, R Dehdashti, SJ Schwandt, ML Southall, N Austin, CP Eskay, R Ciccocioppo, R Zheng, W Heilig, M AF Thorsell, Annika Tapocik, Jenica D. Liu, Ke Zook, Michelle Bell, Lauren Flanigan, Meghan Patnaik, Samarjit Marugan, Juan Damadzic, Ruslan Dehdashti, Seameen J. Schwandt, Melanie L. Southall, Noel Austin, Christopher P. Eskay, Robert Ciccocioppo, Roberto Zheng, Wei Heilig, Markus TI A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NEUROPEPTIDE-S RECEPTOR; CORTICOTROPIN-RELEASING-FACTOR; HYPOTHALAMIC HYPOCRETIN SYSTEM; COCAINE-SEEKING BEHAVIOR; GENE-EXPRESSION; SPATIAL MEMORY; SHA 68; ETHANOL; ACTIVATION; WITHDRAWAL AB The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism. C1 [Thorsell, Annika; Tapocik, Jenica D.; Zook, Michelle; Bell, Lauren; Flanigan, Meghan; Damadzic, Ruslan; Schwandt, Melanie L.; Eskay, Robert; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Liu, Ke; Patnaik, Samarjit; Marugan, Juan; Dehdashti, Seameen J.; Southall, Noel; Austin, Christopher P.; Zheng, Wei] Nat Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Thorsell, Annika] Linkoping Univ, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. [Ciccocioppo, Roberto] Univ Camerino, Pharmacol Unit, Sch Pharm, I-62032 Camerino, Italy. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,Bldg 10-CRC Rm 1-5330, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; mheilig@mail.nih.gov RI Southall, Noel/H-8991-2012; Schwandt, Melanie/L-9866-2016; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Thorsell, Annika/0000-0003-3535-3845; Flanigan, Meghan/0000-0002-3185-7459 FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism, NIH FX This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism, NIH. We thank Dr. Reinscheid for generously providing the NPSR clone originally used to generate NPSR-CHO cell line, Sam Michael for assistance in robotic screen, and Paul Shinn for compound management. NR 44 TC 12 Z9 13 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 12 PY 2013 VL 33 IS 24 BP 10132 EP 10142 DI 10.1523/JNEUROSCI.4742-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 162AB UT WOS:000320235300028 PM 23761908 ER PT J AU Ascierto, ML Idowu, MO Zhao, YD Khalak, H Payne, KK Wang, XY Dumur, CI Bedognetti, D Tomei, S Ascierto, PA Shanker, A Bear, HD Wang, E Marincola, FM De Maria, A Manjili, MH AF Ascierto, Maria Libera Idowu, Michael O. Zhao, Yingdong Khalak, Hanif Payne, Kyle K. Wang, Xiang-Yang Dumur, Catherine I. Bedognetti, Davide Tomei, Sara Ascierto, Paolo A. Shanker, Anil Bear, Harry D. Wang, Ena Marincola, Francesco M. De Maria, Andrea Manjili, Masoud H. TI Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Breast cancer prognosis; Molecular markers; Innate immunity; NK cells; Tumour relapse; Tumour microenvironment ID NATURAL-KILLER-CELLS; PROGNOSTIC-SIGNIFICANCE; IMMUNOLOGICAL CONSTANT; MEDIATED SUPPRESSION; ACTIVATING RECEPTORS; MELANOMA METASTASES; ANTITUMOR IMMUNITY; FOXP3 EXPRESSION; SELF-TOLERANCE; TUMOR-CELLS AB Background: Recent observations suggest that immune-mediated tissue destruction is dependent upon coordinate activation of immune genes expressed by cells of the innate and adaptive immune systems. Methods: Here, we performed a retrospective pilot study to investigate whether the coordinate expression of molecular signature mostly associated with NK cells could be used to segregate breast cancer patients into relapse and relapse-free outcomes. Results: By analyzing primary breast cancer specimens derived from patients who experienced either 58-116 months (similar to 5-9 years) relapse-free survival or developed tumor relapse within 9-76 months (similar to 1-6 years) we found that the expression of molecules involved in activating signaling of NK cells and in NK cells: target interaction is increased in patients with favorable prognosis. Conclusions: The parameters identified in this study, together with the prognostic signature previously reported by our group, highlight the cooperation between the innate and adaptive immune components within the tumor microenvironment. C1 [Ascierto, Maria Libera; Bedognetti, Davide; Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ascierto, Maria Libera; Bedognetti, Davide; Wang, Ena; Marincola, Francesco M.] NIH, FOCIS Ctr Excellence, Bethesda, MD 20892 USA. [Idowu, Michael O.; Dumur, Catherine I.] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Pathol, Richmond, VA USA. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Khalak, Hanif; Tomei, Sara] WCMC, Doha, Qatar. [Payne, Kyle K.; Manjili, Masoud H.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Massey Canc Ctr, Richmond, VA 23298 USA. [Wang, Xiang-Yang] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Human Genet, Richmond, VA USA. [Ascierto, Paolo A.] Fdn G Pascale, Ist Nazl Tumori, Unit Med Oncol & Innovat Therapy, Naples, Italy. [Ascierto, Maria Libera; De Maria, Andrea] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Ascierto, Maria Libera; De Maria, Andrea] Univ Genoa, Ctr Excellence Biomed Res, Genoa, Italy. [Bear, Harry D.] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Surg, Richmond, VA USA. [De Maria, Andrea] IRCCS Az Osp Univ, San Martino IST Ist Nazl Ric Canc, Genoa, Italy. [Shanker, Anil] Vanderbilt Univ, Sch Med, Dept Biochem & Canc Biol,Meharry Med Coll, Lab Lymphocyte Funct,Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Ascierto, ML (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM asciertoml@cc.nih.gov RI de maria, andrea/F-7116-2016; OI de maria, andrea/0000-0001-5782-333X; Shanker, Anil/0000-0001-6372-3669; Bedognetti, Davide/0000-0002-5857-773X FU NIH-NCI Cancer Centre [P30 CA016059]; Conquer Cancer Foundation of the American Society of Clinical Oncology; VCU Massey Cancer Centre Tissue; Data Acquisition and Analysis Core; VCU Massey Cancer Centre; Commonwealth Foundation for Cancer Research FX Patient tissue samples and services in support of the research project were provided by the VCU Massey Cancer Centre Tissue and Data Acquisition and Analysis Core, supported, in part, with funding from NIH-NCI Cancer Centre Support Grant P30 CA016059. Davide Bedognetti was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology (2011 YIA). MH Manjili, HD Bear, MO Idowu, CI Dumur, KK Payne, E Wang and FM Marincola hold a patent assigned to Virginia Commonwealth University (VCU) titled "Gene Signatures with rejection or recurrence of Cancer" PCT/US2012/030312.; We gratefully acknowledge the support of VCU Massey Cancer Centre, the Commonwealth Foundation for Cancer Research. NR 57 TC 21 Z9 22 U1 1 U2 10 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 JUN 12 PY 2013 VL 11 AR 145 DI 10.1186/1479-5876-11-145 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 172PI UT WOS:000321016200001 PM 23758773 ER PT J AU Havland, I Lundholm, C Lichtenstein, P Neiderhiser, JM Ganiban, JM Spotts, EL Walum, H Reiss, D Almqvist, C AF Havland, Ida Lundholm, Cecilia Lichtenstein, Paul Neiderhiser, Jenae M. Ganiban, Jody M. Spotts, Erica L. Walum, Hasse Reiss, David Almqvist, Catarina TI The Observed Association between Maternal Anxiety and Adolescent Asthma: Children of Twin Design Suggest Familial Effects SO PLOS ONE LA English DT Article ID CHILDHOOD ASTHMA; ENVIRONMENTAL-INFLUENCES; STRESS; BEHAVIOR; MOTHERS; DEPRESSION; RISK AB Background: Previous studies indicate that maternal anxiety is associated with asthma in the adolescent child, but mechanisms are unclear. Objective: To investigate the association between maternal anxiety and maternal, self-and register-based report of asthma in the adolescent child, and whether the association remains after control of familial confounding (shared environmental and genetic factors). Method: From the Twin and Offspring Study of Sweden, 1691 mothers (1058 twins) and their adolescent child were included. The association between maternal self-reported anxiety (Beck Anxiety Inventory (BAI) and Karolinska Scales of Personality (KSP) somatic or psychic anxiety) and asthma based on subjective (maternal or child report) or objective (register-based diagnosis and medication) measures were analysed using logistic regression. The children-of-twins design was used to explore whether genes or environment contribute to the association. Results: Maternal BAI anxiety (OR 2.02, CI 1.15-3.55) was significantly associated with adolescent asthma reported by the mother. Maternal KSP somatic anxiety (OR 1.74, CI 1.04-2.91) and psychic anxiety (OR 1.74, CI 1.05-2.86) was significantly associated with breathlessness reported by the adolescent child. In contrast, maternal anxiety was not associated with increased risk for the register-based outcomes of asthma diagnosis or medication. The results remained also after adjusting for covariates and the children-of-twins analyses which indicate that the association was due to familial confounding. Conclusions: We found some associations between maternal anxiety and subjectively reported offspring asthma or breathlessness which may be due to familial effects. A likely candidate for explaining this familial confounding is heritable personality traits associated with both anxiety and subjective measures of asthma. C1 [Havland, Ida; Lundholm, Cecilia; Lichtenstein, Paul; Walum, Hasse; Almqvist, Catarina] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Ganiban, Jody M.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Spotts, Erica L.] NIA, Div Behav & Social Res, NIH, Bethesda, MD 20892 USA. [Reiss, David] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Almqvist, Catarina] Dept Womens & Childrens Hlth, Stockholm, Sweden. [Almqvist, Catarina] Astrid Lindgren Childrens Hosp, Stockholm, Sweden. RP Almqvist, C (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM catarina.almqvist@ki.se OI lichtenstein, paul/0000-0003-3037-5287; Lundholm, Cecilia/0000-0002-6546-3650 FU National Institute of Mental Health [R01MH54610]; Stockholm County Council; Karolinska Institutet; Swedish Research Council [80748301, 2011-3060]; Swedish Heart and Lung Foundation; Strategic Research Program in Epidemiology at Karolinska Institutet FX This project was supported by grant R01MH54610 from the National Institute of Mental Health. Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, grants from the Swedish Research Council (grant numbers 80748301 and 2011-3060), the Swedish Heart and Lung Foundation and the Strategic Research Program in Epidemiology at Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 3 Z9 3 U1 4 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2013 VL 8 IS 6 AR e66040 DI 10.1371/journal.pone.0066040 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163FW UT WOS:000320322400073 PM 23776601 ER PT J AU Ioannidis, JPA Chang, CQ Lam, TK Schully, SD Khoury, MJ AF Ioannidis, John P. A. Chang, Christine Q. Lam, Tram Kim Schully, Sheri D. Khoury, Muin J. TI The Geometric Increase in Meta-Analyses from China in the Genomic Era SO PLOS ONE LA English DT Article ID WIDE ASSOCIATION; KNOWLEDGE INTEGRATION; GENETIC ASSOCIATIONS; CONTROLLED-TRIALS; COMMON DISEASES; COMPLEX TRAITS; EPIDEMIOLOGY; BIAS; POLYMORPHISMS; REPLICATION AB Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses. C1 [Ioannidis, John P. A.; Chang, Christine Q.; Lam, Tram Kim; Schully, Sheri D.; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Humanities & Sci, Dept Stat, Stanford, CA 94305 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Ioannidis, JPA (reprint author), NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. EM jioannid@stanford.edu NR 35 TC 12 Z9 12 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2013 VL 8 IS 6 AR e65602 DI 10.1371/journal.pone.0065602 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163FW UT WOS:000320322400037 PM 23776510 ER PT J AU Sim, X Jensen, RA Ikram, MK Cotch, MF Li, XH MacGregor, S Xie, J Smith, AV Boerwinkle, E Mitchell, P Klein, R Klein, BEK Glazer, NL Lumley, T McKnight, B Psaty, BM de Jong, PTVM Hofman, A Rivadeneira, F Uitterlinden, AG van Duijn, CM Aspelund, T Eiriksdottir, G Harris, TB Jonasson, F Launer, LJ Attia, J Baird, PN Harrap, S Holliday, EG Inouye, M Rochtchina, E Scott, RJ Viswanathan, A Li, G Smith, NL Wiggins, KL Kuo, JZ Taylor, KD Hewitt, AW Martin, NG Montgomery, GW Sun, C Young, TL Mackey, DA van Zuydam, NR Doney, ASF Palmer, CNA Morris, AD Rotter, JI Tai, ES Gudnason, V Vingerling, JR Siscovick, DS Wang, JJ Wong, TY AF Sim, Xueling Jensen, Richard A. Ikram, M. Kamran Cotch, Mary Frances Li, Xiaohui MacGregor, Stuart Xie, Jing Smith, Albert Vernon Boerwinkle, Eric Mitchell, Paul Klein, Ronald Klein, Barbara E. K. Glazer, Nicole L. Lumley, Thomas McKnight, Barbara Psaty, Bruce M. de Jong, Paulus T. V. M. Hofman, Albert Rivadeneira, Fernando Uitterlinden, Andre G. van Duijn, Cornelia M. Aspelund, Thor Eiriksdottir, Gudny Harris, Tamara B. Jonasson, Fridbert Launer, Lenore J. Attia, John Baird, Paul N. Harrap, Stephen Holliday, Elizabeth G. Inouye, Michael Rochtchina, Elena Scott, Rodney J. Viswanathan, Ananth Li, Guo Smith, Nicholas L. Wiggins, Kerri L. Kuo, Jane Z. Taylor, Kent D. Hewitt, Alex W. Martin, Nicholas G. Montgomery, Grant W. Sun, Cong Young, Terri L. Mackey, David A. van Zuydam, Natalie R. Doney, Alex S. F. Palmer, Colin N. A. Morris, Andrew D. Rotter, Jerome I. Tai, E. Shyong Gudnason, Vilmundur Vingerling, Johannes R. Siscovick, David S. Wang, Jie Jin Wong, Tien Y. CA Wellcome Trust Case Control Consor Global BPGen Consortium TI Genetic Loci for Retinal Arteriolar Microcirculation SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; BLUE MOUNTAINS EYE; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; ANTIHYPERTENSIVE DRUG THERAPIES; INCIDENT SEVERE HYPERTENSION; CORONARY-HEART-DISEASE; BEAVER DAM EYE; VESSEL DIAMETERS; VASCULAR CALIBER; MICROVASCULAR ABNORMALITIES AB Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5x10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11x10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined. C1 [Sim, Xueling] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Jensen, Richard A.; Glazer, Nicole L.; Lumley, Thomas; McKnight, Barbara; Psaty, Bruce M.; Li, Guo; Wiggins, Kerri L.; Wellcome Trust Case Control Consor] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ikram, M. Kamran; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Ikram, M. Kamran; Vingerling, Johannes R.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Li, Xiaohui; Kuo, Jane Z.; Taylor, Kent D.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [MacGregor, Stuart; Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Xie, Jing; Baird, Paul N.; Hewitt, Alex W.; Mackey, David A.; Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia. [Smith, Albert Vernon; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur Capital Region, Iceland. [Smith, Albert Vernon; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Mitchell, Paul; Rochtchina, Elena] Univ Sydney, Ctr Vision Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Mitchell, Paul; Rochtchina, Elena] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Glazer, Nicole L.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Glazer, Nicole L.] Boston Univ, Dept Med, Boston, MA USA. [Lumley, Thomas; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, Dept Clin & Mol Ophthalmogenet, Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [de Jong, Paulus T. V. M.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Vingerling, Johannes R.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Jonasson, Fridbert] Univ Iceland, Dept Ophthalmol, Reykjavik, Iceland. [Jonasson, Fridbert] Landspitalinn Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Attia, John; Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Attia, John] John Hunter Hosp, Dept Med, Newcastle, NSW, Australia. [Attia, John] Hunter Med Res Inst, Newcastle, NSW, Australia. [Harrap, Stephen] Univ Melbourne, Dept Physiol, Melbourne, Australia. [Inouye, Michael] Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic, Australia. [Inouye, Michael] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci, Newcastle, NSW 2300, Australia. [Viswanathan, Ananth] Moorfields Eye Hosp, NIHR, Biomed Res Ctr Ophthalmol, London, England. [Viswanathan, Ananth] UCL, Inst Ophthalmol, London, England. [Smith, Nicholas L.] Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Sun, Cong] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Young, Terri L.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [van Zuydam, Natalie R.; Doney, Alex S. F.; Palmer, Colin N. A.; Morris, Andrew D.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. RP Wong, TY (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. EM tien_yin_wong@nuhs.edu.sg RI Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Hewitt, Alex/D-1936-2013; Smith, Albert/K-5150-2015; Matullo, Giuseppe/K-6383-2016; Mackey, David/H-5340-2014; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; Newhouse, Stephen/C-9330-2011; Beckmann, Jacques S /A-9772-2008; Grobbee, Diederick/C-7651-2014; van der Schouw, Yvonne/F-8327-2014; Aspelund, Thor/C-5983-2008; Colaus, PsyColaus/K-6607-2013; Attia, John/F-5376-2013; Altshuler, David/A-4476-2009; Pfeufer, Arne/B-6634-2013; Palmer, Colin/C-7053-2008; Macgregor, Stuart/C-6442-2009; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Blackwell, Jenefer/H-3015-2015; OI Seedorf, Udo/0000-0003-4652-5358; Org, Elin/0000-0003-1451-9375; Baird, Paul/0000-0002-1305-3502; Cotch, Mary Frances/0000-0002-2046-4350; Harrap, Stephen/0000-0003-2907-6714; Zeggini, Eleftheria/0000-0003-4238-659X; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Luben, Robert/0000-0002-5088-6343; Gudnason, Vilmundur/0000-0001-5696-0084; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Hewitt, Alex/0000-0002-5123-5999; Smith, Albert/0000-0003-1942-5845; Mackey, David/0000-0001-7914-4709; Bochud, Murielle/0000-0002-5727-0218; Newhouse, Stephen/0000-0002-1843-9842; Beckmann, Jacques S /0000-0002-9741-1900; Grobbee, Diederick/0000-0003-4472-4468; van der Schouw, Yvonne/0000-0002-4605-435X; Aspelund, Thor/0000-0002-7998-5433; Attia, John/0000-0001-9800-1308; Altshuler, David/0000-0002-7250-4107; Palmer, Colin/0000-0002-6415-6560; Macgregor, Stuart/0000-0001-6731-8142; Wang, Jie Jin/0000-0001-9491-4898; Wain, Louise/0000-0003-4951-1867; Sacerdote, Carlotta/0000-0002-8008-5096; Klein, Ronald/0000-0002-4428-6237; Forouhi, Nita/0000-0002-5041-248X; Marrugat, Jaume/0000-0003-3320-554X; Ikram, Mohammad Kamran/0000-0003-0173-9571; Tai, E Shyong/0000-0003-2929-8966; Martin, Nicholas/0000-0003-4069-8020 FU National Institute on Aging [ZIAAG007380]; National Institutes of Health (NIH) [N01-AG-12100]; National Eye Institute at the NIH in the United States [ZIAEY000401]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute c [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC45133, HL075366, HL080295, HL087652]; National Institute on Aging (NIA) [AG-023269, AG-15928, AG-20098,, AG-027058]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics; National Heart, Lung, and Blood Institute [T32HL007902]; Netherlands Organization of Scientific Research NWO [175.010.2005.011]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for scientific research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European commission (DG XII); Municipality of Rotterdam; Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht. Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research (NWO); Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Rotterdamse Vereniging Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn; Blinden-Penning, Amsterdam; Blindenhulp, Gravenzande; Henkes Stichting, Rotterdam; Topcon Europe BV, Capelle aan de IJssel; Medical Workshop BV, Groningen; Australian National Health & Medical Research Council, Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2; BMES [085475/B/08/Z, 085475/08/Z]; National Institutes of Health Research (NIHR) Biomedical Research Centre for Ophthalmology; Moorfields Eye Hospital; UCL Institute of Ophthalmology, London, UK; Australian National Health and Medical Research Council (NHMRC); Clifford Craig Medical Research Trust; Ophthalmic Research Institute of Australia (ORIA); Glaucoma Australia; American Health Assistance Foundation (AHAF); Peggy and Leslie Cranbourne Foundation; Foundation for Children; NHMRC; Jack Brockhoff Foundation; NEI; NIH/National Eye Institute (NEI) [1RO1EY018246]; Netherlands Scientific Organization [NWO 480-05-003]; National Heart, Lung, and Blood Institute (NHLBI); MESA; NHLBI [N02-HL-6-4278]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX This work was supported by multiple funding agencies and details for each cohort were given below. The Age, Gene/Environment Susceptibility - Reykjavik Study was funded by the Intramural Research Program of the National Institute on Aging (ZIAAG007380, National Institutes of Health (NIH) contract N01-AG-12100); and the National Eye Institute (ZIAEY000401) at the NIH in the United States; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Health Study research reported in this article was supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC45133, and grants HL075366, HL080295, HL087652, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). This research was also supported by the National Institute on Aging (NIA) contracts AG-023269, AG-15928, AG-20098, and AG-027058. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Additional funding came from the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR) and the National Heart, Lung, and Blood Institute Training Grant T32HL007902 (RAJ). The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (no. 175.010.2005.011). This study was further supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for scientific research (NWO); the Netherlands Organization for the Health Research and Development (ZonMw); The Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; The European commission (DG XII); and the Municipality of Rotterdam. The ophthalmic part of the Rotterdam Study was supported by Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht.; Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research (NWO); Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Rotterdamse Vereniging Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn; Blinden-Penning, Amsterdam; Blindenhulp, Gravenzande; Henkes Stichting, Rotterdam; Topcon Europe BV, Capelle aan de IJssel; Medical Workshop BV, Groningen; all in the Netherlands; Heidelberg Engineering, Dossenheim, Germany. The Blue Mountains Eye Study has been supported by the Australian National Health & Medical Research Council, Canberra Australia (Grant Numbers 974159, 211069, 457349, 512423, 475604, 529912, and the funding for Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye); In addition, funding by the Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 (A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster) has supported the genotyping costs of the entire BMES population (Grant numbers 085475/B/08/Z and 085475/08/Z). We also acknowledge the funding body National Institutes of Health Research (NIHR) Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK. The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004-2009). We also thank the following organisations for their financial support: Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia (ORIA), Glaucoma Australia, American Health Assistance Foundation (AHAF), Peggy and Leslie Cranbourne Foundation, Foundation for Children, NHMRC project grant (2005-2007), Jack Brockhoff Foundation, NEI Project Grant (2007-2010). Genotyping for part of the Australian sample was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder was performed by the NIH Center for Inherited Research (CIDR) as part of an NIH/National Eye Institute (NEI) grant 1RO1EY018246, Principal Investigator Terri L Young and we are grateful to Dr Camilla Day and staff. Australian sample imputation analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 5 Z9 5 U1 0 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2013 VL 8 IS 6 AR e65804 DI 10.1371/journal.pone.0065804 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163FW UT WOS:000320322400057 PM 23776548 ER PT J AU Nikitina, T Wang, DF Gomberg, M Grigoryev, SA Zhurkin, VB AF Nikitina, Tatiana Wang, Difei Gomberg, Misha Grigoryev, Sergei A. Zhurkin, Victor B. TI Combined Micrococcal Nuclease and Exonuclease III Digestion Reveals Precise Positions of the Nucleosome Core/Linker Junctions: Implications for High-Resolution Nucleosome Mapping SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE nucleosome positioning; micrococcal nuclease; exonuclease III; linker histone; 601 nucleosome ID BASE-PAIR RESOLUTION; RAT-LIVER CHROMATIN; STAPHYLOCOCCAL NUCLEASE; DNA INTERACTIONS; CORE PARTICLE; IN-VITRO; SEQUENCE; HISTONE; ORGANIZATION; GENOME AB Micrococcal nuclease (MNase) is extensively used in genome-wide mapping of nucleosomes but its preference for AT-rich DNA leads to errors in establishing precise positions of nucleosomes. Here, we show that the MNase digestion of nucleosomes assembled on a strong nucleosome positioning sequence, Widom's clone 601, releases nucleosome cores whose sizes are strongly affected by the linker DNA sequence. Our experiments produced nucleosomal DNA sizes varying between 147 and 155 bp, with positions of the MNase cuts reflecting positions of the A. T pairs rather than the nucleosome core/linker junctions determined by X-ray crystallography. Extent of chromatosomal DNA protection by linker histone H1 also depends on the linker DNA sequence. Remarkably, we found that a combined treatment with MNase and exonuclease III (exoIII) overcomes MNase sequence preference producing nucleosomal DNA trimmed symmetrically and precisely at the core/linker junctions regardless of the underlying DNA sequence. We propose that combined MNase/exoIII digestion can be applied to in situ chromatin for unbiased genome-wide mapping of nucleosome positions that is not influenced by DNA sequences at the core/linker junctions. The same approach can be also used for the precise mapping of the extent of linker DNA protection by H1 and other protein factors associated with nucleosome linkers. Published by Elsevier Ltd. C1 [Nikitina, Tatiana; Wang, Difei; Zhurkin, Victor B.] NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Gomberg, Misha; Grigoryev, Sergei A.] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA USA. RP Grigoryev, SA (reprint author), Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA USA. EM sag17@psu.edu; zhurkin@nih.gov RI Wang, Difei/E-7066-2010 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Science Foundation [MCB-1021681] FX The authors are grateful to David Clark and Hope Cole for valuable discussion of the conditions used for the combined MNase/exoIII digestion and to Igor Panyutin and M. Onyshchenko for help with high-resolution gels. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (V.B.Z.), and by National Science Foundation grant MCB-1021681 (S.A.G.). NR 56 TC 8 Z9 8 U1 2 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 12 PY 2013 VL 425 IS 11 BP 1946 EP 1960 DI 10.1016/j.jmb.2013.02.026 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164OL UT WOS:000320419300008 PM 23458408 ER PT J AU White, A Danis, M AF White, Amina Danis, Marion TI Enhancing Patient-Centered Communication and Collaboration by Using the Electronic Health Record in the Examination Room SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ACTIVATION C1 [White, Amina; Danis, Marion] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP White, A (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM amina.white@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 8 TC 36 Z9 36 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 12 PY 2013 VL 309 IS 22 BP 2327 EP 2328 DI 10.1001/jama.2013.6030 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 161EV UT WOS:000320176000019 PM 23757080 ER PT J AU Conte, A Defazio, G Ferrazzano, G Hallett, M Macerollo, A Fabbrini, G Berardelli, A AF Conte, Antonella Defazio, Giovanni Ferrazzano, Gina Hallett, Mark Macerollo, Antonella Fabbrini, Giovanni Berardelli, Alfredo TI Is increased blinking a form of blepharospasm? SO NEUROLOGY LA English DT Article ID SOMATOSENSORY TEMPORAL DISCRIMINATION; MULTIPLE SYSTEM ATROPHY; REFLEX RECOVERY CYCLE; PARKINSONS-DISEASE; BOTULINUM TOXIN; HEMIFACIAL SPASM; EYELID MOVEMENTS; CRANIAL DYSTONIA; FOCAL DYSTONIAS; TORTICOLLIS AB Objective: The aim of this study was to investigate whether increased blink rate (BR) is part of the clinical spectrum of primary blepharospasm (BSP). Methods: We enrolled 40 patients (16 patients with an increased BR but without typical orbicularis oculi [OO] spasms, and 24 patients with typical involuntary OO spasms) and 18 healthy subjects. The BR, blink reflex recovery cycle, and somatosensory temporal discrimination threshold (STDT) were tested in patients and controls. Results: Patients who had typical OO spasms had an altered R2 recovery cycle whereas those who had an increased BR alone had a normal blink reflex recovery cycle. STDT values were higher in patients than in healthy subjects and no difference was found in the STDT abnormalities in the 2 groups of patients. Conclusions: Our study shows that, despite the similar STDT abnormalities, the different changes in the R2 recovery cycle in patients with BSP and those with increased BR alone suggest that these disorders arise from different pathologic mechanisms. C1 [Conte, Antonella; Ferrazzano, Gina; Fabbrini, Giovanni; Berardelli, Alfredo] Univ Roma La Sapienza, Dept Neurol & Psychiat, Rome, Italy. [Conte, Antonella; Fabbrini, Giovanni; Berardelli, Alfredo] IRCCS Neuromed Inst, Pozzilli, IS, Italy. [Defazio, Giovanni; Macerollo, Antonella] Aldo Moro Univ Bari, Dept Neurosci & Sensory Organs, Bari, Italy. [Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Bethesda, MD USA. RP Berardelli, A (reprint author), Univ Roma La Sapienza, Dept Neurol & Psychiat, Rome, Italy. EM alfredo.berardelli@uniroma1.it FU Benign Essential Blepharospasm Research Foundation FX This study was supported by the Benign Essential Blepharospasm Research Foundation. NR 37 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 11 PY 2013 VL 80 IS 24 BP 2236 EP 2241 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 304FW UT WOS:000330733500015 PM 23751916 ER PT J AU Illuzzi, JL Harris, NA Manvilla, BA Kim, D Li, MX Drohat, AC Wilson, DM AF Illuzzi, Jennifer L. Harris, Nicole A. Manvilla, Brittney A. Kim, Daemyung Li, Mengxia Drohat, Alexander C. Wilson, David M., III TI Functional Assessment of Population and Tumor-Associated APE1 Protein Variants SO PLOS ONE LA English DT Article ID BASE-EXCISION-REPAIR; DNA-POLYMERASE-BETA; HUMAN APURINIC ENDONUCLEASE; MAJOR HUMAN; APURINIC/APYRIMIDINIC ENDONUCLEASE; MECHANISTIC INSIGHTS; CANCER-RISK; SITE; IDENTIFICATION; MICE AB Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant AP site repair enzyme in mammals. APE1 also maintains 3'-5' exonuclease and 3'-repair activities, and regulates transcription factor DNA binding through its REF-1 function. Since complete or severe APE1 deficiency leads to embryonic lethality and cell death, it has been hypothesized that APE1 protein variants with slightly impaired function will contribute to disease etiology. Our data indicate that except for the endometrial cancer-associated APE1 variant R237C, the polymorphic variants Q51H, I64V and D148E, the rare population variants G241R, P311S and A317V, and the tumor-associated variant P112L exhibit normal thermodynamic stability of protein folding; abasic endonuclease, 3'-5' exonuclease and REF-1 activities; coordination during the early steps of base excision repair; and intracellular distribution when expressed exogenously in HeLa cells. The R237C mutant displayed reduced AP-DNA complex stability, 3'-5' exonuclease activity and 3'-damage processing. Re-sequencing of the exonic regions of APE1 uncovered no novel amino acid substitutions in the 60 cancer cell lines of the NCI-60 panel, or in HeLa or T98G cancer cell lines; only the common D148E and Q51H variants were observed. Our results indicate that APE1 missense mutations are seemingly rare and that the cancer-associated R237C variant may represent a reduced-function susceptibility allele. C1 [Illuzzi, Jennifer L.; Li, Mengxia; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Harris, Nicole A.] Sanford Burnham Med Res Inst, Dept Cardiopathol, Orlando, FL USA. [Manvilla, Brittney A.; Drohat, Alexander C.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Drohat, Alexander C.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Kim, Daemyung] Cheongju Univ, Dept Genet Engn, Cheongju, South Korea. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institutes of Health (NIH), National Institute on Aging; NIH [R01-GM72711, T32GM 066706-07] FX This research was supported by the Intramural Research Program at the National Institutes of Health (NIH), National Institute on Aging, and an NIH grant to ACD (R01-GM72711). BAM was supported by an NIH training grant (T32GM 066706-07). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 7 Z9 7 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2013 VL 8 IS 6 AR e65922 DI 10.1371/journal.pone.0065922 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169CU UT WOS:000320755400081 PM 23776569 ER PT J AU Milaneschi, Y Cesari, M Simonsick, EM Vogelzangs, N Kanaya, AM Yaffe, K Patrignani, P Metti, A Kritchevsky, SB Pahor, M Ferrucci, L Penninx, BWJH AF Milaneschi, Yuri Cesari, Matteo Simonsick, Eleanor M. Vogelzangs, Nicole Kanaya, Alka M. Yaffe, Kristine Patrignani, Paola Metti, Andrea Kritchevsky, Stephen B. Pahor, Marco Ferrucci, Luigi Penninx, Brenda W. J. H. CA Hlth ABC Study TI Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and Women SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; MAJOR DEPRESSION; OXIDATIVE STRESS; PLATELET ACTIVATION; 8-ISO-PROSTAGLANDIN F2-ALPHA; CARDIOVASCULAR-DISEASE; BODY-COMPOSITION; SEX-DIFFERENCES; INFLAMMATION; RISK AB It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha) ), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70-79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF(2 alpha) was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF(2 alpha) than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p= 0.03, Cohen's d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences. C1 [Milaneschi, Yuri; Vogelzangs, Nicole; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr GGZ InGeest, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri; Vogelzangs, Nicole; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr GGZ InGeest, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Milaneschi, Yuri; Simonsick, Eleanor M.; Ferrucci, Luigi] NIH, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD USA. [Cesari, Matteo] Univ Toulouse, Inst Vieillissement, Toulouse, France. [Cesari, Matteo; Pahor, Marco] Univ Florida, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL USA. [Kanaya, Alka M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Patrignani, Paola] Univ G DAnnunzio, Dept Neurosci & Imaging, Chieti, Italy. [Patrignani, Paola] Univ G DAnnunzio, Ctr Excellent Aging, Chieti, Italy. [Metti, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. RP Milaneschi, Y (reprint author), Vrije Univ Amsterdam, Med Ctr GGZ InGeest, Dept Psychiat, Amsterdam, Netherlands. EM y.milaneschi@ggzingeest.nl RI Cesari, Matteo/A-4649-2008; OI Cesari, Matteo/0000-0002-0348-3664; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging (NIA) Contracts [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health; National Institute on Aging; National Institute on Aging [R01AG26556] FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Assaying of 8-iso-PGF2 alpha was supported by the by the National Institute on Aging (R01AG26556). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 13 Z9 13 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2013 VL 8 IS 6 AR e65406 DI 10.1371/journal.pone.0065406 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169CU UT WOS:000320755400028 PM 23776478 ER PT J AU Ramanunninair, M Le, JH Onodera, S Fulvini, AA Pokorny, BA Silverman, J Devis, R Arroyo, JM He, Y Boyne, A Bera, J Halpin, R Hine, E Spiro, DJ Bucher, D AF Ramanunninair, Manojkumar Le, Jianhua Onodera, Shiroh Fulvini, Andrew A. Pokorny, Barbara A. Silverman, Jeanmarie Devis, Rene Arroyo, Jennifer M. He, Yu Boyne, Alex Bera, Jayati Halpin, Rebecca Hine, Erin Spiro, David J. Bucher, Doris TI Molecular Signature of High Yield (Growth) Influenza A Virus Reassortants Prepared as Candidate Vaccine Seeds SO PLOS ONE LA English DT Article ID EMBRYONATED CHICKEN EGGS; AMINO-ACID SUBSTITUTIONS; PANDEMIC INFLUENZA; MESSENGER-RNA; SYNONYMOUS MUTATIONS; MATRIX PROTEIN; GENE SEGMENTS; PB1 PROTEIN; NS1 PROTEIN; HEMAGGLUTININ AB Background: Human influenza virus isolates generally grow poorly in embryonated chicken eggs. Hence, gene reassortment of influenza A wild type (wt) viruses is performed with a highly egg adapted donor virus, A/Puerto Rico/8/1934 (PR8), to provide the high yield reassortant (HYR) viral 'seeds' for vaccine production. HYR must contain the hemagglutinin (HA) and neuraminidase (NA) genes of wt virus and one to six 'internal' genes from PR8. Most studies of influenza wt and HYRs have focused on the HA gene. The main objective of this study is the identification of the molecular signature in all eight gene segments of influenza A HYR candidate vaccine seeds associated with high growth in ovo. Methodology: The genomes of 14 wt parental viruses, 23 HYRs (5 H1N1; 2, 1976 H1N1-SOIV; 2, 2009 H1N1pdm; 2 H2N2 and 12 H3N2) and PR8 were sequenced using the high-throughput sequencing pipeline with big dye terminator chemistry. Results: Silent and coding mutations were found in all internal genes derived from PR8 with the exception of the M gene. The M gene derived from PR8 was invariant in all 23 HYRs underlining the critical role of PR8 M in high yield phenotype. None of the wt virus derived internal genes had any silent change(s) except the PB1 gene in X-157. The highest number of recurrent silent and coding mutations was found in NS. With respect to the surface antigens, the majority of HYRs had coding mutations in HA; only 2 HYRs had coding mutations in NA. Significance: In the era of application of reverse genetics to alter influenza A virus genomes, the mutations identified in the HYR gene segments associated with high growth in ovo may be of great practical benefit to modify PR8 and/or wt virus gene sequences for improved growth of vaccine 'seed' viruses. C1 [Ramanunninair, Manojkumar; Le, Jianhua; Onodera, Shiroh; Fulvini, Andrew A.; Pokorny, Barbara A.; Silverman, Jeanmarie; Devis, Rene; Arroyo, Jennifer M.; He, Yu; Bucher, Doris] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Boyne, Alex; Bera, Jayati; Halpin, Rebecca; Hine, Erin] J Craig Venter Inst, Dept Infect Dis, Rockville, MD USA. [Spiro, David J.] NIAID, SARS & Related Viral Resp Dis Branch, Div Microbiol & Infect Dis, NIH,DHHS, Bethesda, MD 20892 USA. RP Bucher, D (reprint author), New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. EM doris_bucher@nymc.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C]; International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)-Influenza Vaccine Supply Task Force FX Research support for preparation of the NYMC reassortants was provided by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)-Influenza Vaccine Supply Task Force. This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900007C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 101 TC 9 Z9 9 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2013 VL 8 IS 6 AR e65955 DI 10.1371/journal.pone.0065955 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169CU UT WOS:000320755400090 PM 23776579 ER PT J AU Shan, ZH Shakoori, A Bodaghi, S Goldsmith, P Jin, J Wiest, JS AF Shan, Zhihong Shakoori, Abbas Bodaghi, Sohrab Goldsmith, Paul Jin, Jen Wiest, Jonathan S. TI TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo SO PLOS ONE LA English DT Article ID HUMAN LUNG-CANCER; HOMOZYGOUS DELETIONS; CHROMOSOME 9P; MICROSATELLITE ANALYSIS; CARCINOMA; MELANOMA; HETEROZYGOSITY; REGION; IDENTIFICATION; PROTEINS AB We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p. C1 [Shan, Zhihong; Bodaghi, Sohrab; Wiest, Jonathan S.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Shakoori, Abbas; Jin, Jen] Mayo Clin & Mayo Fdn, Adv Genome Technol Ctr, Rochester, MN 55905 USA. [Goldsmith, Paul] NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wiest, JS (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM wiestj@mail.nih.gov FU Intramural Research Program of the 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 5 Z9 6 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2013 VL 8 IS 6 AR e66114 DI 10.1371/journal.pone.0066114 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169CU UT WOS:000320755400111 PM 23776618 ER PT J AU Wan, C Sun, JP Chen, WZ Yuan, XH Chong, HH Prabakaran, P Dimitrov, DS He, YX AF Wan, Chao Sun, Jianping Chen, Weizao Yuan, Xiaohui Chong, Huihui Prabakaran, Ponraj Dimitrov, Dimiter S. He, Yuxian TI Epitope Mapping of M36, a Human Antibody Domain with Potent and Broad HIV-1 Inhibitory Activity SO PLOS ONE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; IMMUNODEFICIENCY-VIRUS TYPE-1; AFFINITY-SELECTED PEPTIDES; ENVELOPE GLYCOPROTEIN; COMPUTATIONAL PREDICTION; NEUTRALIZING ANTIBODIES; ENTRY INHIBITORS; FUSION PROTEINS; GP120 ENVELOPE; BINDING-SITE AB M36 is the first member of a novel class of potent HIV-1 entry inhibitors based on human engineered antibody domains (eAds). It exhibits broad inhibitory activity suggesting that its CD4-induced epitope is highly conserved. Here, we describe fine mapping of its epitope by using several approaches. First, a panel of mimotopes was affinity-selected from a random peptide library and potential m36-binding residues were computationally predicted. Second, homology modeling of m36 and molecular docking of m36 onto gp120 revealed potentially important residues in gp120-m36 interactions. Third, the predicted contact residues were verified by site-directed mutagenesis. Taken together, m36 epitope comprising three discontinuous sites including six key gp120 residues (Site C1: Thr123 and Pro124; Site C3: Glu370 and Ile371; Site C4: Met426 and Trp427) were identified. In the 3D structure of gp120, the sites C1 and C4 are located in the bridging sheet and the site C3 is within the b15-alpha 3 excursion, which play essential roles for the receptor- and coreceptor-binding and are major targets of neutralizing antibodies. Based on these results we propose a precise localization of the m36 epitope and suggest a mechanism of its broad inhibitory activity which could help in the development of novel HIV-1 therapeutics based on eAds. C1 [Wan, Chao; Sun, Jianping; Yuan, Xiaohui; Chong, Huihui; He, Yuxian] Chinese Acad Med Sci, Inst Pathogen Biol, MOH Key Lab Syst Biol Pathogens, Beijing 100730, Peoples R China. [Wan, Chao; Sun, Jianping; Yuan, Xiaohui; Chong, Huihui; He, Yuxian] Chinese Acad Med Sci, Inst Pathogen Biol, AIDS Res Ctr, Beijing 100730, Peoples R China. [Wan, Chao; Sun, Jianping; Yuan, Xiaohui; Chong, Huihui; He, Yuxian] Peking Union Med Coll, Beijing 100021, Peoples R China. [Chen, Weizao; Prabakaran, Ponraj; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21701 USA. RP He, YX (reprint author), Chinese Acad Med Sci, Inst Pathogen Biol, MOH Key Lab Syst Biol Pathogens, Beijing 100730, Peoples R China. EM yhe@ipb.pumc.edu.cn FU National Major projects for Infectious Diseases Control and Prevention [2012ZX10001008]; National Outstanding Youth Award of Natural Science Foundation of China [81025009]; National 973 Program of China [2010CB530100] FX This work was supported by National Major projects for Infectious Diseases Control and Prevention (2012ZX10001008), National Outstanding Youth Award of Natural Science Foundation of China (81025009), and National 973 Program of China (2010CB530100). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 5 Z9 5 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2013 VL 8 IS 6 AR e66638 DI 10.1371/journal.pone.0066638 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169CU UT WOS:000320755400152 PM 23776690 ER PT J AU Solomon, BD Nguyen, AD Bear, KA Wolfsberg, TG AF Solomon, Benjamin D. Anh-Dao Nguyen Bear, Kelly A. Wolfsberg, Tyra G. TI Clinical Genomic Database SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome sequencing; genomic medicine; whole-genome sequencing ID NONPOLYPOSIS COLORECTAL-CANCER; COLON-CANCER; EXOME; GENE; MUTATIONS; DISEASE; PHENYLKETONURIA; INDIVIDUALS; CHALLENGE; MEDICINE AB Technological advances have greatly increased the availability of human genomic sequencing. However, the capacity to analyze genomic data in a clinically meaningful way lags behind the ability to generate such data. To help address this obstacle, we reviewed all conditions with genetic causes and constructed the Clinical Genomic Database (CGD) (http://research.nhgri.nih.gov/CGD/), a searchable, freely Web-accessible database of conditions based on the clinical utility of genetic diagnosis and the availability of specific medical interventions. The CGD currently includes a total of 2,616 genes organized clinically by affected organ systems and interventions (including preventive measures, disease surveillance, and medical or surgical interventions) that could be reasonably warranted by the identification of pathogenic mutations. To aid independent analysis and optimize new data incorporation, the CGD also includes all genetic conditions for which genetic knowledge may affect the selection of supportive care, informed medical decision-making, prognostic considerations, reproductive decisions, and allow avoidance of unnecessary testing, but for which specific interventions are not otherwise currently available. For each entry, the CGD includes the gene symbol, conditions, allelic conditions, clinical categorization (for both manifestations and interventions), mode of inheritance, affected age group, description of interventions/rationale, links to other complementary databases, including databases of variants and presumed pathogenic mutations, and links to PubMed references (>20,000). The CGD will be regularly maintained and updated to keep pace with scientific discovery. Further content-based expert opinions are actively solicited. Eventually, the CGD may assist the rapid curation of individual genomes as part of active medical care. C1 [Solomon, Benjamin D.; Bear, Kelly A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Anh-Dao Nguyen; Wolfsberg, Tyra G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Bear, Kelly A.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD 20889 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX The authors thank Leslie G. Biesecker, Derek A. T. Cummings, James P. Evans, Donald W. Hadley, and Maximilian Muenke for support, mentorship, and critical input; Andreas D. Baxevanis for bioinformatic discussions and support; Mark Fredriksen for programming assistance; and all the experts who provided input related to individual genes and conditions. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 31 TC 19 Z9 19 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 11 PY 2013 VL 110 IS 24 BP 9851 EP 9855 DI 10.1073/pnas.1302575110 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 171LM UT WOS:000320930100061 PM 23696674 ER PT J AU Um, JH Brown, AL Singh, SK Chen, Y Gucek, M Lee, BS Luckey, MA Kim, MK Park, JH Sleckman, BP Gellert, M Chung, JH AF Um, Jee-Hyun Brown, Alexandra L. Singh, Samarendra K. Chen, Yong Gucek, Marjan Lee, Baeck-Seung Luckey, Megan A. Kim, Myung K. Park, Jung-Hyun Sleckman, Barry P. Gellert, Martin Chung, Jay H. TI Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE energy coupling; immune diversity ID UPSTREAM KINASE; ENERGY SENSOR; ADIPOCYTES; MECHANISM; LIPOLYSIS; CLEAVAGE; CAMP; PHOSPHODIESTERASES; COMPLEXES; DELETION AB The ability to sense metabolic stress is critical for successful cellular adaptation. In eukaryotes, the AMP-activated protein kinase (AMPK), a highly conserved serine/threonine kinase, functions as a critical metabolic sensor. AMPK is activated by the rising ADP/ATP and AMP/ATP ratios during conditions of energy depletion and also by increasing intracellular Ca2+. In response to metabolic stress, AMPK maintains energy homeostasis by phosphorylating and regulating proteins that are involved in many physiological processes including glucose and fatty acid metabolism, transcription, cell growth, mitochondrial biogenesis, and autophagy. Evidence is mounting that AMPK also plays a role in a number of pathways unrelated to energy metabolism. Here, we identify the recombination-activating gene 1 protein (RAG1) as a substrate of AMPK. The RAG1/RAG2 complex is a lymphoid-specific endonuclease that catalyzes specific DNA cleavage during V(D)J recombination, which is required for the assembly of the Ig and T-cell receptor genes of the immune system. AMPK directly phosphorylates RAG1 at serine 528, and the phosphorylation enhances the catalytic activity of the RAG complex, resulting in increased cleavage of oligonucleotide substrates in vitro, or increased recombination of an extrachromosomal substrate in a cellular assay. Our results suggest that V(D) J recombination can be regulated by AMPK activation, providing a potential new link between metabolic stress and development of B and T lymphocytes. C1 [Um, Jee-Hyun; Brown, Alexandra L.; Kim, Myung K.; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Um, Jee-Hyun] Gachon Univ, Lee Gil Ya Canc & Diabet Inst, Korea Mouse Metab Phenotyping Ctr, Inchon 406840, South Korea. [Singh, Samarendra K.; Gellert, Martin] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Lee, Baeck-Seung; Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Luckey, Megan A.; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gellert@helix.nih.gov; chungj@nhlbi.nih.gov RI chen, yong/E-2432-2011; Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health; National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01 AI047829, R01AI074953] FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Cancer Institute, National Institutes of Health, and by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants R01 AI047829 and R01AI074953. NR 41 TC 5 Z9 5 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 JUN 11 PY 2013 VL 110 IS 24 BP 9873 EP 9878 DI 10.1073/pnas.1307928110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 171LM UT WOS:000320930100065 PM 23716691 ER PT J AU Hofmann, JN Liao, LM Strickland, PT Shu, XO Yang, G Ji, BT Li, HL Rothman, N Kamangar, F Gao, YT Zheng, W Chow, WH AF Hofmann, Jonathan N. Liao, Linda M. Strickland, Paul T. Shu, Xiao-Ou Yang, Gong Ji, Bu-Tian Li, Hong-Lan Rothman, Nathaniel Kamangar, Farin Gao, Yu-Tang Zheng, Wei Chow, Wong-Ho TI Polycyclic aromatic hydrocarbons: determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study SO BMC CANCER LA English DT Article DE 1-hydroxypyrene glucuronide; Polycyclic aromatic hydrocarbons; Colorectal cancer; China ID DNA-ADDUCTS; ESOPHAGEAL CANCER; MEAT CONSUMPTION; EXPOSURE; ADENOMA; ASSOCIATION; SMOKING; WORKERS; COLON; PLANT AB Background: Associations between polycyclic aromatic hydrocarbons (PAHs) and colorectal cancer have been reported previously but few studies have characterized PAH exposure using biological measurements. We evaluated colorectal cancer risk in relation to urinary concentration of 1-hydroxypyrene glucuronide (1-OHPG), a polycyclic aromatic hydrocarbon (PAH) metabolite, and assessed determinants of PAH exposure among controls in the Shanghai Women's Health Study (SWHS). Methods: Concentrations of 1-OHPG were measured in spot urine samples collected from 343 colorectal cancer cases and 343 individually matched controls. Questionnaires were administered to collect information on demographic characteristics and reported exposures. Odds ratios were calculated for risk of colorectal cancer in relation to quartiles of urinary 1-OHPG concentration. Potential determinants of natural log-transformed urinary 1-OHPG concentration were evaluated among a combined sample of controls from this study and another nested case-control study in the SWHS (N-total=652). Results: No statistically significant differences in risk of colorectal cancer by urinary 1-OHPG levels were observed. Among controls, the median (interquartile range) urinary 1-OHPG concentration was 2.01 pmol/mL (0.95-4.09). Active and passive smoking, using coal as a cooking fuel, eating foods that were cooked well done, and recent consumption of fried dough (e. g., youtiao) were associated with elevated levels of 1-OHPG, though only active smoking and fried dough consumption achieved statistical significance in multivariate analyses. Conclusions: This study does not provide evidence of an association between urinary levels of 1-OHPG and risk of colorectal cancer among women. Several environmental and dietary sources of PAH exposure were identified. Overall, the levels of 1-OHPG in this population of predominantly non-smoking women were considerably higher than levels typically observed among non-smokers in Europe, North America, and other developed regions. C1 [Hofmann, Jonathan N.; Liao, Linda M.; Ji, Bu-Tian; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Strickland, Paul T.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Li, Hong-Lan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E132,MSC 9771, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov OI Liao, Linda/0000-0002-1923-5294 FU National Institutes of Health [R37 CA070867]; NIH Intramural Research Program [N02 CP1101066] FX This research was supported by National Institutes of Health research grant R37 CA070867 (PI: W. Zheng) and by NIH Intramural Research Program contract N02 CP1101066. The authors thank the research staff of the Shanghai Women's Health Study. NR 30 TC 5 Z9 5 U1 1 U2 40 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 11 PY 2013 VL 13 AR 282 DI 10.1186/1471-2407-13-282 PG 9 WC Oncology SC Oncology GA 166IE UT WOS:000320547100001 PM 23758680 ER PT J AU Wang, SJ Huang, P Nie, LM Xing, RJ Liu, DB Wang, Z Lin, J Chen, SH Niu, G Lu, GM Chen, XY AF Wang, Shouju Huang, Peng Nie, Liming Xing, Ruijun Liu, Dingbin Wang, Zhe Lin, Jing Chen, Shouhui Niu, Gang Lu, Guangming Chen, Xiaoyuan TI Single Continuous Wave Laser Induced Photodynamic/Plasmonic Photothermal Therapy Using Photosensitizer-Functionalized Gold Nanostars SO ADVANCED MATERIALS LA English DT Article DE gold nanostars; chlorin e6; continuous wave lasers; photodynamic therapy; plasmonic photothermal therapy ID GRAPHENE OXIDE; CANCER-CELLS; FLUENCE RATE; NANOPARTICLES; NANORODS; NANOCRYSTALS; FEMTOSECOND; DESTRUCTION; DELIVERY C1 [Wang, Shouju; Lu, Guangming] Nanjing Univ, Dept Med Imaging, Jinling Hosp, Sch Clin,Med Coll, Nanjing 210000, Jiangsu, Peoples R China. [Wang, Shouju; Huang, Peng; Nie, Liming; Xing, Ruijun; Liu, Dingbin; Wang, Zhe; Lin, Jing; Chen, Shouhui; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Huang, Peng; Lin, Jing] Shanghai Jiao Tong Univ, Inst Micronano Sci & Technol, Shanghai 200240, Peoples R China. [Nie, Liming; Wang, Zhe] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Lu, GM (reprint author), Nanjing Univ, Dept Med Imaging, Jinling Hosp, Sch Clin,Med Coll, Nanjing 210000, Jiangsu, Peoples R China. EM cjr.luguangming@vip.163.com; shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Nie, Liming/F-7718-2016; Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Basic Research Program of China (973 program) [2010CB933901, 2011CB707702, 2013CB733800, 2013CB733802]; National Science Foundation of China (NSFC) [81272987, 81028009, 81120108013, 30930028]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported in part, by the National Basic Research Program of China (973 program, 2010CB933901, 2011CB707702, 2013CB733800 and 2013CB733802), the National Science Foundation of China (NSFC) (81272987, 81028009, 81120108013 and 30930028) and by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 35 TC 152 Z9 152 U1 28 U2 294 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0935-9648 J9 ADV MATER JI Adv. Mater. PD JUN 11 PY 2013 VL 25 IS 22 BP 3055 EP 3061 DI 10.1002/adma.201204623 PG 7 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 160PJ UT WOS:000320131300005 PM 23404693 ER PT J AU Sheets, RL AF Sheets, Rebecca L. TI Opinion on adventitious agents testing for vaccines: Why do we worry so much about adventitious agents in vaccines? SO VACCINE LA English DT Review DE Adventitious agents; Viral contamination; Biologicals; Viral vaccines; 3 R's; Risk-based Quality by Design ID RISK-ASSESSMENT; VIRUS; SV40 AB The manner in which viral vaccines are produced in a biological system makes them vulnerable to microbial contamination. Considerable effort is expended to avoid such contamination and to detect it if it occurred. Is this effort warranted, efficient, scientifically sound, and rational? When asked for my opinion on these matters, I agreed to discuss the basis and historical context for why we do what we do and proffer opinion on what we might do instead or in addition, as we look forward to the inclusion of new strategies and methods in our arsenal. Being an advocate of the 3 R's policy, I invite a re-examination of the traditional in vivo methods in particular. I also advocate for a risk-based approach consistent with "Quality by Design" as a more scientific and rational means of addressing these issues. In the end, vaccinologists need to reassure the public that the vaccines they or their children receive are safe and pure and that all reasonable measures are taken to safeguard them. Published by Elsevier Ltd. C1 NIAID, CAPT USPHS, USNIH, DAIDS, Bethesda, MD 20892 USA. RP Sheets, RL (reprint author), NIAID, CAPT USPHS, USNIH, DAIDS, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsheets@niaid.nih.gov NR 21 TC 2 Z9 3 U1 0 U2 6 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 JUN 10 PY 2013 VL 31 IS 26 BP 2791 EP 2795 DI 10.1016/j.vaccine.2013.03.023 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 168ZD UT WOS:000320745600002 PM 23528414 ER PT J AU Matyas, GR Mayorov, AV Rice, KC Jacobson, AE Cheng, KJ Iyer, MR Li, FY Beck, Z Janda, KD Alving, CR AF Matyas, Gary R. Mayorov, Alexander V. Rice, Kenner C. Jacobson, Arthur E. Cheng, Kejun Iyer, Malliga R. Li, Fuying Beck, Zoltan Janda, Kim D. Alving, Carl R. TI Liposomes containing monophosphoryl lipid A: A potent adjuvant system for inducing antibodies to heroin hapten analogs SO VACCINE LA English DT Article DE Liposomes containing monophosphoryl lipid A; Adjuvant system; Opiate vaccine; Antibodies to heroin haptens ID MORPHINE/HEROIN VACCINE; ALUMINUM-HYDROXIDE; DRUG-ABUSE; PEPTIDES; SPECIFICITIES; CHOLESTEROL; ANTIGENS; CODEINE; RELAPSE; RATS AB In order to create an effective immunization approach for a potential vaccine to heroin, liposomes containing monophosphoryl lipid A [L(MPLA)] were tested as an adjuvant system to induce antibodies to heroin hapten analogs. Four synthetic haptens and two immunization strategies were employed. In the first strategy, a hydrophobic 23 amino acid immunogenic peptide derived from the membrane proximal external region of gp41 from HIV-1 envelope protein was embedded as a carrier in the outer surface of L(MPLA), to which was conjugated a 15 amino acid universal T cell epitope and a terminal heroin hapten analog. In the second strategy, tetanus toxoid (TT) carrier protein was decorated with haptens by conjugation, and the hapten-conjugated protein was mixed with L(MPLA). After immunization of mice, each of the immunization strategies was effective for induction of IgG anti-hapten antibodies. The first immunization strategy induced a mean end-point IgG titer against one of two haptens tested of approximately 12,800; however, no detectable antibodies were induced against the liposome-associated HIV-1 carrier peptide. In the second immunization strategy, depending on the hapten used for decorating the TT, end-point IgG titers ranged from 100,000 to 6,500,000. In this strategy, in which hapten was conjugated to the TT, end-point IgG titers of 400,000 to the TT carrier were observed with each conjugate. However, upon mixing unconjugated TT with L(MPLA), anti-TT titers of 6,500,000 were observed. We conclude that L(MPLA) serves as a potent adjuvant for inducing antibodies to candidate heroin haptens. However, antibodies to the carrier peptide or protein were partly or completed inhibited by the presence of conjugated hapten. Published by Elsevier Ltd. C1 [Matyas, Gary R.; Mayorov, Alexander V.; Beck, Zoltan; Alving, Carl R.] Walter Reed Army Inst Res, Lab Adjuvant & Antigen Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Mayorov, Alexander V.; Beck, Zoltan] Henry M Jackson Fdn Adv Mil Med, US Mil HIV Res Program, Bethesda, MD 20817 USA. [Rice, Kenner C.; Jacobson, Arthur E.; Cheng, Kejun; Li, Fuying] NIDA, Chem Biol Res Branch, NIH, Rockville, MD 20852 USA. [Iyer, Malliga R.] NIAAA, NIH, Rockville, MD 20852 USA. [Janda, Kim D.] Scripps Res Inst, Dept Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Janda, Kim D.] Scripps Res Inst, Dept Immunol, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Janda, Kim D.] Scripps Res Inst, Worm Inst Res & Med, La Jolla, CA 92037 USA. RP Alving, CR (reprint author), Walter Reed Army Inst Res, Lab Adjuvant & Antigen Res, US Mil HIV Res Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM calving@hivresearch.org OI Matyas, Gary/0000-0002-2074-2373 FU Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-07-2-067]; U.S. Army Medical Research and Materiel Command (MRMC) [W81XWH-07-2-067]; MRMC [Y1-DA0121-01]; National Institute on Drug Abuse [Y1-DA0121-01]; NIH Intramural Research Program of the National Institute on Drug Abuse; NIH Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS; NIH [DA 026625] FX This work was supported through a Cooperative Agreement Award (no. W81XWH-07-2-067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command (MRMC). The work was partially supported by an interagency agreement (Y1-DA0121-01 to CRA) between MRMC and the National Institute on Drug Abuse. The work of KC, FL, MRI, AEJ, and KCR was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. KJ was supported in part by NIH grant no. DA 026625. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adhered to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. NR 40 TC 18 Z9 18 U1 0 U2 31 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 JUN 10 PY 2013 VL 31 IS 26 BP 2804 EP 2810 DI 10.1016/j.vaccine.2013.04.027 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 168ZD UT WOS:000320745600004 PM 23624097 ER PT J AU Puetz, TW Morley, CA Herring, MP AF Puetz, Timothy W. Morley, Christopher A. Herring, Matthew P. TI Effects of Creative Arts Therapies on Psychological Symptoms and Quality of Life in Patients With Cancer SO JAMA INTERNAL MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; ALTERNATIVE MEDICINE USE; BREAST-CANCER; MUSIC-THERAPY; COMPLEMENTARY THERAPIES; CHEMOTHERAPY TREATMENT; DEPRESSIVE SYMPTOMS; PALLIATIVE CARE; METAANALYSIS; ANXIETY AB Importance: Creative arts therapies (CATs) can reduce anxiety, depression, pain, and fatigue and increase quality of life (QOL) in patients with cancer. However, no systematic review of randomized clinical trials (RCTs) examining the effects of CAT on psychological symptoms among cancer patients has been conducted. Objectives: To estimate the effect of CAT on psychological symptoms and QOL in cancer patients during treatment and follow-up and to determine whether the effect varied according to patient, intervention, and design characteristics. Evidence Review: We searched ERIC, Google Scholar, MEDLINE, PsycInfo, PubMed, and Web of Science from database inception to January 2012. Studies included RCTs in which cancer patients were randomized to a CAT or control condition and anxiety, depression, pain, fatigue and/or QOL were measured pre- and post-intervention. Twenty-seven studies involving 1576 patients were included. We extracted data on effect sizes, moderators, and study quality. Hedges d effect sizes were computed, and random-effects models were used to estimate sampling error and population variance. Findings: During treatment, CAT significantly reduced anxiety (Delta = 0.28 [95% CI, 0.11-0.44]), depression (Delta = 0.23 [0.05-0.40]), and pain (Delta = 0.54 [0.33-0.75]) and increased QOL (Delta = 0.50 [0.25-0.74]). Pain was significantly reduced during follow-up (Delta = 0.59 [95% CI, 0.42-0.77]). Anxiety reductions were strongest for studies in which (1) a non-CAT therapist administered the intervention compared with studies that used a creative arts therapist and (2) a waiting-list or usual-care comparison was used. Pain reductions were largest during inpatient treatment and for homogeneous cancer groups in outpatient settings; significantly smaller reductions occurred in heterogeneous groups in outpatient settings. Conclusions and Relevance: Exposure to CAT can improve anxiety, depression, and pain symptoms and QOL among cancer patients, but this effect is reduced during follow-up. C1 [Puetz, Timothy W.] NIH, Off Director, Bethesda, MD 20892 USA. [Morley, Christopher A.] ArtReach Fdn, Atlanta, GA USA. [Herring, Matthew P.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. RP Herring, MP (reprint author), Univ Alabama Birmingham, Dept Epidemiol, 1530 3rd Ave S,Ryals Publ Hlth Bldg 210E, Birmingham, AL 35294 USA. EM mph8@uab.edu RI Herring, Matthew/O-2265-2014 OI Herring, Matthew/0000-0002-6835-5321 NR 82 TC 16 Z9 16 U1 2 U2 64 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUN 10 PY 2013 VL 173 IS 11 BP 960 EP 969 DI 10.1001/jamainternmed.2013.836 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 159MT UT WOS:000320050200006 PM 23699646 ER PT J AU Davidson, KW Bigger, JT Burg, MM Carney, RM Chaplin, WF Czajkowski, S Dornelas, E Duer-Hefele, J Frasure-Smith, N Freedland, KE Haas, DC Jaffe, AS Ladapo, JA Lesperance, F Medina, V Newman, JD Osorio, GA Parsons, F Schwartz, JE Shaffer, JA Shapiro, PA Sheps, DS Vaccarino, V Whang, W Ye, SQ AF Davidson, Karina W. Bigger, J. Thomas Burg, Matthew M. Carney, Robert M. Chaplin, William F. Czajkowski, Susan Dornelas, Ellen Duer-Hefele, Joan Frasure-Smith, Nancy Freedland, Kenneth E. Haas, Donald C. Jaffe, Allan S. Ladapo, Joseph A. Lesperance, Francois Medina, Vivian Newman, Jonathan D. Osorio, Gabrielle A. Parsons, Faith Schwartz, Joseph E. Shaffer, Jonathan A. Shapiro, Peter A. Sheps, David S. Vaccarino, Viola Whang, William Ye, Siqin TI Centralized, Stepped, Patient Preference-Based Treatment for Patients With Post-Acute Coronary Syndrome Depression CODIACS Vanguard Randomized Controlled Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE PREVENTION; AMERICAN-HEART-ASSOCIATION; LONGER-TERM OUTCOMES; MYOCARDIAL-INFARCTION; COLLABORATIVE CARE; MAJOR DEPRESSION; PSYCHOSOCIAL-EVALUATION; COST-EFFECTIVENESS; RISK-FACTORS; HEALTH AB Importance: Controversy remains about whether depression can be successfully managed after acute coronary syndrome (ACS) and the costs and benefits of doing so. Objective: To determine the effects of providing post-ACS depression care on depressive symptoms and health care costs. Design: Multicenter randomized controlled trial. Setting: Patients were recruited from 2 private and 5 academic ambulatory centers across the United States. Participants: A total of 150 patients with elevated depressive symptoms (Beck Depression Inventory [BDI] score >= 10) 2 to 6 months after an ACS, recruited between March 18, 2010, and January 9, 2012. Interventions: Patients were randomized to 6 months of centralized depression care (patient preference for problem-solving treatment given via telephone or the Internet, pharmacotherapy, both, or neither), stepped every 6 to 8 weeks (active treatment group; n=73), or to locally determined depression care after physician notification about the patient's depressive symptoms (usual care group; n=77). Main Outcome Measures: Change in depressive symptoms during 6 months and total health care costs. Results: Depressive symptoms decreased significantly more in the active treatment group than in the usual care group (differential change between groups, -3.5 BDI points; 95% CI, -6.1 to -0.7; P=.01). Although mental health care estimated costs were higher for active treatment than for usual care, overall health care estimated costs were not significantly different (difference adjusting for confounding, -$325; 95% CI, -$2639 to $1989; P=.78). Conclusions: For patients with post-ACS depression, active treatment had a substantial beneficial effect on depressive symptoms. This kind of depression care is feasible, effective, and may be cost-neutral within 6 months; therefore, it should be tested in a large phase 3 pragmatic trial. C1 [Davidson, Karina W.; Bigger, J. Thomas; Burg, Matthew M.; Duer-Hefele, Joan; Medina, Vivian; Newman, Jonathan D.; Osorio, Gabrielle A.; Parsons, Faith; Schwartz, Joseph E.; Shaffer, Jonathan A.; Shapiro, Peter A.; Whang, William; Ye, Siqin] Columbia Univ, Med Ctr, Dept Med, Ctr Behav Cardiovasc Hlth, New York, NY 10032 USA. [Carney, Robert M.; Freedland, Kenneth E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Chaplin, William F.] St Johns Univ, Dept Psychol, Jamaica, NY 11439 USA. [Czajkowski, Susan] NHLBI, Behav Med Sci Res Grp, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Dornelas, Ellen] Yale Univ, Dept Med, Hartford Hosp, New Haven, CT 06520 USA. [Frasure-Smith, Nancy] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Frasure-Smith, Nancy; Lesperance, Francois] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Haas, Donald C.] Penn Cardiac Care Mercer Bucks, Dept Med, Yardley, PA USA. [Jaffe, Allan S.] Mayo Clin, Dept Med, Rochester, MN USA. [Ladapo, Joseph A.] NYU, Dept Med, New York, NY 10016 USA. [Schwartz, Joseph E.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. [Sheps, David S.] Univ Florida, Dept Med, Gainesville, FL USA. [Vaccarino, Viola] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA. [Vaccarino, Viola] Morehouse Sch Med, Atlanta, GA 30310 USA. RP Davidson, KW (reprint author), Columbia Univ, Coll Phys & Surg, Ctr Behav Cardiovasc Hlth, 622 W 168 St,PH 9-948, New York, NY 10032 USA. EM kd2124@columbia.edu RI Lesperance, Francois/C-4716-2015; OI Lesperance, Francois/0000-0003-4604-2823; Ladapo, Joseph/0000-0002-8518-4800; Newman, Jonathan/0000-0001-6855-7305 FU National Institutes of Health (NIH), Bethesda, Maryland [5RC2HL101663, HL-088117, HL-84034]; Columbia University's CTSA from National Center for Advancing Translational Sciences/NIH [UL1TR000040]; National Heart, Lung, and Blood Institute FX This work was supported by grants 5RC2HL101663, HL-088117, and HL-84034 from the National Institutes of Health (NIH), Bethesda, Maryland, and was supported in part by Columbia University's CTSA grant No. UL1TR000040 from National Center for Advancing Translational Sciences/NIH.; This trial was funded by the National Heart, Lung, and Blood Institute, which had no formal role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. NR 45 TC 36 Z9 38 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUN 10 PY 2013 VL 173 IS 11 BP 997 EP 1004 DI 10.1001/jamainternmed.2013.915 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 159MT UT WOS:000320050200014 PM 23471421 ER PT J AU Yardley, DA Ismail-Khan, RR Melichar, B Lichinitser, M Munster, PN Klein, PM Cruickshank, S Miller, KD Lee, MJ Trepel, JB AF Yardley, Denise A. Ismail-Khan, Roohi R. Melichar, Bohuslav Lichinitser, Mikhail Munster, Pamela N. Klein, Pamela M. Cruickshank, Scott Miller, Kathy D. Lee, Min J. Trepel, Jane B. TI Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; T-CELL LYMPHOMA; REFRACTORY SOLID TUMORS; HEMATOLOGIC MALIGNANCIES; ANTICANCER AGENTS; TRIAL; DEPSIPEPTIDE; MULTICENTER; MS-275 AB Purpose Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. Patients and Methods Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. Results One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. Conclusion Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway. (C) 2013 by American Society of Clinical Oncology C1 [Yardley, Denise A.] Sarah Cannon Res Inst, Nashville, TN USA. [Yardley, Denise A.] Tennessee Oncol, Nashville, TN USA. [Ismail-Khan, Roohi R.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Melichar, Bohuslav] Palacky Univ, Sch Med, CR-77147 Olomouc, Czech Republic. [Melichar, Bohuslav] Teaching Hosp, Olomouc, Czech Republic. [Lichinitser, Mikhail] Russian Acad Med Sci, Blokhin Russian Oncol Res Ctr, Moscow, Russia. [Munster, Pamela N.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Klein, Pamela M.] PMK Consulting, San Francisco, CA USA. [Klein, Pamela M.; Cruickshank, Scott] Syndax Pharmaceut, Waltham, MA USA. [Miller, Kathy D.] Indiana Univ Sch Med, Indianapolis, IN USA. [Lee, Min J.; Trepel, Jane B.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yardley, DA (reprint author), Sarah Cannon Canc Ctr, 250 25th Ave North,Suite 100, Nashville, TN 37203 USA. EM dyardley@tnonc.com FU Syndax Pharmaceuticals FX Supported by Syndax Pharmaceuticals. NR 27 TC 99 Z9 101 U1 3 U2 13 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 JUN 10 PY 2013 VL 31 IS 17 BP 2128 EP + DI 10.1200/JCO.2012.43.7251 PG 9 WC Oncology SC Oncology GA 160FZ UT WOS:000320104400020 PM 23650416 ER PT J AU Smith, AW Bellizzi, KM Keegan, THM Zebrack, B Chen, VW Neale, AV Hamilton, AS Shnorhavorian, M Lynch, CF AF Smith, Ashley Wilder Bellizzi, Keith M. Keegan, Theresa H. M. Zebrack, Brad Chen, Vivien W. Neale, Anne Victoria Hamilton, Ann S. Shnorhavorian, Margarett Lynch, Charles F. TI Health-Related Quality of Life of Adolescent and Young Adult Patients With Cancer in the United States: The Adolescent and Young Adult Health Outcomes and Patient Experience Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GENERIC CORE SCALES; MULTIDIMENSIONAL FATIGUE SCALE; UNIVERSITY-STUDENT POPULATION; PEDIATRIC CANCER; SURVIVORS; RELIABILITY; VALIDITY; FEASIBILITY; PEDSQL(TM); IMPACT AB Purpose Adolescents and young adults (AYAs) diagnosed with cancer face numerous physical, psychosocial, and practical challenges. This article describes the health-related quality of life (HRQOL) and associated demographic and health-related characteristics of this developmentally diverse population. Patients and Methods Data are from the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study, a population-based cohort of 523 AYA patients with cancer, ages 15 to 39 years at diagnosis from 2007 to 2009. Comparisons are made by age group and with general and healthy populations. Multiple linear regression models evaluated effects of demographic, disease, health care, and symptom variables on multiple domains of HRQOL using the Pediatric Quality of Life Inventory (PedsQL) and the Short-Form Health Survey 12 (SF-12). Results Overall, respondents reported significantly worse HRQOL across both physical and mental health scales than did general and healthy populations. The greatest deficits were in limitations to physical and emotional roles, physical and social functioning, and fatigue. Teenaged patients (ages 15 to 17 years) reported worse physical and work/school functioning than patients 18 to 25 years old. Regression models showed that HRQOL was worse for those in treatment, with current/recent symptoms, or lacking health insurance at any time since diagnosis. In addition, sarcoma patients, Hispanic patients, and those with high school or lower education reported worse physical health. Unmarried patients reported worse mental health. Conclusion Results suggest that AYAs with cancer have major decrements in several physical and mental HRQOL domains. Vulnerable subgroups included Hispanic patients, those with less education, and those without health insurance. AYAs also experienced higher levels of fatigue that were influenced by current symptoms and treatment. Future research should explore ways to address poor functioning in this understudied group. (C) 2013 by American Society of Clinical Oncology C1 [Smith, Ashley Wilder] NCI, Bethesda, MD 20892 USA. [Bellizzi, Keith M.] Univ Connecticut, Storrs, CT USA. [Keegan, Theresa H. M.] Canc Prevent Inst California, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Hamilton, Ann S.] Univ So Calif, Los Angeles, CA USA. [Zebrack, Brad] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Neale, Anne Victoria] Wayne State Univ, Detroit, MI USA. [Chen, Vivien W.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Shnorhavorian, Margarett] Univ Washington, Seattle, WA 98195 USA. [Shnorhavorian, Margarett] Seattle Childrens Hosp, Seattle, WA USA. [Lynch, Charles F.] Univ Iowa, Iowa City, IA USA. RP Smith, AW (reprint author), NCI, Outcomes Res Branch, 6130 Execut Blvd,MSC 7344,Execut Plaza North,Rm 4, Bethesda, MD 20892 USA. EM smithas@mail.nih.gov FU [N01PC-2010-00032]; [N01PC-2010-00140]; [N01PC-2010-00034]; [N01PC-2010-00035]; [N01PC-2010-00029]; [N01PC2010-00028]; [N01PC-2010-00030] FX Supported by Contracts No. N01PC-2010-00032, N01PC-2010-00140, N01PC-2010-00034, N01PC-2010-00035, N01PC-2010-00029, N01PC2010-00028, and N01PC-2010-00030. NR 31 TC 46 Z9 46 U1 0 U2 23 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 JUN 10 PY 2013 VL 31 IS 17 BP 2136 EP U127 DI 10.1200/JCO.2012.47.3173 PG 13 WC Oncology SC Oncology GA 160FZ UT WOS:000320104400021 PM 23650427 ER PT J AU Yang, HP Anderson, WF Rosenberg, PS Trabert, B Gierach, GL Wentzensen, N Cronin, KA Sherman, ME AF Yang, Hannah P. Anderson, William F. Rosenberg, Philip S. Trabert, Britton Gierach, Gretchen L. Wentzensen, Nicolas Cronin, Kathleen A. Sherman, Mark E. TI Ovarian Cancer Incidence Trends in Relation to Changing Patterns of Menopausal Hormone Therapy Use in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN PLUS PROGESTIN; BREAST-CANCER; METASTATIC TUMORS; RATES; WOMEN; TRIAL; AGE; OOPHORECTOMY; ENDOMETRIAL; KRUKENBERG AB Purpose After a report from the Women's Health Initiative (WHI) in 2002, a precipitous decline in menopausal hormonal therapy (MHT) use in the United States was linked to a decline in breast cancer incidence rates. Given that MHT use is also associated with increased ovarian cancer risk, we tested whether ovarian cancer incidence rates changed after 2002. Methods Using the North American Association of Central Cancer Registries database (1995 to 2008; N = 171,142 incident ovarian cancers), we applied standard analytic approaches and age-period-cohort (APC) models to estimate ovarian cancer incidence rate changes before (1995 to 2002) and after (2003 to 2008) the WHI report. Results Among women age >= 50 years, age-standardized ovarian cancer incidence declined by 0.8% per year (95% CI, -1.8% to -0.5% per year) before the WHI announcement; after the WHI report, the rate declined by 2.4% per year (95% CI, -2.5% to -2.2% per year). APC models confirmed an accelerated decline in ovarian cancer incidence after the WHI report, adjusted for age and birth cohort effects. This sudden change was notable among women most likely to have used MHT (ie, women age 50 to 69 years, white women, and residents of regions with highest MHT prescription frequency). The largest changes were found for the endometrioid histologic subtype. Conclusion After a marked reduction in MHT use around 2002, ovarian cancer incidence rates demonstrated an accelerated decline, with the largest changes for endometrioid carcinomas. This strong temporal association, although not proving a causal role of hormones in ovarian carcinogenesis, suggests that future analytic research supporting cancer control efforts should clarify the role of hormonal exposures on the development and behavior of subtypes of ovarian cancer. (C) 2013 by American Society of Clinical Oncology C1 [Yang, Hannah P.; Anderson, William F.; Rosenberg, Philip S.; Trabert, Britton; Gierach, Gretchen L.; Wentzensen, Nicolas; Cronin, Kathleen A.; Sherman, Mark E.] NCI, Bethesda, MD 20892 USA. RP Yang, HP (reprint author), 6120 Execut Blvd,EPS-5030, Rockville, MD 20852 USA. EM yanghan@mail.nih.gov RI Trabert, Britton/F-8051-2015; Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD FX Supported entirely by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 36 TC 20 Z9 20 U1 1 U2 11 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 JUN 10 PY 2013 VL 31 IS 17 BP 2146 EP U135 DI 10.1200/JCO.2012.45.5758 PG 8 WC Oncology SC Oncology GA 160FZ UT WOS:000320104400022 PM 23650423 ER PT J AU Dudley, ME Gross, CA Somerville, RPT Hong, Y Schaub, NP Rosati, SF White, DE Nathan, D Restifo, NP Steinberg, SM Wunderlich, JR Kammula, US Sherry, RM Yang, JC Phan, GQ Hughes, MS Laurencot, CM Rosenberg, SA AF Dudley, Mark E. Gross, Colin A. Somerville, Robert P. T. Hong, Young Schaub, Nicholas P. Rosati, Shannon F. White, Donald E. Nathan, Debbie Restifo, Nicholas P. Steinberg, Seth M. Wunderlich, John R. Kammula, Udai S. Sherry, Richard M. Yang, James C. Phan, Giao Q. Hughes, Marybeth S. Laurencot, Carolyn M. Rosenberg, Steven A. TI Randomized Selection Design Trial Evaluating CD8(+)-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REGULATORY T-CELLS; METASTATIC MELANOMA; TRANSFER IMMUNOTHERAPY; RAPID EXPANSION; CANCER; RECOGNITION; REGRESSION; STANDARD; EFFICACY; CULTURES AB Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+)lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+)peripheral blood lymphocytes (P =.01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [ RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P =.04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs. (C) 2013 by American Society of Clinical Oncology C1 [Dudley, Mark E.; Gross, Colin A.; Somerville, Robert P. T.; Hong, Young; Schaub, Nicholas P.; Rosati, Shannon F.; White, Donald E.; Nathan, Debbie; Restifo, Nicholas P.; Steinberg, Seth M.; Wunderlich, John R.; Kammula, Udai S.; Sherry, Richard M.; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Laurencot, Carolyn M.; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, CRC 3W-5752,10 Ctr Dr, Bethesda, MD 20892 USA. EM mark_dudley@nih.gov OI Gross, Colin/0000-0002-7061-5073; Yang, James Chih-Hsin/0000-0002-5586-5138; Restifo, Nicholas P./0000-0003-4229-4580 FU Meyer family; Milstein family FX Supported in part by an unrestricted grant through the generous contributions of the Meyer and Milstein families. NR 29 TC 68 Z9 69 U1 1 U2 9 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 JUN 10 PY 2013 VL 31 IS 17 BP 2152 EP U144 DI 10.1200/JCO.2012.46.6441 PG 9 WC Oncology SC Oncology GA 160FZ UT WOS:000320104400023 PM 23650429 ER PT J AU Romond, EH Rastogi, P Jeong, JH AF Romond, Edward H. Rastogi, Priya Jeong, Jong-Hyeon TI Questionable Validity of Cardiac Risk Score on the Basis of the NSABP B-31 Model Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Romond, Edward H.] Natl Surg Adjuvant Breast & Bowel Project, Pittsurgh, PA USA. [Romond, Edward H.] Univ Kentucky, Lucille Parker Markey Canc Ctr, Lexington, KY USA. [Rastogi, Priya] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Rastogi, Priya] Univ Pittsburgh, Magee Womens Hosp, Sch Med, Pittsburgh, PA 15213 USA. [Jeong, Jong-Hyeon] Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Jeong, Jong-Hyeon] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Romond, EH (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsurgh, PA USA. FU NCI NIH HHS [U10-CA-69974, U10-CA-37377, U10-CA-12027, U10-CA-69651] 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 JUN 10 PY 2013 VL 31 IS 17 BP 2225 EP 2225 DI 10.1200/JCO.2012.48.3701 PG 1 WC Oncology SC Oncology GA 160FZ UT WOS:000320104400035 PM 23901419 ER PT J AU McDavid, A Crane, PK Newton, KM Crosslin, DR McCormick, W Weston, N Ehrlich, K Hart, E Harrison, R Kukull, WA Rottscheit, C Peissig, P Stefanski, E McCarty, CA Zuvich, RL Ritchie, MD Haines, JL Denny, JC Schellenberg, GD de Andrade, M Kullo, I Li, RL Mirel, D Crenshaw, A Bowen, JD Li, G Tsuang, D McCurry, S Teri, L Larson, EB Jarvik, GP Carlson, CS AF McDavid, Andrew Crane, Paul K. Newton, Katherine M. Crosslin, David R. McCormick, Wayne Weston, Noah Ehrlich, Kelly Hart, Eugene Harrison, Robert Kukull, Walter A. Rottscheit, Carla Peissig, Peggy Stefanski, Elisha McCarty, Catherine A. Zuvich, Rebecca Lynn Ritchie, Marylyn D. Haines, Jonathan L. Denny, Joshua C. Schellenberg, Gerard D. de Andrade, Mariza Kullo, Iftikhar Li, Rongling Mirel, Daniel Crenshaw, Andrew Bowen, James D. Li, Ge Tsuang, Debby McCurry, Susan Teri, Linda Larson, Eric B. Jarvik, Gail P. Carlson, Chris S. TI Enhancing the Power of Genetic Association Studies through the Use of Silver Standard Cases Derived from Electronic Medical Records SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; CATEGORICAL-DATA; COMMON VARIANTS; MISCLASSIFICATION; DIAGNOSIS; CRITERIA; LINKAGE; CD2AP AB The feasibility of using imperfectly phenotyped "silver standard" samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results. C1 [McDavid, Andrew; Carlson, Chris S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Crane, Paul K.; McCormick, Wayne; Larson, Eric B.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Newton, Katherine M.; Weston, Noah; Ehrlich, Kelly; Hart, Eugene; Harrison, Robert; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Crosslin, David R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kukull, Walter A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Rottscheit, Carla; Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Stefanski, Elisha] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Zuvich, Rebecca Lynn; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Denny, Joshua C.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [de Andrade, Mariza] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Kullo, Iftikhar] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Li, Rongling] NHGRI, NIH, Bethesda, MD 20892 USA. [Mirel, Daniel; Crenshaw, Andrew] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bowen, James D.] Swedish Med Ctr, Dept Neurol, Seattle, WA USA. [Li, Ge; Tsuang, Debby] Univ Washington, Dept Psychiat, Sch Med, Seattle, WA 98195 USA. [Tsuang, Debby] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [McCurry, Susan; Teri, Linda] Univ Washington, Sch Nursing, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Sch Med, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. RP McDavid, A (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM amcdavid@fhcrc.org RI Crane, Paul/C-8623-2014; Jarvik, Gail/N-6476-2014; Tsuang, Debby/L-7234-2016; OI Jarvik, Gail/0000-0002-6710-8708; Tsuang, Debby/0000-0002-4716-1894; Kukull, Walter/0000-0001-8761-9014; Crane, Paul/0000-0003-4278-7465; McDavid, Andrew/0000-0002-6581-1213 FU National Institutes of Health (NIH) [HG004610, AG06781, U01HG004438] FX This study was funded by National Institutes of Health (NIH) award HG004610, AG06781 (Group Health Cooperative) and U01HG004438. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 7 Z9 7 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2013 VL 8 IS 6 AR e63481 DI 10.1371/journal.pone.0063481 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VY UT WOS:000320440500003 PM 23762230 ER PT J AU Cho, YS Lee, GY Sajja, HK Qian, WP Cao, ZH He, WL Karna, P Chen, XY Mao, H Wang, YA Yang, L AF Cho, Young-Seok Lee, Gee Young Sajja, Hari Krishna Qian, Weiping Cao, Zehong He, Weiling Karna, Prasanthi Chen, Xiaoyuan Mao, Hui Wang, Y. Andrew Yang, Lily TI Targeted Delivery of siRNA-Generating DNA Nanocassettes Using Multifunctional Nanoparticles SO SMALL LA English DT Article ID CARCINOMA IN-SITU; SYSTEMIC DELIVERY; MAMMALIAN-CELLS; GENE-EXPRESSION; CANCER-CELLS; VIVO; RECEPTOR; RNA; STABILITY; UROKINASE AB Molecular therapy using a small interfering RNA (siRNA) has shown promise in the development of novel therapeutics. Various formulations have been used for in vivo delivery of siRNAs. However, the stability of short double-stranded RNA molecules in the blood and efficiency of siRNA delivery into target organs or tissues following systemic administration have been the major issues that limit applications of siRNA in human patients. In this study, multifunctional siRNA delivery nanoparticles are developed that combine imaging capability of nanoparticles with urokinase plasminogen activator receptor-targeted delivery of siRNA expressing DNA nanocassettes. This theranostic nanoparticle platform consists of a nanoparticle conjugated with targeting ligands and double-stranded DNA nanocassettes containing a U6 promoter and a shRNA gene for in vivo siRNA expression. Targeted delivery and gene silencing efficiency of firefly luciferase siRNA nanogenerators are demonstrated in tumor cells and in animal tumor models. Delivery of survivin siRNA expressing nanocassettes into tumor cells induces apoptotic cell death and sensitizes cells to chemotherapy drugs. The ability of expression of siRNAs from multiple nanocassettes conjugated to a single nanoparticle following receptor-mediated internalization should enhance the therapeutic effect of the siRNA-mediated cancer therapy. C1 [Yang, Lily] Emory Univ, Sch Med, Dept Surg, Clin C, Atlanta, GA 30322 USA. [Cho, Young-Seok; Lee, Gee Young; Sajja, Hari Krishna; Qian, Weiping; Cao, Zehong; Karna, Prasanthi; Mao, Hui] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [He, Weiling] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou 510180, Guangdong, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Wang, Y. Andrew] Ocean Nanotech LLC, Springdale, AR 72764 USA. RP Yang, L (reprint author), Emory Univ, Sch Med, Dept Surg, Clin C, Room C-4088,1365 C Clifton Rd, Atlanta, GA 30322 USA. EM Lyang02@emory.edu FU NIH [U01CA151810, R01CA154129A01, U54 CA119338, P50CA128613]; Catholic University of Korea; Songeui Scholar Research Grant FX We thank Dr. Fengzhi Li for providing the survivin shRNA sequence, Dr. Steven Dowdy for information on the SV40 nuclear localization sequence, Dr. Rosa Hwang for luciferase gene stable MIA PaCa-2 cell line, and Dr. Adam Marcus for the MCF-7 GFP stable cell line and for his assistance with the Olympus OV-100 imaging system at the Emory Integrated Cell Imaging Core. This research project was supported by the following NIH grants: U01CA151810 (Yang and Mao), R01CA154129A01 (Yang), U54 CA119338 (Nie), and P50CA128613 (Shin). Dr. Young-Seok Cho was supported by a Songeui Scholar Research Grant funded by the Catholic University of Korea. Dr. Lily Yang is the Nancy Panoz Chair of Surgery in Cancer Research. NR 46 TC 15 Z9 15 U1 4 U2 48 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 J9 SMALL JI Small PD JUN 10 PY 2013 VL 9 IS 11 BP 1964 EP 1973 DI 10.1002/smll.201201973 PG 10 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 156PC UT WOS:000319833700013 PM 23292656 ER PT J AU Burroughs, AM Iyer, LM Aravind, L AF Burroughs, A. Maxwell Iyer, Lakshminarayan M. Aravind, L. TI Two novel PIWI families: roles in inter-genomic conflicts in bacteria and Mediator-dependent modulation of transcription in eukaryotes SO BIOLOGY DIRECT LA English DT Article ID ARGONAUTE SILENCING COMPLEX; RNA-POLYMERASE-II; CRYSTAL-STRUCTURE; RESTRICTION ENZYMES; PASSENGER-STRAND; PROTEIN FAMILIES; STRUCTURAL BASIS; DNA-REPLICATION; SLICER ACTIVITY; GUIDE-STRAND AB Background: The PIWI module, found in the PIWI/AGO superfamily of proteins, is a critical component of several cellular pathways including germline maintenance, chromatin organization, regulation of splicing, RNA interference, and virus suppression. It binds a guide strand which helps it target complementary nucleic strands. Results: Here we report the discovery of two divergent, novel families of PIWI modules, the first such to be described since the initial discovery of the PIWI/AGO superfamily over a decade ago. Both families display conservation patterns consistent with the binding of oligonucleotide guide strands. The first family is bacterial in distribution and is typically encoded by a distinctive three-gene operon alongside genes for a restriction endonuclease fold enzyme and a helicase of the DinG family. The second family is found only in eukaryotes. It is the core conserved module of the Med13 protein, a subunit of the CDK8 subcomplex of the transcription regulatory Mediator complex. Conclusions: Based on the presence of the DinG family helicase, which specifically acts on R-loops, we infer that the first family of PIWI modules is part of a novel RNA-dependent restriction system which could target invasive DNA from phages, plasmids or conjugative transposons. It is predicted to facilitate restriction of actively transcribed invading DNA by utilizing RNA guides. The PIWI family found in the eukaryotic Med13 proteins throws new light on the regulatory switch through which the CDK8 subcomplex modulates transcription at Mediator-bound promoters of highly transcribed genes. We propose that this involves recognition of small RNAs by the PIWI module in Med13 resulting in a conformational switch that propagates through the Mediator complex. Reviewers: This article was reviewed by Sandor Pongor, Frank Eisenhaber and Balaji Santhanam. C1 [Burroughs, A. Maxwell; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU US Department of Health and Human Services (National Library of Medicine, NIH) FX The authors' research is supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH). NR 91 TC 8 Z9 9 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUN 8 PY 2013 VL 8 AR 13 DI 10.1186/1745-6150-8-13 PG 15 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 177NU UT WOS:000321382700001 PM 23758928 ER PT J AU Patel, VB Wang, ZC Fan, D Zhabyeyev, P Basu, R Das, SK Wang, W DesAulniers, J Holland, SM Kassiri, Z Oudit, GY AF Patel, Vaibhav B. Wang, Zuocheng Fan, Dong Zhabyeyev, Pavel Basu, Ratnadeep Das, Subhash K. Wang, Wang DesAulniers, Jessica Holland, Steven M. Kassiri, Zamaneh Oudit, Gavin Y. TI Loss of p47(phox) Subunit Enhances Susceptibility to Biomechanical Stress and Heart Failure Because of Dysregulation of Cortactin and Actin Filaments SO CIRCULATION RESEARCH LA English DT Article DE actin cytoskeleton; cortactin; heart failure; mechanotransduction; pressure overload; p47(phox); remodeling ID NADPH OXIDASE ACTIVATION; CHRONIC GRANULOMATOUS-DISEASE; LUNG ENDOTHELIAL-CELLS; SMOOTH-MUSCLE-CELLS; ANGIOTENSIN-II; CARDIAC-HYPERTROPHY; NAD(P)H OXIDASE; PRESSURE-OVERLOAD; PATHOLOGICAL HYPERTROPHY; TYROSINE PHOSPHORYLATION AB Rationale: The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox) or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47(phox) subunit and is linked to heart failure. We hypothesized that loss of p47(phox) subunit will result in decreased reactive oxygen species production and resistance to heart failure. Objective: To define the role of p47(phox) in pressure overload-induced biomechanical stress. Methods and Results: Eight-week-old male p47(phox) null (p47(phox) knockout [KO]), Nox2 null (Nox2KO), and wild-type mice were subjected to transverse aortic constriction-induced pressure overload. Contrary to our hypothesis, p47(phox)KO mice showed markedly worsened systolic dysfunction in response to pressure overload at 5 and 9 weeks after transverse aortic constriction compared with wild-type-transverse aortic constriction mice. We found that biomechanical stress upregulated N-cadherin and beta-catenin in p47(phox)KO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of focal adhesion kinase. p47(phox) interacts with cytosolic cortactin by coimmunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane on biomechanical stress where cortactin interacted with N-cadherin, resulting in adaptive cytoskeletal remodeling. However, p47(phox)KO hearts showed impaired interaction of cortactin with N-cadherin, resulting in loss of biomechanical stress-induced actin polymerization and cytoskeletal remodeling. In contrast, Nox2 does not interact with cortactin, and Nox2-deficient hearts were protected from pressure overload-induced adverse myocardial and intracellular cytoskeletal remodeling. Conclusions: We showed a novel role of p47(phox) subunit beyond and independent of nicotinamide adenine dinucleotide phosphate oxidase activity as a regulator of cortactin and adaptive cytoskeletal remodeling, leading to a paradoxically enhanced susceptibility to biomechanical stress and heart failure. C1 [Patel, Vaibhav B.; Wang, Zuocheng; Zhabyeyev, Pavel; Das, Subhash K.; DesAulniers, Jessica; Oudit, Gavin Y.] Univ Alberta, Dept Med, Div Cardiol, Edmonton, AB T6G 2S2, Canada. [Patel, Vaibhav B.; Wang, Zuocheng; Fan, Dong; Zhabyeyev, Pavel; Basu, Ratnadeep; Das, Subhash K.; Wang, Wang; DesAulniers, Jessica; Kassiri, Zamaneh; Oudit, Gavin Y.] Univ Alberta, Mazankowski Alberta Heart Inst, Edmonton, AB T6G 2S2, Canada. [Fan, Dong; Basu, Ratnadeep; Wang, Wang; Kassiri, Zamaneh; Oudit, Gavin Y.] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2S2, Canada. [Holland, Steven M.] NIAID, Bethesda, MD 20892 USA. RP Oudit, GY (reprint author), Univ Alberta, Dept Med, Div Cardiol, Mazankowski Alberta Heart Inst, Edmonton, AB T6G 2S2, Canada. EM gavin.oudit@ualberta.ca RI Zhabyeyev, Pavel/E-8715-2016; OI Zhabyeyev, Pavel/0000-0003-0652-3235; Patel, Vaibhav/0000-0001-5917-5962 FU Canadian Institutes of Health Research [MOP 58998-GYO, MOP 86602-GYO, MOP 84279-ZK]; Heart and Stroke Foundation of Canada; Alberta Innovates-Health Solutions FX This work was supported by funding from the Canadian Institutes of Health Research (MOP 58998-GYO, MOP 86602-GYO and MOP 84279-ZK), Heart and Stroke Foundation of Canada, and Alberta Innovates-Health Solutions. NR 62 TC 27 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 7 PY 2013 VL 112 IS 12 BP 1542 EP + DI 10.1161/CIRCRESAHA.111.300299 PG 31 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 298UV UT WOS:000330350900011 PM 23553616 ER PT J AU Zhou, ZH Kumari, N Nekhai, S Clouse, KA Wahl, LM Yamada, KM Dhawan, S AF Zhou, Zhao-Hua Kumari, Namita Nekhai, Sergei Clouse, Kathleen A. Wahl, Larry M. Yamada, Kenneth M. Dhawan, Subhash TI Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1; Heme oxygenase-1; Macrophages; CCR-5; Chemokines ID MONOCYTE-DERIVED MACROPHAGES; HIV-1 INFECTION; CARBON-MONOXIDE; EXPRESSION; REPLICATION; SECRETION; MALARIA; CELLS AB We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtually negative for mature virions as revealed by transmission electron microscopy. LPS activation of MDM markedly enhanced the expression of heme oxygenase-1 (HO-1), a potent inducible cytoprotective enzyme. Increased HO-1 expression was accompanied by elevated production of macrophage inflammatory chemokines (MIP1 alpha and MIP1 beta) by LPS-activated MDM, significantly decreased-surface chemokine receptor-5 (CCR-5) expression, and substantially reduced virus replication. Treatment of cells with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) attenuated the LPS-mediated responses, HIV-1 replication and secretion of MIP1 alpha, MIP1 beta, and LD78 beta chemokines with little change in surface CCR-5 expression. These results identify a novel role for HO-1 in the modulation of host immune response against HIV infection of MDM. Published by Elsevier Inc. C1 [Zhou, Zhao-Hua; Clouse, Kathleen A.] US FDA, Ctr Drug Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD USA. [Kumari, Namita; Nekhai, Sergei] Howard Univ, Dept Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Wahl, Larry M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Viral Immunol Sect, Lab Mol Virol,Div Emerging & Transfus Transmitted, Bethesda, MD USA. RP Dhawan, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Viral Immunol Sect, Lab Mol Virol,Div Emerging & Transfus Transmitted, Bethesda, MD USA. EM subhash.dhawan@fda.hhs.gov FU FDA; NIDCR FX We thank Dr. Krishnakumar Devadas, Dr. Viswanath Ragupathy, Dr. Indira Hewlett and Dr. Robin Biswas for helpful suggestions and critical review of the manuscript. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. Supported by FDA and NIDCR Intramural Research Programs. NR 20 TC 11 Z9 11 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 7 PY 2013 VL 435 IS 3 BP 373 EP 377 DI 10.1016/j.bbrc.2013.04.095 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 171DI UT WOS:000320904900009 PM 23665328 ER PT J AU Smith, MJ Germolec, DR Frawley, RP White, KL AF Smith, Matthew J. Germolec, Dori R. Frawley, Rachel P. White, Kimber L., Jr. TI Immunomodulatory effects of black cohosh (Actaea racemosa) extract in female B6C3F1/N mice SO TOXICOLOGY LA English DT Article DE Black cohosh extract; Actaea racemosa; Immunotoxicity; Immunomodulation; Herbal medicines; Immune system ID NATURAL-KILLER-CELL; SPRAGUE-DAWLEY RATS; PHENOTYPIC MARKER EXPRESSION; INDICA ROXB. EXTRACTS; CIMICIFUGA-RACEMOSA; IMMUNE-RESPONSES; F-1 GENERATIONS; CYCLOARTANE GLYCOSIDES; SUBCHRONIC EXPOSURE; ISOFERULIC ACID AB Black cohosh extracts (BCE; Actaea racemosa) are being used worldwide as an alternative to hormone replacement therapy for the management of menstrual and menopausal symptoms, yet the effects of BCE on the immune system are largely unknown. Female B6C3F1/N mice were treated daily with BCE (0, 62.5, 125, 250, 500, or 1000 mg/kg) for 28 days by oral gavage. Liver weights were significantly increased (26-32%) at the 1000 mg/kg dose. Dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin were observed. Decreasing trends were observed in all thymic T cell populations, with the most notable dose-responsive effects on immature thymocytes. In the spleen, dose-related decreases were observed in all cell phenotypes evaluated, reaching the level of statistical significance at the 1000 mg/kg BCE dose. Splenic natural killer (NK) cell numbers were significantly decreased at all BCE doses, with the exception of absolute NK numbers at the 125 mg/kg dose. No effects were observed on T-dependent antibody responses of the humoral immune system, including the antibody-forming cell response to sheep erythrocytes (sRBC) and IgM antibody levels to both sRBC and keyhole limpet hemocyanin. Cytotoxic T cell (T-CTL) activity was increased, as was the mixed leukocyte response in one of two studies. Anti-CD3 mediated proliferation and the delayed-type hypersensitivity response were unaffected. No effects were observed on innate immunity or on bone marrow cellularity and colony-forming units. Overall, BCE exposure in B6C3F1/N mice for 28 days at doses up to 1000 mg/kg had minimal immune effects, with the exception of an increased T-CTL response. Published by Elsevier Ireland Ltd. C1 [Smith, Matthew J.; White, Kimber L., Jr.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Germolec, Dori R.; Frawley, Rachel P.] NIEHS, Natl Toxicol Program, Morrisville, NC 27560 USA. RP Smith, MJ (reprint author), ImmunoTox Inc, Virginia BioTechnol Res Pk,800 East Leigh St,Suit, Richmond, VA 23219 USA. EM msmith@immunotox.com; germolec@niehs.nih.gov; frawleyr@niehs.nih.gov; kwhite@immunotox.com OI Frawley, Rachel/0000-0001-8490-8240 FU NTP [N01-ES-55538] FX Special thanks to Ronnetta Brown, Jackson Mitchell, Anthony Rapisardi, Dr. Wimolnut Auttachoat, and Dr. Tai Guo for outstanding technical assistance in conducting this research. The authors would also like to acknowledge the outstanding technical assistance of Deborah Musgrove, who was responsible for conducting the technically challenging bone marrow colony assays. The authors also thank Drs. Minerva Mercado-Feliciano and Michelle C. Cora for their critical review of the manuscript. This work was supported by NTP Contract N01-ES-55538. NR 65 TC 4 Z9 4 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 7 PY 2013 VL 308 BP 146 EP 157 DI 10.1016/j.tox.2013.03.017 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 173OT UT WOS:000321089500017 PM 23571075 ER PT J AU Carrasco, M Eckstein, M Krauzlis, R Verghese, P AF Carrasco, Marisa Eckstein, Miguel Krauzlis, Rich Verghese, Preeti TI Attentional modulation: Target selection, active search and cognitive processing SO VISION RESEARCH LA English DT Editorial Material ID NORMALIZATION MODEL; SPATIAL ATTENTION; RESPONSE GAIN; VISUAL-SEARCH; CONTRAST; PERFORMANCE C1 [Carrasco, Marisa] NYU, New York, NY 10003 USA. [Eckstein, Miguel] Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. [Krauzlis, Rich] NIH, Bethesda, MD 20892 USA. [Verghese, Preeti] Smith Kettlewell Eye Inst, San Francisco, CA USA. RP Carrasco, M (reprint author), NYU, New York, NY 10003 USA. EM marisa.carrasco@nyu.edu; eckstein@psych.ucsb.edu; richard.krauzlis@nih.gov; preeti@ski.org FU Intramural NIH HHS [Z99 EY999999] NR 31 TC 0 Z9 0 U1 2 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN 7 PY 2013 VL 85 SI SI BP 1 EP 4 DI 10.1016/j.visres.2013.05.001 PG 4 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 171CU UT WOS:000320903500001 PM 23747085 ER PT J AU Eckstein, MP Mack, SC Liston, DB Bogush, L Menzel, R Krauzlis, RJ AF Eckstein, Miguel P. Mack, Stephen C. Liston, Dorion B. Bogush, Lisa Menzel, Randolf Krauzlis, Richard J. TI Rethinking human visual attention: Spatial cueing effects and optimality of decisions by honeybees, monkeys and humans SO VISION RESEARCH LA English DT Article DE Visual attention; Computational modeling; Posner cueing paradigm; Human monkey bee psychophysics; Bayesian ideal observer ID SIGNAL-DETECTION-THEORY; LEARNING SITUATION; APIS-MELLIFERA; SEARCH; PROBABILITY; BEHAVIOR; UNCERTAINTY; PERCEPTION; MODELS; CUES AB Visual attention is commonly studied by using visuo-spatial cues indicating probable locations of a target and assessing the effect of the validity of the cue on perceptual performance and its neural correlates. Here, we adapt a cueing task to measure spatial cueing effects on the decisions of honeybees and compare their behavior to that of humans and monkeys in a similarly structured two-alternative forced-choice perceptual task. Unlike the typical cueing paradigm in which the stimulus strength remains unchanged within a block of trials, for the monkey and human studies we randomized the contrast of the signal to simulate more real world conditions in which the organism is uncertain about the strength of the signal. A Bayesian ideal observer that weights sensory evidence from cued and uncued locations based on the cue validity to maximize overall performance is used as a benchmark of comparison against the three animals and other suboptimal models: probability matching, ignore the cue, always follow the cue, and an additive bias/single decision threshold model. We find that the cueing effect is pervasive across all three species but is smaller in size than that shown by the Bayesian ideal observer. Humans show a larger cueing effect than monkeys and bees show the smallest effect. The cueing effect and overall performance of the honeybees allows rejection of the models in which the bees are ignoring the cue, following the cue and disregarding stimuli to be discriminated, or adopting a probability matching strategy. Stimulus strength uncertainty also reduces the theoretically predicted variation in cueing effect with stimulus strength of an optimal Bayesian observer and diminishes the size of the cueing effect when stimulus strength is low. A more biologically plausible model that includes an additive bias to the sensory response from the cued location, although not mathematically equivalent to the optimal observer for the case stimulus strength uncertainty, can approximate the benefits of the more computationally complex optimal Bayesian model. We discuss the implications of our findings on the field's common conceptualization of covert visual attention in the cueing task and what aspects, if any, might be unique to humans. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Eckstein, Miguel P.; Mack, Stephen C.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Liston, Dorion B.] San Jose State Univ, San Jose, CA 95192 USA. [Liston, Dorion B.] NASA, Ames Res Ctr, Moffett Field, CA 94035 USA. [Bogush, Lisa; Menzel, Randolf] Free Univ Berlin, Dept Biol, Berlin, Germany. [Krauzlis, Richard J.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Eckstein, MP (reprint author), Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Vis & Image Understanding Lab, Santa Barbara, CA 93106 USA. EM eckstein@psych.ucsb.edu; mack@psych.ucsb.edu; dorion.b.liston@nasa.gov; bogusch@neurobiologie.fu-berlin.de; menzel@neurobiologie.fu-berlin.de; richard.krauzlis@nih.gov FU NEI NIH HHS [R01 EY015925] NR 76 TC 8 Z9 8 U1 2 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN 7 PY 2013 VL 85 SI SI BP 5 EP 19 DI 10.1016/j.visres.2012.12.011 PG 15 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 171CU UT WOS:000320903500002 PM 23298793 ER PT J AU Chen, KQ Liu, MY Liu, Y Wang, CY Yoshimura, T Gong, WH Le, YY Tessarollo, L Wang, JM AF Chen, Keqiang Liu, Mingyong Liu, Ying Wang, Chunyan Yoshimura, Teizo Gong, Wanghua Le, Yingying Tessarollo, Lino Wang, Ji Ming TI Signal Relay by CC Chemokine Receptor 2 (CCR2) and Formylpeptide Receptor 2 (Fpr2) in the Recruitment of Monocyte-derived Dendritic Cells in Allergic Airway Inflammation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOLL-LIKE RECEPTORS; INDUCED PULMONARY INFLAMMATION; ANTIMICROBIAL-PEPTIDE; EPITHELIAL-CELLS; BLOOD MONOCYTES; BONE-MARROW; DISEASE; LUNG; RESPONSES; MIGRATION AB Chemoattractant receptors regulate leukocyte accumulation at sites of inflammation. In allergic airway inflammation, although a chemokine receptor CCR2 was implicated in mediating monocyte- derived dendritic cell (DC) recruitment into the lung, we previously also discovered reduced accumulation of DCs in the inflamed lung in mice deficient in formylpeptide receptor Fpr2 (Fpr2(-/-)). We therefore investigated the role of Fpr2 in the trafficking of monocyte- derived DCs in allergic airway inflammation in cooperation with CCR2. We report that in allergic airway inflammation, CCR2 mediated the recruitment of monocyte- derived DCs to the perivascular region, and Fpr2 was required for further migration of the cells into the bronchiolar area. We additionally found that the bronchoalveolar lavage liquid from mice with airway inflammation contained both the CCR2 ligand CCL2 and an Fpr2 agonist CRAMP. Furthermore, similar to Fpr2(-/-) mice, in the inflamed airway of CRAMP(-/-) mice, DC trafficking into the peribronchiolar areas was diminished. Our study demonstrates that the interaction of CCR2 and Fpr2 with their endogenous ligands sequentially mediates the trafficking of DCs within the inflamed lung. C1 [Chen, Keqiang; Liu, Mingyong; Liu, Ying; Wang, Chunyan; Yoshimura, Teizo; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Gong, Wanghua] SAIC Frederick, Frederick, MD 21702 USA. [Le, Yingying] Chinese Acad Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China. RP Wang, JM (reprint author), Frederick Natl Lab Canc Res, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Bldg 560,Rm 31-76, Frederick, MD 21702 USA. EM wangji@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; NCI, National Institutes of Health FX This work was supported, in whole or in part, by Frederick National Laboratory for Cancer Research, National Institutes of Health Contract HHSN261200800001E. This work was also supported by the Intramural Research Program of the NCI, National Institutes of Health. NR 50 TC 12 Z9 13 U1 0 U2 8 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 JUN 7 PY 2013 VL 288 IS 23 BP 16262 EP 16273 DI 10.1074/jbc.M113.450635 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163ZU UT WOS:000320378900006 PM 23603910 ER PT J AU Kugler, JE Horsch, M Huang, D Furusawa, T Rochman, M Garrett, L Becker, L Bohla, A Holter, SM Prehn, C Rathkolb, B Racz, I Aguilar-Pimentel, JA Adler, T Adamski, J Beckers, J Busch, DH Eickelberg, O Klopstock, T Ollert, M Stoger, T Wolf, E Wurst, W Yildirim, AO Zimmer, A Gailus-Durner, V Fuchs, H de Angelis, MH Garfinkel, B Orly, J Ovcharenko, I Bustin, M AF Kugler, Jamie E. Horsch, Marion Huang, Di Furusawa, Takashi Rochman, Mark Garrett, Lillian Becker, Lore Bohla, Alexander Hoelter, Sabine M. Prehn, Cornelia Rathkolb, Birgit Racz, Ildiko Aguilar-Pimentel, Juan Antonio Adler, Thure Adamski, Jerzy Beckers, Johannes Busch, Dirk H. Eickelberg, Oliver Klopstock, Thomas Ollert, Markus Stoeger, Tobias Wolf, Eckhard Wurst, Wolfgang Yildirim, Ali Oender Zimmer, Andreas Gailus-Durner, Valerie Fuchs, Helmut de Angelis, Martin Hrabe Garfinkel, Benny Orly, Joseph Ovcharenko, Ivan Bustin, Michael TI High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HMG CHROMOSOMAL-PROTEINS; HISTONE H1; BINDING-PROTEIN; CHROMATIN-STRUCTURE; IONIZING-RADIATION; TRIBBLES HOMOLOG; LIVING CELLS; GENE; EXPRESSION; MOUSE AB The nuclei of most vertebrate cells contain members of the high mobility group N (HMGN) protein family, which bind specifically to nucleosome core particles and affect chromatin structure and function, including transcription. Here, we study the biological role of this protein family by systematic analysis of phenotypes and tissue transcription profiles in mice lacking functional HMGN variants. Phenotypic analysis of Hmgn1(tm1/tm1), Hmgn3(tm1/tm1), and Hmgn5(tm1/tm1) mice and their wild type littermates with a battery of standardized tests uncovered variant-specific abnormalities. Gene expression analysis of four different tissues in each of the Hmgn(tm1/tm1) lines reveals very little overlap between genes affected by specific variants in different tissues. Pathway analysis reveals that loss of an HMGN variant subtly affects expression of numerous genes in specific biological processes. We conclude that within the biological framework of an entire organism, HMGNs modulate the fidelity of the cellular transcriptional profile in a tissue- and HMGN variant-specific manner. C1 [Kugler, Jamie E.; Furusawa, Takashi; Rochman, Mark; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Horsch, Marion; Becker, Lore; Prehn, Cornelia; Rathkolb, Birgit; Adler, Thure; Adamski, Jerzy; Beckers, Johannes; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrabe] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, D-85764 Neuherberg, Germany. [Huang, Di; Ovcharenko, Ivan] NIH, Computat Biol Branch, NCBI, Natl Lib Med, Bethesda, MD 20892 USA. [Adamski, Jerzy; Beckers, Johannes] Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, D-85350 Freising Weihenstephan, Germany. [Garrett, Lillian; Hoelter, Sabine M.; Wurst, Wolfgang] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Dev Genet, German Mouse Clin, Neuherberg, Germany. [Becker, Lore; Klopstock, Thomas] Univ Munich, Dept Neurol, Friedrich Baur Inst, D-80539 Munich, Germany. [Bohla, Alexander; Eickelberg, Oliver; Stoeger, Tobias; Yildirim, Ali Oender] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Lung Biol & Dis, German Mouse Clin,Comprehens Pneumol Ctr, Neuherberg, Germany. [Rathkolb, Birgit; Wolf, Eckhard] Univ Munich, Gene Ctr, Munich, Germany. [Racz, Ildiko; Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, Bonn, Germany. [Aguilar-Pimentel, Juan Antonio] Tech Univ Munich, Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Ctr Allergy & Environm, Neuherberg, Germany. [Aguilar-Pimentel, Juan Antonio; Ollert, Markus] Tech Univ Munich, Biederstein, Dept Dermatol & Allergy, D-80290 Munich, Germany. [Aguilar-Pimentel, Juan Antonio; Ollert, Markus] Tech Univ Munich, Clin Res Div Mol & Clin Allergotoxicol, D-80290 Munich, Germany. [Adler, Thure; Busch, Dirk H.] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80290 Munich, Germany. [Klopstock, Thomas; de Angelis, Martin Hrabe] Tech Univ Munich, German Ctr Vertigo & Balance Disorders, D-80290 Munich, Germany. [Klopstock, Thomas; Wurst, Wolfgang] German Ctr Neurodegenerat Dis, Site Munich, Munich, Germany. [Wurst, Wolfgang] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Wurst, Wolfgang] Tech Univ Munich, Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Neuherberg, Germany. [de Angelis, Martin Hrabe] German Ctr Diabet Res, Neuherberg, Germany. [Bohla, Alexander; Eickelberg, Oliver; Stoeger, Tobias; Yildirim, Ali Oender] German Ctr Lung Res, Munich, Germany. [Garfinkel, Benny; Orly, Joseph] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Zimmer, Andreas/B-8357-2009; Racz, Ildiko/C-3074-2009; Beckers, Johannes/K-7237-2012; Becker, Lore/E-3717-2010; Gailus-Durner, Valerie/M-7337-2014; Fuchs, Helmut/M-7347-2014; Stoger, Tobias/M-9861-2014; Hrabe de Angelis, Martin/F-5531-2012; Holter, Sabine/N-5868-2014; Bustin, Michael/G-6155-2015 OI Garfinkel, Benjamin/0000-0002-2790-1349; Yildirim, Ali Onder/0000-0003-1969-480X; Wolf, Eckhard/0000-0002-0430-9510; Prehn, Cornelia/0000-0002-1274-4715; Becker, Lore/0000-0002-6890-4984; Racz, Ildiko/0000-0002-1549-3616; Beckers, Johannes/0000-0001-7874-3822; Fuchs, Helmut/0000-0002-5143-2677; Stoger, Tobias/0000-0002-2790-0389; Hrabe de Angelis, Martin/0000-0002-7898-2353; Holter, Sabine/0000-0003-4878-5241; FU National Institutes of Health grants from the Center for Cancer Research, NCI; Research Program of the National Library of Medicine; United States-Israeli Binational Foundation [2009326]; German Federal Ministry of Education and Research; German Center for Vertigo and Balance Disorders [01 EO 0901]; Infrafrontier [01KX1012]; Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Research in an Aging Society [HA-21]; National Genome Research Network-Plus [01GS0850, 01GS0851, 01GS0852, 01GS0853, 01GS0854, GS0868] FX This work was supported, in whole or in part, by National Institutes of Health grants from the Center for Cancer Research, NCI. This work was also supported by the Research Program of the National Library of Medicine; Grant 2009326 from the United States-Israeli Binational Foundation; German Federal Ministry of Education and Research to the German Center for Diabetes Research; German Center for Vertigo and Balance Disorders Grant 01 EO 0901, Infrafrontier Grant 01KX1012, and Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Research in an Aging Society Grant HA-21.; We thank Reinhard Seeliger, Anke Bettenbrock, Jan Einicke, Michael Farberbock, Ralf Fischer, Corinne Graf, Christine Hollauer, Elfi Holupirek, Maria Kugler, Soren Kundt, Simon Orth, Florian Schleicher, Ann-Elisabeth Schwarz, Nadine Senger, Yvonne Sonntag, Bettina Sperling, Alida Theil, and Anja Wohlbier, as well as the mouse embryonic fibroblasts animal caretaker team for expert technical assistance. The German Mouse Clinic was supported by National Genome Research Network-Plus Grants 01GS0850, 01GS0851, 01GS0852, 01GS0853, 01GS0854, and GS0868. NR 68 TC 17 Z9 17 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2013 VL 288 IS 23 BP 16690 EP 16703 DI 10.1074/jbc.M113.463315 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163ZU UT WOS:000320378900044 PM 23620591 ER PT J AU Frisz, JF Klitzing, HA Lou, KY Hutcheon, ID Weber, PK Zimmerberg, J Kraft, ML AF Frisz, Jessica F. Klitzing, Haley A. Lou, Kaiyan Hutcheon, Ian D. Weber, Peter K. Zimmerberg, Joshua Kraft, Mary L. TI Sphingolipid Domains in the Plasma Membranes of Fibroblasts Are Not Enriched with Cholesterol SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ION MASS-SPECTROMETRY; LIPID-MEMBRANES; INFLUENZA-VIRUS; PROTEINS; CELLS; RAFTS; ACTIN; HEMAGGLUTININ; ORGANIZATION; ADHESION AB The plasma membranes of mammalian cells are widely expected to contain domains that are enriched with cholesterol and sphingolipids. In this work, we have used high-resolution secondary ion mass spectrometry to directly map the distributions of isotope-labeled cholesterol and sphingolipids in the plasma membranes of intact fibroblast cells. Although acute cholesterol depletion reduced sphingolipid domain abundance, cholesterol was evenly distributed throughout the plasma membrane and was not enriched within the sphingolipid domains. Thus, we rule out favorable cholesterol-sphingolipid interactions as dictating plasma membrane organization in fibroblast cells. Because the sphingolipid domains are disrupted by drugs that depolymerize the cells actin cytoskeleton, cholesterol must instead affect the sphingolipid organization via an indirect mechanism that involves the cytoskeleton. C1 [Frisz, Jessica F.; Klitzing, Haley A.; Kraft, Mary L.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Lou, Kaiyan; Kraft, Mary L.] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Hutcheon, Ian D.; Weber, Peter K.] Lawrence Livermore Natl Lab, Glenn T Seaborg Inst, Livermore, CA 94551 USA. [Zimmerberg, Joshua] Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Kraft, ML (reprint author), Univ Illinois, Dept Chem & Biomol Engn, 600 S Mathews Ave, Urbana, IL 61801 USA. EM mlkraft@illinois.edu FU Career Award at the Scientific Interface from the Burroughs Wellcome Fund; NICHD; National Institutes of Health; National Institutes of Health Training Program in the Chemistry-Biology Interface [T32 GM070421]; National Science Foundation [CHE-1058809]; Laboratory Directed Research and Development funding at the Lawrence Livermore National Laboratory; U.S. Department of Energy [DE-AC52-07NA27344] FX This work was supported in part by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund (to M. L. K.), the Intramural Program of the NICHD, National Institutes of Health, National Institutes of Health Training Program in the Chemistry-Biology Interface T32 GM070421 (to J. F. F.), National Science Foundation Grant CHE-1058809, and Laboratory Directed Research and Development funding at the Lawrence Livermore National Laboratory. Work at the Lawrence Livermore National Laboratory was performed under the auspices of U.S. Department of Energy Contract DE-AC52-07NA27344. NR 38 TC 51 Z9 51 U1 0 U2 26 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 JUN 7 PY 2013 VL 288 IS 23 BP 16855 EP 16861 DI 10.1074/jbc.M113.473207 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163ZU UT WOS:000320378900058 PM 23609440 ER PT J AU Kwon, HS Johnson, TV Tomarev, SI AF Kwon, Heung Sun Johnson, Thomas V. Tomarev, Stanislav I. TI Myocilin Stimulates Osteogenic Differentiation of Mesenchymal Stem Cells through Mitogen-activated Protein Kinase Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OPEN-ANGLE GLAUCOMA; HUMAN TRABECULAR MESHWORK; OSTEOBLAST DIFFERENTIATION; OSTERIX EXPRESSION; GENE-EXPRESSION; TRANSGENIC MICE; MUTATED MOUSE; MAPK PATHWAY; BONE-MARROW; ER STRESS AB Myocilin is a secreted glycoprotein that is expressed in ocular and non-ocular tissues. Mutations in the MYOCILIN gene may lead to juvenile-and adult-onset primary open-angle glaucoma. Here we report that myocilin is expressed in bone marrow-derived mesenchymal stem cells (MSCs) and plays a role in their differentiation into osteoblasts in vitro and in osteogenesis in vivo. Expression of myocilin was detected in MSCs derived from mouse, rat, and human bone marrow, with human MSCs exhibiting the highest level of myocilin expression. Expression of myocilin rose during the course of human MSC differentiation into osteoblasts but not into adipocytes, and treatment with exogenous myocilin further enhanced osteogenesis. MSCs derived from Myoc-null mice had a reduced ability to differentiate into the osteoblastic lineage, which was partially rescued by exogenous extracellular myocilin treatment. Myocilin also stimulated osteogenic differentiation of wild-type MSCs, which was associated with activation of the p38, Erk1/2, and JNK MAP kinase signaling pathways as well as up-regulated expression of the osteogenic transcription factors Runx2 and Dlx5. Finally, cortical bone thickness and trabecular volume, as well as the expression level of osteopontin, a known factor of bone remodeling and osteoblast differentiation, were reduced dramatically in the femurs of Myoc-null mice compared with wild-type mice. These data suggest that myocilin should be considered as a target for improving the bone regenerative potential of MSCs and may identify a new role for myocilin in bone formation and/or maintenance in vivo. C1 [Kwon, Heung Sun; Johnson, Thomas V.; Tomarev, Stanislav I.] NEI, SRGCB, LRCMB, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, SRGCB, LRCMB, NIH, Bldg 6,Room 212,6 Ctr Dr, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov RI Johnson, Thomas/C-9351-2011 OI Johnson, Thomas/0000-0002-5372-5457 FU National Institutes of Health; National Eye Institute FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, National Eye Institute. NR 57 TC 15 Z9 18 U1 0 U2 8 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 JUN 7 PY 2013 VL 288 IS 23 BP 16882 EP 16894 DI 10.1074/jbc.M112.422972 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163ZU UT WOS:000320378900061 PM 23629661 ER PT J AU Yang, JB Singh, V Cha, BY Chen, TE Sarker, R Murtazina, R Jin, S Zachos, NC Patterson, GH Tse, CM Kovbasnjuk, O Li, XH Donowitz, M AF Yang, Jianbo Singh, Varsha Cha, Boyoung Chen, Tian-E Sarker, Rafiquel Murtazina, Rakhilya Jin, Shi Zachos, Nicholas C. Patterson, George H. Tse, C. Ming Kovbasnjuk, Olga Li, Xuhang Donowitz, Mark TI NHERF2 Protein Mobility Rate Is Determined by a Unique C-terminal Domain That Is Also Necessary for Its Regulation of NHE3 Protein in OK Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NA+/H+ EXCHANGER ISOFORM; ILEAL BRUSH-BORDER; PLASMA-MEMBRANE; CA2+-DEPENDENT INHIBITION; SCAFFOLDING PROTEINS; DEPENDENT MECHANISM; BINDING PARTNERS; 2-PHOTON FRAP; H+ EXCHANGER; LIPID RAFTS AB Na+/H+ exchanger regulatory factor (NHERF) proteins are a family of PSD-95/Discs-large/ZO-1 (PDZ)-scaffolding proteins, three of which (NHERFs 1-3) are localized to the brush border in kidney and intestinal epithelial cells. All NHERF proteins are involved in anchoring membrane proteins that contain PDZ recognition motifs to form multiprotein signaling complexes. In contrast to their predicted immobility, NHERF1, NHERF2, and NHERF3 were all shown by fluorescence recovery after photobleaching/confocal microscopy to be surprisingly mobile in the microvilli of the renal proximal tubule OK cell line. Their diffusion coefficients, although different among the three, were all of the same magnitude as that of the transmembrane proteins, suggesting they are all anchored in the microvilli but to different extents. NHERF3 moves faster than NHERF1, and NHERF2 moves the slowest. Several chimeras and mutants of NHERF1 and NHERF2 were made to determine which part of NHERF2 confers the slower mobility rate. Surprisingly, the slower mobility rate of NHERF2 was determined by a unique C-terminal domain, which includes a nonconserved region along with the ezrin, radixin, moesin (ERM) binding domain. Also, this C-terminal domain of NHERF2 determined its greater detergent insolubility and was necessary for the formation of larger multiprotein NHERF2 complexes. In addition, this NHERF2 domain was functionally significant in NHE3 regulation, being necessary for stimulation by lysophosphatidic acid of activity and increased mobility of NHE3, as well as necessary for inhibition of NHE3 activity by calcium ionophore 4-Br-A23187. Thus, multiple functions of NHERF2 require involvement of an additional domain in this protein. C1 [Yang, Jianbo; Singh, Varsha; Cha, Boyoung; Chen, Tian-E; Sarker, Rafiquel; Murtazina, Rakhilya; Jin, Shi; Zachos, Nicholas C.; Tse, C. Ming; Kovbasnjuk, Olga; Li, Xuhang; Donowitz, Mark] Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol, Baltimore, MD 21205 USA. [Donowitz, Mark] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. [Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD 20892 USA. RP Donowitz, M (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol & Hepatol, 925 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM mdonowit@jhmi.edu RI Yang, Jianbo/G-1254-2013 FU National Institutes of Health from NIDDK [R01DK26523, R01DK61765, P01DK072084, K08DK088950]; National Institutes of Health [P30DK089502] FX This work was supported in part by National Institutes of Health Grants R01DK26523, R01DK61765, P01DK072084, and K08DK088950 from NIDDK.; We thank John Gibas and Molee Chakraborty (Johns Hopkins University) for technical assistance. We thank Dr. Chris Yun (Emory University) for providing rabbit polyclonal antibody against NHERF2 and plasmid pcDNA3.1-LPA5R. We thank Dr. Jerrold Turner (University of Chicago) for providing the Caco-2/bbe cell line. We acknowledge use of the Kudsi Imaging Core Facility of the Conte Hopkins Digestive Disease Basic and Translational Research Core Center (supported by National Institutes of Health Grant P30DK089502). NR 55 TC 9 Z9 9 U1 0 U2 13 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 JUN 7 PY 2013 VL 288 IS 23 BP 16960 EP 16974 DI 10.1074/jbc.M113.470799 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163ZU UT WOS:000320378900068 PM 23612977 ER PT J AU Zhang, H Fiszman, M Shin, D Wilkowski, B Rindflesch, TC AF Zhang, Han Fiszman, Marcelo Shin, Dongwook Wilkowski, Bartlomiej Rindflesch, Thomas C. TI Clustering cliques for graph-based summarization of the biomedical research literature SO BMC BIOINFORMATICS LA English DT Article DE Clique clustering; Graph-based summarization; Multi-document summarization; Semantic predications ID TEXT; CENTRALITY; NETWORKS; EXTRACTION; DOCUMENTS; DISCOVERY; KNOWLEDGE; TOPICS; UMLS AB Background: Graph-based notions are increasingly used in biomedical data mining and knowledge discovery tasks. In this paper, we present a clique-clustering method to automatically summarize graphs of semantic predications produced from PubMed citations (titles and abstracts). Results: SemRep is used to extract semantic predications from the citations returned by a PubMed search. Cliques were identified from frequently occurring predications with highly connected arguments filtered by degree centrality. Themes contained in the summary were identified with a hierarchical clustering algorithm based on common arguments shared among cliques. The validity of the clusters in the summaries produced was compared to the Silhouette-generated baseline for cohesion, separation and overall validity. The theme labels were also compared to a reference standard produced with major MeSH headings. Conclusions: For 11 topics in the testing data set, the overall validity of clusters from the system summary was 10% better than the baseline (43% versus 33%). While compared to the reference standard from MeSH headings, the results for recall, precision and F-score were 0.64, 0.65, and 0.65 respectively. C1 [Zhang, Han] China Med Univ, Dept Med Informat, Shenyang 110001, Liaoning, Peoples R China. [Zhang, Han; Fiszman, Marcelo; Shin, Dongwook; Rindflesch, Thomas C.] Natl Lib Med, Bethesda, MD 20894 USA. [Wilkowski, Bartlomiej] Tech Univ Denmark, DTUInformat, DK-2800 Lyngby, Denmark. [Wilkowski, Bartlomiej] Statens Serum Inst, Danish Natl Biobank, Natl Hlth Surveillance & Res, DK-2300 Copenhagen, Denmark. RP Zhang, H (reprint author), China Med Univ, Dept Med Informat, Shenyang 110001, Liaoning, Peoples R China. EM zhanghan@mail.cmu.edu.cn RI chen, zhu/K-5923-2013 FU U.S. Department of Energy; National Library of Medicine; National Institutes of Health, National Library of Medicine; Ministry of Education of China [13YJC870030]; Lundbeckfonden through the Center for Integrated Molecular Brain Imaging (Cimbi.org); Otto Monsteds Fond; Kaj og Hermilla Ostenfelds Fond; Ingenior Alexandre Haynman og hustru Nina Haynmans Fond FX The first and fourth authors were supported by an appointment to the National Library of Medicine Research Participation Program administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the National Library of Medicine. This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The first author was also supported by the Youth Fund on Humanities and Social Sciences of the Ministry of Education of China (grant number 13YJC870030).; The fourth author also gratefully acknowledges funding from the Lundbeckfonden through the Center for Integrated Molecular Brain Imaging (Cimbi.org), Otto Monsteds Fond, Kaj og Hermilla Ostenfelds Fond, and the Ingenior Alexandre Haynman og hustru Nina Haynmans Fond. NR 50 TC 9 Z9 10 U1 2 U2 19 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 JUN 7 PY 2013 VL 14 AR UNSP 182 DI 10.1186/1471-2105-14-182 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 164BK UT WOS:000320383600001 PM 23742159 ER PT J AU Sarkar, SK Bumb, A Mill, M Neuman, KC AF Sarkar, Susanta K. Bumb, Ambika Mills, Maria Neuman, Keir C. TI SnapShot: Single-Molecule Fluorescence SO CELL LA English DT Editorial Material ID MICROSCOPY C1 NHLBI, NIH, Lab Mol Biophys, Bethesda, MD USA. RP Sarkar, SK (reprint author), NHLBI, NIH, Lab Mol Biophys, Bethesda, MD USA. RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 NR 10 TC 2 Z9 2 U1 3 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 6 PY 2013 VL 153 IS 6 BP 1408 EP + DI 10.1016/j.cell.2013.05.024 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 158NQ UT WOS:000319979200024 PM 23746850 ER PT J AU Krzewski, K Gil-Krzewska, A Nguyen, V Peruzzi, G Coligan, JE AF Krzewski, Konrad Gil-Krzewska, Aleksandra Victoria Nguyen Peruzzi, Giovanna Coligan, John E. TI LAMP1/CD107a is required for efficient perforin delivery to lytic granules and NK-cell cytotoxicity SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; IMMUNOLOGICAL SYNAPSE; MEMBRANE-PROTEINS; PLASMA-MEMBRANE; UP-REGULATION; TARGET-CELLS; GRANZYME-B; LYMPHOCYTES; EXOCYTOSIS AB Secretory lysosomes of natural killer (NK) cells, containing perforin and granzymes, are indispensable for NK-cell cytotoxicity because their release results in the induction of target-cell apoptosis. Lysosome-associated membrane protein (LAMP) 1/CD107a is used as a marker for NK-cell degranulation, but its role in NK-cell biology is unknown. We show that LAMP1 silencing causes inhibition of NK-cell cytotoxicity, as LAMP1 RNA interference (RNAi) cells fail to deliver granzyme B to target cells. Reduction of LAMP1 expression affects the movement of lytic granules and results in decreased levels of perforin, but not granzyme B, in the granules. In LAMP1 RNAi cells, more perforin is retained outside of lysosomal compartments in trans-Golgi network-derived transport vesicles. Disruption of expression of LAMP1 binding partner, adaptor protein 1 (AP-1) sorting complex, also causes retention of perforin in the transport vesicles and inhibits cytotoxicity, indicating that the interaction between AP-1 sorting complex and LAMP1 on the surface of the transport vesicles is important for perforin trafficking to lytic granules. We conclude that the decreased level of perforin in lytic granules of LAMP1-deficient cells, combined with disturbed motility of the lytic granules, leads to the inability to deliver apoptosis-inducing granzyme B to target cells and to inhibition of NK-cell cytotoxicity. C1 [Krzewski, Konrad; Gil-Krzewska, Aleksandra; Victoria Nguyen; Peruzzi, Giovanna; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Krzewski, K (reprint author), NIAID, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 205, Rockville, MD 20852 USA. EM krzewskikj@niaid.nih.gov; jcoligan@niaid.nih.gov OI Peruzzi, Giovanna/0000-0002-6517-9107 FU National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural programs of the National Institute of Allergy and Infectious Diseases. NR 51 TC 25 Z9 25 U1 0 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 6 PY 2013 VL 121 IS 23 BP 4672 EP 4683 DI 10.1182/blood-2012-08-453738 PG 12 WC Hematology SC Hematology GA 184MW UT WOS:000321895700011 PM 23632890 ER PT J AU Hurley, CK Woolfrey, A Wang, T Haagenson, M Umejiego, J Aljurf, M Askar, M Battiwalla, M Dehn, J Horan, J Oudshoorn, M Pidala, J Saber, W Turner, V Lee, SJ Spellman, SR AF Hurley, Carolyn Katovich Woolfrey, Ann Wang, Tao Haagenson, Michael Umejiego, John Aljurf, Mahmoud Askar, Medhat Battiwalla, Minoo Dehn, Jason Horan, John Oudshoorn, Machteld Pidala, Joseph Saber, Wael Turner, Victoria Lee, Stephanie J. Spellman, Stephen R. TI The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors SO BLOOD LA English DT Article ID CORD BLOOD TRANSPLANTATION; GRAFT FAILURE; MARROW TRANSPLANTATION; SELECTION; ANTIBODIES; RECIPIENTS; DIRECTION; REGISTRY AB The impact of HLA homozygosity at mismatched (MM) loci on the outcome of 2687 myeloablative unrelated donor hematopoietic cell transplantations performed for malignant disease was evaluated among 4 groups: 7/8 bidirectional MM transplants (donor and recipient heterozygous MM, n = 1393), 7/8 host-versus-graft (HVG) vector MM (recipient homozygous, n = 112), 7/8 graft-versus-host (GVH) vector MM (donor homozygous, n = 119), and 8/8 matches (n = 1063). Multivariate analyses found 7/8 GVH (P = .001) and bidirectional MM groups (P < .0001) had significantly worse transplant-related mortality and overall and disease-free survival than the 8/8 match group, a difference not observed with the 7/8 HVG MM group (P > .01). The 3 7/8 groups differed only for grades III-IV acute GVH disease (GVHD), where HVG MM had less GVHD than the 7/8 bidirectional MM (hazard ratio [HR] 0.52, P = .0016) and GVH MM (HR 0.43, P = .0009) groups but not the 8/8 group (HR 0.83, P = .39). There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment, or graft failure. GVH MM have the same risk as 7/8 bidirectional MM. 7/8 HVG MM confer a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared with a 7/8 bidirectional MM. C1 [Hurley, Carolyn Katovich] Georgetown Univ, Washington, DC USA. [Woolfrey, Ann; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wang, Tao] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Haagenson, Michael; Umejiego, John; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN 55413 USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia. [Askar, Medhat] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Dehn, Jason] Natl Marrow Donor Program, Minneapolis, MN USA. [Horan, John] Emory Univ, Atlanta, GA 30322 USA. [Oudshoorn, Machteld] Europdonor Fdn, Leiden, Netherlands. [Oudshoorn, Machteld] Leiden Univ, Med Ctr, Leiden, Netherlands. [Pidala, Joseph] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Saber, Wael] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Turner, Victoria] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Spellman, SR (reprint author), Ctr Int Blood & Marrow Transplant Res, 3001 Broadway St NE, Minneapolis, MN 55413 USA. EM sspellma@nmdp.org FU Office of Naval Research [N00014-11-1-0590, N00014-10-1-0199, N00014-10-1-0204, N00014-11-1-0339]; National Cancer Institute [P30 CA51008]; Public Health Service from the National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases from NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Allos, Inc; Amgen, Inc; Angioblast; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; Fresenius Biotech North America, Inc; Gamida Cell-Teva Joint Venture Ltd; Genentech, Inc; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc; Millennium: The Takeda Oncology Co, Milliman USA, Inc; Miltenyi Biotec, Inc; National Marrow Donor Program; OptumHealth Care Solutions, Inc; Osiris Therapeutics, Inc; Otsuka America Pharmaceutical, Inc; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc; StemCyte; A Global Cord Blood Therapeutics Co; Stemsoft Software, Inc; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc; Therakos, Inc; Wellpoint, Inc FX This research was supported, in part, by funding from the Office of Naval Research (N00014-11-1-0590 and N00014-10-1-0199) (C. K. H.), and the National Cancer Institute (P30 CA51008) (L. Weiner). The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; contract HHSH234200637015C with the Health Resources and Services Administration (HRSA/DHHS); 2 grants (N00014-10-1-0204 and N00014-11-1-0339) from the Office of Naval Research; and grants from Allos, Inc, Amgen, Inc, Angioblast, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Buchanan Family Foundation, CaridianBCT, Celgene Corporation, CellGenix GmbH, Children's Leukemia Research Association, Fresenius Biotech North America, Inc, Gamida Cell-Teva Joint Venture Ltd, Genentech, Inc, Genzyme Corporation, GlaxoSmithKline, HistoGenetics, Inc, Kiadis Pharma, The Leukemia & Lymphoma Society, The Medical College of Wisconsin, Merck & Co, Inc, Millennium: The Takeda Oncology Co, Milliman USA, Inc, Miltenyi Biotec, Inc, National Marrow Donor Program, OptumHealth Care Solutions, Inc, Osiris Therapeutics, Inc, Otsuka America Pharmaceutical, Inc, RemedyMD, Sanofi, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, Inc, StemCyte, A Global Cord Blood Therapeutics Co, Stemsoft Software, Inc, Swedish Orphan Biovitrum, Tarix Pharmaceuticals, Teva Neuroscience, Inc, Therakos, Inc, and Wellpoint, Inc, as well as an anonymous donation to the Medical College of Wisconsin. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 18 TC 13 Z9 13 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 6 PY 2013 VL 121 IS 23 BP 4800 EP 4806 DI 10.1182/blood-2013-01-480343 PG 7 WC Hematology SC Hematology GA 184MW UT WOS:000321895700026 PM 23637130 ER PT J AU Zemp, FJ McKenzie, BA Lun, XQ Maxwell, L Reilly, KM McFadden, G Yong, VW Forsyth, PA AF Zemp, Franz J. McKenzie, Brienne A. Lun, Xueqing Maxwell, Lori Reilly, Karlyne M. McFadden, Grant Yong, V. Wee Forsyth, Peter A. TI Resistance to Oncolytic Myxoma Virus Therapy in Nf1(-/-)/Trp53(-/-) Syngeneic Mouse Glioma Models Is Independent of Anti-Viral Type-I Interferon SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; CENTRAL-NERVOUS-SYSTEM; IMMUNOCOMPETENT ANIMAL-MODELS; MALIGNANT GLIOMAS; PANCREATIC-CANCER; GLIOBLASTOMA; CELLS; MUTANT; MICE; VIROTHERAPY AB Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1(+/-)Trp53(+/-) mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFN alpha/beta) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFN alpha/beta in response to MYXV infection. To confirm IFN alpha/beta did not play a role in this resistance, we ablated the ability of tumours to respond to IFN alpha/beta via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFN alpha/beta is not responsible for the MYXV treatment resistance seen in syngeneic glioma models. C1 [Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Maxwell, Lori; Forsyth, Peter A.] Univ Calgary, Southern Alberta Canc Res Inst, Tom Baker Canc Ctr, Clark H Smith Brain Tumor Ctr,Dept Oncol, Calgary, AB, Canada. [Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Maxwell, Lori; Forsyth, Peter A.] Univ Calgary, Clark H Smith Brain Tumor Ctr, Calgary, AB, Canada. [Reilly, Karlyne M.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [McFadden, Grant] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Yong, V. Wee] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Yong, V. Wee] Univ Calgary, Dept Oncol, Hotchkiss Brain Inst, Calgary, AB, Canada. [Forsyth, Peter A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Forsyth, Peter A.] Univ S Florida, Tampa, FL USA. RP Forsyth, PA (reprint author), Univ Calgary, Southern Alberta Canc Res Inst, Tom Baker Canc Ctr, Clark H Smith Brain Tumor Ctr,Dept Oncol, Calgary, AB, Canada. EM Peter.Forsyth@moffitt.org FU Canadian Cancer Society Research Institute (CCSRI); Canadian Cancer Society (PAF); Terry Fox Foundation; V Foundation; Canadian Institutes of Health Research (CIHR); Alberta Innovates Health Solutions; Izaak Walton Killam scholarship; NIH [R01 AI080607, R21 CA149869, R01 CA138541]; Bankhead Coley Foundation [1BT02]; NIH, NCI [ZIA BC 010541] FX This work was funded by the Canadian Cancer Society Research Institute (CCSRI) with funds raised by the Canadian Cancer Society (PAF), a Program Project Grant from the Terry Fox Foundation (PAF), the V Foundation (PAF), and the Canadian Institutes of Health Research (CIHR) (VWY). During this work FJZ was funded by Alberta Innovates Health Solutions, Vanier Scholarship from CIHR, and the Izaak Walton Killam scholarship. BAM was funded by CIHR. GM's lab is funded by NIH grants (R01 AI080607, R21 CA149869 and R01 CA138541) and by the Bankhead Coley Foundation (1BT02). KMR's lab is funded by the Intramural Research Program of NIH, NCI (ZIA BC 010541). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 6 Z9 6 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 6 PY 2013 VL 8 IS 6 AR e65801 DI 10.1371/journal.pone.0065801 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173SK UT WOS:000321099000107 PM 23762429 ER PT J AU Chang, CH Curtis, JD Maggi, LB Faubert, B Villarino, AV O'Sullivan, D Huang, SCC van der Windt, GJW Blagih, J Qiu, J Weber, JD Pearce, EJ Jones, RG Pearce, EL AF Chang, Chih-Hao Curtis, Jonathan D. Maggi, Leonard B., Jr. Faubert, Brandon Villarino, Alejandro V. O'Sullivan, David Huang, Stanley Ching-Cheng van der Windt, Gerritje J. W. Blagih, Julianna Qiu, Jing Weber, Jason D. Pearce, Edward J. Jones, Russell G. Pearce, Erika L. TI Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis SO CELL LA English DT Article ID MESSENGER-RNA STABILITY; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; ENERGY-METABOLISM; OVARIAN-CANCER; ACTIVATION; DIFFERENTIATION; EXPRESSION; GLUTAMINE; MECHANISM; BINDING AB A "switch'' from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-gamma is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3' UTR of IFN-gamma mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function. C1 [Chang, Chih-Hao; Curtis, Jonathan D.; O'Sullivan, David; Huang, Stanley Ching-Cheng; van der Windt, Gerritje J. W.; Qiu, Jing; Pearce, Edward J.; Pearce, Erika L.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Maggi, Leonard B., Jr.; Weber, Jason D.] Washington Univ, Sch Med, Div Mol Oncol, BRIGHT Inst, St Louis, MO 63110 USA. [Faubert, Brandon; Blagih, Julianna; Jones, Russell G.] McGill Univ, Dept Physiol, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada. [Villarino, Alejandro V.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Pearce, EL (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. EM erikapearce@path.wustl.edu OI Faubert, Brandon/0000-0002-2886-886X FU NIH [AI091965, CA158823, CA164062]; CIHR [MOP-93799]; Emerald Foundation Young Investigator Award FX We thank Andrey Shaw, Ken Murphy, Skip Virgin, Abul Abbas, Eyal Amiel, Rong Zeng, Qiongyu Chen, Monika Vig, Georgia Perona-Wright, Bart Everts, and the Goodman Cancer Research Centre Metabolomics Core Facility at McGIll University. This work was supported in part by grants from the NIH (AI091965 and CA158823 to E.L.P. and CA164062 to E.J.P.), CIHR (MOP-93799 to R.G.J.), The Arthritis Society of Canada (R.G.J.), NWO (G.J.W.v.d.W.), and the Emerald Foundation Young Investigator Award ( E.L.P.). C.- H.C., L.B.M., J.D.W., A.V.V., E.J.P., R. G. J., and E. L. P. designed the research. C.C., J.D.C., S.C.- C.H., G. J.W.v.d., D.O., J.B., B.F., J.Q., and E.L.P. analyzed data. C. C., J. D. C., L.B.M., B.F., S.C.- C.H., D.O., G.J.W.v.d. W., J.Q., and E.L.P. performed experiments. C.C., E.J.P., and E.L.P. contributed to the preparation of the manuscript. C.C. and E.L.P. wrote the manuscript. NR 42 TC 292 Z9 296 U1 8 U2 75 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 6 PY 2013 VL 153 IS 6 BP 1239 EP 1251 DI 10.1016/j.cell.2013.05.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 158NQ UT WOS:000319979200010 PM 23746840 ER PT J AU Callen, E Di Virgilio, M Kruhlak, MJ Nieto-Soler, M Wong, N Chen, HT Faryabi, RB Polato, F Santos, M Starnes, LM Wesemann, DR Lee, JE Tubbs, A Sleckman, BP Daniel, JA Ge, K Alt, FW Fernandez-Capetillo, O Nussenzweig, MC Nussenzweig, A AF Callen, Elsa Di Virgilio, Michela Kruhlak, Michael J. Nieto-Soler, Maria Wong, Nancy Chen, Hua-Tang Faryabi, Robert B. Polato, Federica Santos, Margarida Starnes, Linda M. Wesemann, Duane R. Lee, Ji-Eun Tubbs, Anthony Sleckman, Barry P. Daniel, Jeremy A. Ge, Kai Alt, Frederick W. Fernandez-Capetillo, Oscar Nussenzweig, Michel C. Nussenzweig, Andre TI 53BP1 Mediates Productive and Mutagenic DNA Repair through Distinct Phosphoprotein Interactions SO CELL LA English DT Article ID CLASS SWITCH RECOMBINATION; LYSINE-4 METHYLTRANSFERASE COMPLEX; STRAND BREAK REPAIR; HOMOLOGOUS RECOMBINATION; END RESECTION; BRCT-DOMAIN; DYSFUNCTIONAL TELOMERES; B-CELLS; PTIP; RIF1 AB The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP1(8A), comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP1(8A) recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1(8A). We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP. C1 [Callen, Elsa; Wong, Nancy; Chen, Hua-Tang; Faryabi, Robert B.; Polato, Federica; Santos, Margarida; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Di Virgilio, Michela; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Di Virgilio, Michela; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Nieto-Soler, Maria; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Gen Instabil Grp, Madrid 28029, Spain. [Santos, Margarida; Daniel, Jeremy A.] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, Copenhagen, Denmark. [Wesemann, Duane R.; Alt, Frederick W.] Childrens Hosp, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02115 USA. [Wesemann, Duane R.; Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Lee, Ji-Eun; Ge, Kai] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Tubbs, Anthony; Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Lee, Ji-Eun/F-7891-2011; Faryabi, Robert/H-3544-2015; Fernandez-Capetillo, Oscar/H-3508-2015; Daniel, Jeremy/S-4729-2016; OI Lee, Ji-Eun/0000-0002-3768-7016; Faryabi, Robert/0000-0002-7931-2175; Fernandez-Capetillo, Oscar/0000-0002-2690-6885; Daniel, Jeremy/0000-0002-1981-5571; Tubbs, Anthony/0000-0002-5605-8231; Ge, Kai/0000-0002-7442-5138 FU NIH [AI89972]; American Association of Allergy Asthma and Immunology and CSL Behring; Career Award for Medical Scientists (Burroughs Wellcome Fund); Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Department of Defense grant [BC102335] FX We thank all members of the A. Nussenzweig lab and Davide Robbiani for discussions; Titia de Lange for RIF1f/f mice; Susan Sharrow for flow cytometry; and Sandy Chang for the TRF2 shRNA construct. M.C.N., F.W.A and O.F.-C. are HHMI investigators. D.R.W. was supported by NIH grants AI89972, the American Association of Allergy Asthma and Immunology and CSL Behring, and a Career Award for Medical Scientists (Burroughs Wellcome Fund). This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant to A.N. (BC102335). NR 53 TC 109 Z9 112 U1 2 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 6 PY 2013 VL 153 IS 6 BP 1266 EP 1280 DI 10.1016/j.cell.2013.05.023 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 158NQ UT WOS:000319979200012 PM 23727112 ER PT J AU Phillips-Cremins, JE Sauria, MEG Sanyal, A Gerasimova, TI Lajoie, BR Bell, JSK Ong, CT Hookway, TA Guo, CY Sun, YH Bland, MJ Wagstaff, W Dalton, S McDevitt, TC Sen, RJ Dekker, J Taylor, J Corces, VG AF Phillips-Cremins, Jennifer E. Sauria, Michael E. G. Sanyal, Amartya Gerasimova, Tatiana I. Lajoie, Bryan R. Bell, Joshua S. K. Ong, Chin-Tong Hookway, Tracy A. Guo, Changying Sun, Yuhua Bland, Michael J. Wagstaff, William Dalton, Stephen McDevitt, Todd C. Sen, Ranjan Dekker, Job Taylor, James Corces, Victor G. TI Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment SO CELL LA English DT Article ID CHROMOSOME CONFORMATION CAPTURE; BETA-GLOBIN LOCUS; GENE-EXPRESSION; CHROMATIN CONFORMATION; NUCLEAR ARCHITECTURE; DROSOPHILA GENOME; CELLS; CTCF; TRANSCRIPTION; ENHANCERS AB Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales. C1 [Phillips-Cremins, Jennifer E.; Sauria, Michael E. G.; Bell, Joshua S. K.; Ong, Chin-Tong; Bland, Michael J.; Wagstaff, William; Taylor, James; Corces, Victor G.] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Sauria, Michael E. G.; Taylor, James] Emory Univ, Dept Math & Comp Sci, Atlanta, GA 30322 USA. [Gerasimova, Tatiana I.; Guo, Changying; Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Sun, Yuhua; Dalton, Stephen] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [Phillips-Cremins, Jennifer E.; Sanyal, Amartya; Lajoie, Bryan R.; Dekker, Job] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Phillips-Cremins, Jennifer E.; Sanyal, Amartya; Lajoie, Bryan R.; Dekker, Job] Univ Massachusetts, Sch Med, Program Syst Biol, Worcester, MA 01605 USA. RP Dekker, J (reprint author), Univ Massachusetts, Sch Med, Program Syst Biol, Worcester, MA 01605 USA. EM job.dekker@umassmed.edu; james.taylor@emory.edu; vcorces@emory.edu RI Sun, Yuhua/J-7547-2013; SANYAL, AMARTYA/D-7240-2015; Taylor, James/F-1026-2011; OI SANYAL, AMARTYA/0000-0002-2109-4478; Taylor, James/0000-0001-5079-840X; Phillips-Cremins, Jennifer/0000-0002-4702-0450; Hookway, Tracy/0000-0003-2781-0911; Sauria, Michael/0000-0001-5556-9446 FU National Institute of General Medical Sciences of the NIH [R01GM035463]; National Human Genome Research Institute of the NIH [R01HG003143]; National Institute of Diabetes and Digestive and Kidney Diseases of the NIH [R01DK065806]; W.M. Keck Foundation Distinguished Young Scholar in Biomedical Research Award [RC2HG005542]; American Recovery and Reinvestment Act (ARRA); NIH NRSA postdoctoral fellowship [5F32NS065603]; NIH [PO1GM85354]; Intramural Research Program of the National Institute on Aging (Baltimore, MD) FX Research reported in this publication was supported by the National Institute of General Medical Sciences of the NIH under award number R01GM035463 (V.G.C), the National Human Genome Research Institute of the NIH under award number R01HG003143 (J.D.), the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under award number R01DK065806 (J.T.), a W.M. Keck Foundation Distinguished Young Scholar in Biomedical Research Award (J.D.), and award number RC2HG005542 (J.T.) provided by funds from the American Recovery and Reinvestment Act (ARRA). J.E.P.C. was supported by an NIH NRSA postdoctoral fellowship (5F32NS065603). Funds from NIH grant PO1GM85354 also contributed to this work (S.D.). T.I.G., C.G. and R.S. are supported by the Intramural Research Program of the National Institute on Aging (Baltimore, MD). J.E.P.C. and V.G.C. conceived the project. J.E.P.C. and T.C.M. designed stem cell differentiation experiments. J.E.P.C., A.S., B.R.L., and J.D. designed 5C experiments. J.E.P.C., S.D., and Y.S. designed lentiviral experiments. J.E.P.C., T.I.G., C.G., V.G.C., J.D., and R.S. designed FISH experiments. J.E.P.C., A.S., W.W., J.S.K.B., M.J.B., C.T.O., T.A.H., T.I.G., C.G., and Y.S. performed experiments. M.E.G.S., J.E.P.C., and J.T. developed concepts and code for 5C peak calling pipeline and HMM model. J.E.P.C. performed postpeak calling computational analyses and wrote the paper with input from J.D., M.E.G.S., J.T., and V.G.C. NR 49 TC 302 Z9 308 U1 2 U2 78 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 6 PY 2013 VL 153 IS 6 BP 1281 EP 1295 DI 10.1016/j.cell.2013.04.053 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 158NQ UT WOS:000319979200013 PM 23706625 ER PT J AU Hunninghake, GM Hatabu, H Okajima, Y Gao, W Dupuis, J Latourelle, JC Nishino, M Araki, T Zazueta, OE Kurugol, S Ross, JC Estepar, RS Murphy, E Steele, MP Loyd, JE Schwarz, MI Fingerlin, TE Rosas, IO Washko, GR O'Connor, GT Schwartz, DA AF Hunninghake, Gary M. Hatabu, Hiroto Okajima, Yuka Gao, Wei Dupuis, Josee Latourelle, Jeanne C. Nishino, Mizuki Araki, Tetsuro Zazueta, Oscar E. Kurugol, Sila Ross, James C. Estepar, Raul San Jose Murphy, Elissa Steele, Mark P. Loyd, James E. Schwarz, Marvin I. Fingerlin, Tasha E. Rosas, Ivan O. Washko, George R. O'Connor, George T. Schwartz, David A. TI MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; PATHOLOGICAL FEATURES; REFERENCE VALUES; CLINICAL-COURSE; POPULATION; CAPACITY; EPIDEMIOLOGY; PREVALENCE; PNEUMONIA; EXPOSURE AB Background A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population. Methods We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus. Results Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association. Conclusions The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. C1 [Hunninghake, Gary M.; Zazueta, Oscar E.; Rosas, Ivan O.; Washko, George R.] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. [Hatabu, Hiroto; Okajima, Yuka; Nishino, Mizuki; Araki, Tetsuro] Brigham & Womens Hosp, Ctr Pulm Funct Imaging, Boston, MA 02115 USA. [Hatabu, Hiroto; Okajima, Yuka; Nishino, Mizuki; Araki, Tetsuro; Estepar, Raul San Jose] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Kurugol, Sila; Ross, James C.; Estepar, Raul San Jose] Brigham & Womens Hosp, Dept Radiol, Surg Planning Lab, Boston, MA 02115 USA. [Ross, James C.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Hunninghake, Gary M.; Zazueta, Oscar E.; Rosas, Ivan O.; Washko, George R.] Harvard Univ, Sch Med, Boston, MA USA. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Latourelle, Jeanne C.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Latourelle, Jeanne C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Gao, Wei; Dupuis, Josee; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Murphy, Elissa; Schwarz, Marvin I.; Schwartz, David A.] Univ Colorado, Dept Med, Ctr Pulm, Denver, CO USA. [Fingerlin, Tasha E.] Univ Colorado, Sch Publ Hlth, Denver, CO 80202 USA. [Steele, Mark P.; Loyd, James E.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. RP Hunninghake, GM (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care, 75 Francis St, Boston, MA 02115 USA. EM ghunninghake@partners.org; david.schwartz@ucdenver.edu OI Latourelle, Jeanne/0000-0002-4218-9572; O'Connor, George/0000-0002-6476-3926; Dupuis, Josee/0000-0003-2871-3603 FU National Institutes of Health FX Funded by the National Institutes of Health and others; ClinicalTrials.gov number NCT00005121. NR 25 TC 68 Z9 69 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 6 PY 2013 VL 368 IS 23 BP 2192 EP 2200 DI 10.1056/NEJMoa1216076 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 158DN UT WOS:000319948900007 PM 23692170 ER PT J AU Piot, P Quinn, TC AF Piot, Peter Quinn, Thomas C. TI Response to the AIDS Pandemic - A Global Health Model SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; MALE CIRCUMCISION; HIV PREVENTION; ANTIRETROVIRAL THERAPY; PREEXPOSURE PROPHYLAXIS; INCOME COUNTRIES; FOLLOW-UP; INFECTION; RISK; MEN C1 [Piot, Peter] Univ London London Sch Hyg & Trop Med, London SW6 6RE, England. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Piot, P (reprint author), Univ London London Sch Hyg & Trop Med, Keppel St, London SW6 6RE, England. EM director@lshtm.ac.uk FU Intramural NIH HHS [ZIA AI000361-30] NR 65 TC 43 Z9 47 U1 2 U2 27 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 6 PY 2013 VL 368 IS 23 BP 2210 EP + DI 10.1056/NEJMra1201533 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 158DN UT WOS:000319948900009 PM 23738546 ER PT J AU Shah, S Grady, C AF Shah, Seema Grady, Christine TI When to Start ART in Africa SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Shah, Seema; Grady, Christine] NIH, Bethesda, MD 20892 USA. RP Shah, S (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov NR 2 TC 0 Z9 0 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 6 PY 2013 VL 368 IS 23 BP 2238 EP 2238 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 158DN UT WOS:000319948900027 PM 23738562 ER PT J AU Major, EO Frohman, E Douek, D AF Major, Eugene O. Frohman, Elliot Douek, Daniel TI JC Viremia in Natalizumab-Treated Patients with Multiple Sclerosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY C1 [Major, Eugene O.] NINDS, Bethesda, MD 20892 USA. [Frohman, Elliot] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Douek, Daniel] NIAID, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov FU Intramural NIH HHS [Z01 NS003049-02] NR 5 TC 34 Z9 34 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 6 PY 2013 VL 368 IS 23 BP 2240 EP 2241 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 158DN UT WOS:000319948900032 PM 23738566 ER PT J AU Cooper, JA Manini, TM Paton, CM Yamada, Y Everhart, JE Cummings, S Mackey, DC Newman, AB Glynn, NW Tylavsky, F Harris, T Schoeller, DA AF Cooper, Jamie A. Manini, Todd M. Paton, Chad M. Yamada, Yosuke Everhart, James E. Cummings, Steve Mackey, Dawn C. Newman, Anne B. Glynn, Nancy W. Tylavsky, Fran Harris, Tamara Schoeller, Dale A. CA Hlth ABC Study TI Longitudinal change in energy expenditure and effects on energy requirements of the elderly SO NUTRITION JOURNAL LA English DT Article DE Doubly labeled water; Energy expenditure; Elderly; Energy requirements ID DOUBLY-LABELED WATER; PHYSICAL-ACTIVITY; HUMANS; ADULTS; AMERICANS; OBESITY; HEALTH; YOUNG AB Background: Very little is known about the longitudinal changes in energy requirements in late life. The purposes of this study were to: (1) determine the energy requirements in late life and how they changed during a 7 year time-span, (2) determine whether changes in fat free mass (FFM) were related to changes in resting metabolic rate (RMR), and (3) determine the accuracy of predicted total energy expenditure (TEE) to measured TEE. Methods: TEE was assessed via doubly labeled water (DLW) technique in older adults in both 1999 (n = 302; age: 74 +/- 2.9 yrs) and again in 2006 (n = 87 age: 82 +/- 3.1 yrs). RMR was measured with indirect calorimetry, and body composition was assessed with dual-energy x-ray absorptiometry. Results: The energy requirements in the 9th decade of life were 2208 +/- 376 kcal/d for men and 1814 +/- 337 kcal/d for women. This was a significant decrease from the energy requirements in the 8th decade of life in men (2482 +/- 476 kcal/d vs. 2208 +/- 376 kcal/d) but not in women (1892 +/- 271 kcal/d vs. 1814 +/- 337 kcal/d). In addition to TEE, RMR, and activity EE (AEE) also decreased in men, but not women, while FFM decreased in both men and women. The changes in FFM were correlated with changes in RMR for men (r = 0.49, p < 0.05) but not for women (r = -0.08, ns). Measured TEE was similar to Dietary Reference Intake (DRI) predicted TEE for men (2208 +/- 56 vs. 2305 +/- 35 kcal/d) and women (1814 +/- 42 vs. 1781 +/- 20 kcal/d). However, measured TEE was different than the World Health Organization (WHO) predicted TEE in men (2208 +/- 56 vs. 2915 +/- 31 kcal/d (p < 0.05)) and women (1814 +/- 42 vs. 2315 +/- 21 kcal/d (p < 0.05)). Conclusions: TEE, RMR and AEE decreased in men, but not women, from the 8th to 9th decade of life. The DRI equation to predict TEE was comparable to measured TEE, while the WHO equation over-predicted TEE in our elderly population. C1 [Cooper, Jamie A.; Paton, Chad M.] Texas Tech Univ, Dept Nutr Sci Hospitality & Retailing, Lubbock, TX 79409 USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Yamada, Yosuke] Kyoto Prefectural Univ Med, Lab Sports & Hlth Sci, Kamigyo Ku, Kyoto 6028566, Japan. [Yamada, Yosuke] Japan Soc Promot Sci, Chiyoda Ku, Tokyo 1020083, Japan. [Everhart, James E.] NIDDK, Epidemiol & Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Cummings, Steve; Mackey, Dawn C.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15213 USA. [Glynn, Nancy W.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Tylavsky, Fran] Univ Tennessee, Dept Prevent Med, Memphis, TN 38105 USA. [Harris, Tamara] NIA, NIH, Bethesda, MD 20892 USA. [Schoeller, Dale A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. RP Cooper, JA (reprint author), Texas Tech Univ, Dept Nutr Sci Hospitality & Retailing, POB 41240, Lubbock, TX 79409 USA. EM jamie.a.cooper@ttu.edu RI Yamada, Yosuke/K-8472-2013; Newman, Anne B./C-6408-2013; OI Yamada, Yosuke/0000-0002-4284-6317; Newman, Anne B./0000-0002-0106-1150; Glynn, Nancy/0000-0003-2265-0162 FU NIH [T32 DK007665]; Intramural Research Program of the NIH, National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA grant [R01-AG028050]; NINR grant [R01-NR012459] FX This research was supported in part by NIH T32 DK007665 and by the Intramural Research Program of the NIH, National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. NR 32 TC 7 Z9 8 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD JUN 6 PY 2013 VL 12 AR 73 DI 10.1186/1475-2891-12-73 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 160OS UT WOS:000320129600001 PM 23742706 ER PT J AU Skalka, N Caspi, M Caspi, E Loh, YP Rosin-Arbesfeld, R AF Skalka, N. Caspi, M. Caspi, E. Loh, Y. P. Rosin-Arbesfeld, R. TI Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway SO ONCOGENE LA English DT Article DE Wnt signaling; carboxypeptidase E (CPE); beta-catenin; functional screen ID NEUROPEPTIDE-PROCESSING ENZYME; BETA-CATENIN; SECRETORY GRANULES; CANCER CELLS; AXIN; POLYMERIZATION; TRANSDUCTION; ENDOCRINE; MUTATIONS; PROTEINS AB Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer and is especially implicated in the development and progression of colorectal cancer. The key effector protein of the canonical Wnt pathway is beta-catenin, which functions with T-cell factor/lymphoid enhancer factor to activate expression of Wnt target genes. In this study, we used a new functional screen based on cell survival in the presence of cDNAs encoding proteins that activate the Wnt pathway thus identifying novel Wnt signaling components. Here we identify carboxypeptidase E (vertical bar CPE) and its splice variant, Delta N-CPE, as novel regulators of the Wnt pathway. We show that whereas Delta N-CPE activates the Wnt signal, the full-length CPE (F-CPE) protein is an inhibitor of Wnt/beta-catenin signaling. F-CPE forms a complex with the Wnt3a ligand and the Frizzled receptor. Moreover, F-CPE disrupts disheveled-induced signalosomes that are important for transducing the Wnt signal and reduces beta-catenin protein levels and activity. Taken together, our data indicate that F-CPE and Delta N-CPE regulate the canonical Wnt signaling pathway negatively and positively, respectively, and demonstrate that this screening approach can be a rapid means for isolation of novel Wnt signaling components. C1 [Skalka, N.; Caspi, M.; Caspi, E.; Rosin-Arbesfeld, R.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Rosin-Arbesfeld, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. EM arina@post.tau.ac.il FU Israel Science Foundation; Public Committee for Allocation of Estate Funds, Ministry of Justice, Israel [20120016]; Recanati Foundation; Israel Cancer Association through the Estate of the late Alexander Smidoda; US-Israel Binational Science Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Israel Science Foundation, by grant no. 20120016 from the Public Committee for Allocation of Estate Funds, Ministry of Justice, Israel, the Recanati Foundation, Israel Cancer Association through the Estate of the late Alexander Smidoda, US-Israel Binational Science Foundation and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to YPL. NR 39 TC 9 Z9 10 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 6 PY 2013 VL 32 IS 23 BP 2836 EP 2847 DI 10.1038/onc.2012.308 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 163WR UT WOS:000320369100004 PM 22824791 ER PT J AU Rosales, T Nie, ZQ Kapoor, V Casellas, R Knutson, JR Levens, D AF Rosales, Tilman Nie, Zuqin Kapoor, Varun Casellas, Rafael, Jr. Knutson, Jay R. Levens, David TI Partition of Myc into Immobile vs. Mobile Complexes within Nuclei SO SCIENTIFIC REPORTS LA English DT Article ID ELEVATED C-MYC; DNA-BINDING; CELLS; PROTEIN; MAX; TRANSCRIPTION; RECEPTORS; ONCOGENE AB Myc levels are highly regulated and usually low in vivo. Dimerized with Max, it regulates most expressed genes and so directly and indirectly controls most cellular processes. Intranuclear diffusion of a functional c-Myc-eGFP, expressed from its native locus in murine fibroblasts and 3T3 cells or by transient transfection, was monitored using Two Photon Fluorescence Correlation Spectroscopy, revealing concentration and size (mobility) of complexes. With increased c-Myc-eGFP, a very immobile pool saturates as a 'mobile' pool increases. Both pools diffuse too slowly to be free Myc-Max dimers. Following serum stimulation, eGFP-c-Myc accumulated in the presence of the proteasome inhbitor MG132. Stimulating without MG132, Myc peaked at 2.5 hrs, and at steady was similar to 8 +/- 1.3 nM. Inhbiting Myc-Max dimerization by Max-knockdown or drug treatment increased the 'mobile' c-Myc pool size. These results indicate that Myc populates macromolecular complexes of widely heterogenous size and mobility in vivo. C1 [Rosales, Tilman; Knutson, Jay R.] NHLBI, Lab Mol Biophys, Opt Spect Sect, NIH, Bethesda, MD USA. [Nie, Zuqin; Kapoor, Varun; Casellas, Rafael, Jr.; Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Knutson, JR (reprint author), NHLBI, Lab Mol Biophys, Opt Spect Sect, NIH, Bethesda, MD USA. EM knutsonj@nhlbi.nih.gov; levensd@mail.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural Research Programs of the NIH at National Cancer Institute, Center for Cancer Research; NHLBI FX This research was supported by the Intramural Research Programs of the NIH at National Cancer Institute, Center for Cancer Research and NHLBI. NR 23 TC 3 Z9 3 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 6 PY 2013 VL 3 AR 1953 DI 10.1038/srep01953 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158HO UT WOS:000319960300006 PM 23739641 ER PT J AU Vitale, A Thorne, N Lovell, S Battaile, KP Hu, X Shen, M D'Auria, S Auld, DS AF Vitale, Annalisa Thorne, Natasha Lovell, Scott Battaile, Kevin P. Hu, Xin Shen, Min D'Auria, Sabato Auld, Douglas S. TI Physicochemical Characterization of a Thermostable Alcohol Dehydrogenase from Pyrobaculum aerophilum SO PLOS ONE LA English DT Article ID THROUGHPUT SCREENING ASSAYS; THERMOANAEROBACTER-BROCKII; CLOSTRIDIUM-BEIJERINCKII; CRYSTAL-STRUCTURE; ZINC; SPECIFICITY; RESOLUTION; ENZYMES; BINDING; LIVER AB In this work we characterize an alcohol dehydrogenase (ADH) from the hyperthermophilic archaeon Pyrobaculum aerophilum (PyAeADHII). We have previously found that PyAeADHII has no activity when standard ADH substrates are used but is active when alpha-tetralone is used as substrate. Here, to gain insights into enzyme function, we screened several chemical libraries for enzymatic modulators using an assay employing alpha-tetralone. The results indicate that PyAeADHII activity in the presence of alpha-tetralone was inhibited by compounds such as flunarizine. We also examined metal coordination of the enzyme in solution by performing metal substitution of the enzyme-bound zinc (Zn2+) with cobalt. The solution-based absorption spectra for cobalt substituted PyAeADHII supports substitution at the structural Zn2+ site. To gain structural insight, we obtained the crystal structure of both wild-type and cobalt-substituted PyAeADHII at 1.75 angstrom and 2.20 angstrom resolution, respectively. The X-ray data confirmed one metal ion per monomer present only at the structural site with otherwise close conservation to other ADH enzymes. We next determined the co-crystal structure of the NADPH-bound form of the enzyme at 2.35 angstrom resolution to help define the active site region of the enzyme and this data shows close structural conservation with horse ADH, despite the lack of a catalytic Zn2+ ion in PyAeADHII. Modeling of alpha-tetralone into the NADPH bound structure suggests an arginine as a possible catalytic residue. The data presented here can yield a better understanding of alcohol dehydrogenases lacking the catalytic zinc as well as the structural features inherent to thermostable enzymes. C1 [Vitale, Annalisa; Thorne, Natasha; Hu, Xin; Shen, Min; Auld, Douglas S.] Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Vitale, Annalisa; D'Auria, Sabato] NRC, Inst Prot Biochem, Naples, Italy. [Lovell, Scott] Univ Kansas, Prot Struct Lab, Del Shankel Struct Biol Ctr, Lawrence, KS 66045 USA. [Battaile, Kevin P.] Hauptman Woodward Med Res Inst, Ind Macromol Crystallog Assoc Collaborat Access T, Argonne, IL USA. RP Auld, DS (reprint author), Novartis Inst Biomed Res, Cambridge, MA 02139 USA. EM douglas.auld@novartis.com OI Battaile, Kevin/0000-0003-0833-3259 FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health; Industrial Macromolecular Crystallography Association; Hauptman-Woodward Medical Research Institute; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; National Center for Research Resources [5P20RR017708-10]; National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103420-10] FX This work was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. 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. DE-AC02-06CH11357. Use of the KU COBRE-PSF Protein Structure Laboratory was supported by grants from the National Center for Research Resources (5P20RR017708-10) and the National Institute of General Medical Sciences (8 P20 GM103420-10) from the 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 45 TC 2 Z9 2 U1 2 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 5 PY 2013 VL 8 IS 6 AR e63828 DI 10.1371/journal.pone.0063828 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166TB UT WOS:000320579400006 PM 23755111 ER PT J AU Mobbs, D Hassabis, D Yu, RJ Chu, C Rushworth, M Boorman, E Dalgleish, T AF Mobbs, Dean Hassabis, Demis Yu, Rongjun Chu, Carlton Rushworth, Matthew Boorman, Erie Dalgleish, Tim TI Foraging under Competition: The Neural Basis of Input-Matching in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DECISION-MAKING; HUMAN AMYGDALA; REWARD; STRIATUM; CORTEX; MODULATION; MIDBRAIN; ANXIETY; INSULA; BIAS AB Input-matching is a key mechanism by which animals optimally distribute themselves across habitats to maximize net gains based on the changing input values of food supply rate and competition. To examine the neural systems that underlie this rule in humans, we created a continuous-input foraging task where subjects had to decide to stay or switch between two habitats presented on the left and right of the screen. The subject's decision to stay or switch was based on changing input values of reward-token supply rate and competition density. High density of competition or low-reward token rate was associated with decreased chance of winning. Therefore, subjects attempted to maximize their gains by switching to habitats that possessed low competition density and higher token rate. When it was increasingly disadvantageous to be in a habitat, we observed increased activity in brain regions that underlie preparatory motor actions, including the dorsal anterior cingulate cortex and the supplementary motor area, as well as the insula, which we speculate may be involved in the conscious urge to switch habitats. Conversely, being in an advantageous habitat is associated with activity in the reward systems, namely the striatum and medial prefrontal cortex. Moreover, amygdala and dorsal putamen activity steered interindividual preferences in competition avoidance and pursuing reward. Our results suggest that input-matching decisions are made as a net function of activity in a distributed set of neural systems. Furthermore, we speculate that switching behaviors are related to individual differences in competition avoidance and reward drive. C1 [Mobbs, Dean; Yu, Rongjun; Dalgleish, Tim] MRC, Cognit & Brain Sci Unit, Cambridge CB2 2EF, England. [Mobbs, Dean] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Hassabis, Demis] UCL, Gatsby Computat Neurosci Unit, London WC1N 3BG, England. [Chu, Carlton] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Rushworth, Matthew; Boorman, Erie] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. RP Mobbs, D (reprint author), MRC, Cognit & Brain Sci Unit, Cambridge CB2 2EF, England. EM dmobbs@psych.columbia.edu; demis@gatsby.ucl.ac.uk FU United Kingdom Medical Research Council FX This work was funded by the United Kingdom Medical Research Council. We thank Peter Dayan, Johan Carlin, and Bernhard Staresina for their help and insightful comments. NR 38 TC 9 Z9 9 U1 0 U2 19 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 JUN 5 PY 2013 VL 33 IS 23 BP 9866 EP 9872 DI 10.1523/JNEUROSCI.2238-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 158IS UT WOS:000319963300030 PM 23739983 ER PT J AU Demberg, T Brocca-Cofano, E Kuate, S Aladi, S Vargas-Inchaustegui, DA Venzon, D Kalisz, I Kalyanaraman, VS Lee, EM Pal, R DiPasquale, J Ruprecht, RM Montefiori, DC Srivastava, I Barnett, SW Robert-Guroff, M AF Demberg, Thorsten Brocca-Cofano, Egidio Kuate, Seraphin Aladi, Stanley Vargas-Inchaustegui, Diego A. Venzon, David Kalisz, Irene Kalyanaraman, V. S. Lee, Eun Mi Pal, Ranajit DiPasquale, Janet Ruprecht, Ruth M. Montefiori, David C. Srivastava, Indresh Barnett, Susan W. Robert-Guroff, Marjorie TI Impact of antibody quality and anamnestic response on viremia control post-challenge in a combined Tat/Env vaccine regimen in rhesus macaques SO VIROLOGY LA English DT Article DE HIV vaccine; HIV Tat; HIV Envelope; Rhesus macaque; SHIV challenge; ADCC ID VIRUS SHIV89.6P CHALLENGE; CELLS IN-VITRO; PROTECTIVE EFFICACY; IMMUNE-RESPONSES; DENDRITIC CELLS; REPLICATION-COMPETENT; ANTIRETROVIRAL THERAPY; RECOMBINANT VACCINES; HIV-1 INFECTION; MESSENGER-RNA AB Previously, priming rhesus macaques with Adenovirus type 5 host range mutant-recombinants encoding Tat and Env and boosting with Tat and Env protein in MPL-SE controlled chronic viremia by 4 logs following homologous intravenous SHIV89.6P, challenge. Here we evaluated Tat, Env, and Tat/Env regimens for immunogenicity and protective efficacy using clade C Env, alum adjuvant, and a heterologous intrarectal SHIV1157ipd3N4 challenge. Despite induction of strong cellular and humoral immunity, Tat/Env group T and B-cell memory responses were not significantly enhanced over Tat- or Env-only groups. Lack of viremia control post-challenge was attributed to lower avidity Env antibodies and no anamnestic ADCC response or SHIV1157ipd3N4 neutralizing antibody development post-challenge. Poor biologic activity of the Tat immunogen may have impaired Tat immunity. In the absence of sterilizing immunity, strong anamnestic responses to heterologous virus can help control viremia. Both antibody breadth and optimal adjuvanticity are needed to elicit high-quality antibody for protective efficacy. Published by Elsevier Inc. C1 [Demberg, Thorsten; Brocca-Cofano, Egidio; Kuate, Seraphin; Aladi, Stanley; Vargas-Inchaustegui, Diego A.; DiPasquale, Janet; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kalisz, Irene; Kalyanaraman, V. S.; Lee, Eun Mi; Pal, Ranajit] Adv BioSci Labs Inc, Kensington, MD 20895 USA. [Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Srivastava, Indresh; Barnett, Susan W.] Novartis Vaccines & Diagnost, Cambridge, MA 02139 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU NIH [P01AI048240]; Intramural Research Program of the National Institutes of Health; National Cancer Institute FX We thank Dr. Deborah Weiss, James Treece and all the veterinary staff at ABL for excellent care of our animals and performance of all animal technical procedures. The following reagent was obtained from the AIDS Research and Reference Reagent program, DAIDS, NIAID, NIH: HIV Tat clade B consensus peptides, complete set. This work was supported in part by NIH grant P01AI048240 to R.M.R and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 46 TC 7 Z9 7 U1 1 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 JUN 5 PY 2013 VL 440 IS 2 BP 210 EP 221 DI 10.1016/j.virol.2013.02.024 PG 12 WC Virology SC Virology GA 141VT UT WOS:000318755300012 PM 23528732 ER PT J AU Eaton, WA Trommsdorff, HP AF Eaton, William A. Trommsdorff, H. Peter TI Robin Main Hochstrasser (1931-2013), giant of physical chemistry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 [Eaton, William A.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Trommsdorff, H. Peter] Univ Grenoble 1, CNRS, LIPhy UMR 5588, F-38041 Grenoble, France. RP Eaton, WA (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov; trommsdo@gmail.com NR 3 TC 0 Z9 0 U1 2 U2 17 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 JUN 4 PY 2013 VL 110 IS 23 BP 9189 EP 9190 DI 10.1073/pnas.1307692110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165SD UT WOS:000320503000013 ER PT J AU Rein, A AF Rein, Alan TI Murine leukemia virus p12 functions include hitchhiking into the nucleus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GAG PROTEIN; INTEGRATION; DOMAINS; EVENTS C1 NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. EM reina@mail.nih.gov NR 15 TC 0 Z9 0 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 JUN 4 PY 2013 VL 110 IS 23 BP 9195 EP 9196 DI 10.1073/pnas.1307399110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165SD UT WOS:000320503000016 PM 23708120 ER PT J AU Blackwood, JC Cummings, DAT Broutin, H Iamsirithaworn, S Rohani, P AF Blackwood, Julie C. Cummings, Derek A. T. Broutin, Helene Iamsirithaworn, Sopon Rohani, Pejman TI Deciphering the impacts of vaccination and immunity on pertussis epidemiology in Thailand SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHANGING EPIDEMIOLOGY; UNITED-STATES; RESURGENCE; COMMUNITY; IMMUNIZATION; TRANSMISSION; NETHERLANDS; POPULATION; INFECTION; DYNAMICS AB Pertussis is a highly infectious respiratory disease that is currently responsible for nearly 300,000 annual deaths worldwide, primarily in infants in developing countries. Despite sustained high vaccine uptake, a resurgence in pertussis incidence has been reported in a number of countries. This resurgence has led to critical questions regarding the transmission impacts of vaccination and pertussis immunology. We analyzed pertussis incidence in Thailand-both age-stratified and longitudinal aggregate reports-over the past 30 y. To dissect the contributions of waning pertussis immunity and repeat infections to pertussis epidemiology in Thailand following a pronounced increase in vaccine uptake, we used likelihood-based statistical inference methods to evaluate the support for multiple competing transmission models. We found that, in contrast to other settings, there is no evidence for pertussis resurgence in Thailand, with each model examined pointing to a substantial rise in herd immunity over the past 30 y. Using a variety of empirical metrics, we verified our findings by documenting signatures of changing herd immunity over the study period. Importantly, this work leads to the conclusion that repeat infections have played little role in shaping pertussis epidemiology in Thailand. Our results are surprisingly emphatic in support of measurable impact of herd immunity given the uncertainty associated with pertussis epidemiology. C1 [Blackwood, Julie C.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Blackwood, Julie C.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Cummings, Derek A. T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Broutin, Helene] CNRS, UMR, IRD UM1 UM2 5290 224, F-34394 Montpellier 5, France. [Broutin, Helene] NIH, Div Int Epidemiol & Populat Study, Bethesda, MD 20892 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Iamsirithaworn, Sopon] Minist Publ Hlth, Bureau Epidemiol, Nonthaburi 11000, Thailand. RP Blackwood, JC (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM juliecb@umich.edu FU Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate; Department of Homeland Security; Bill and Melinda Gates Vaccine Modeling Initiative; Fogarty International Center, National Institutes of Health (NIH); NIH [1R01AI101155]; Intramural Research Group of Fogarty International Center, NIH; Burroughs Welcome Fund FX We thank three anonymous reviewers, as well as the laboratories of P. R. and Aaron King, for their helpful comments on previous drafts of this article. Funding for this work was provided by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate (P. R. and D. A. T. C.), Department of Homeland Security, and the Bill and Melinda Gates Vaccine Modeling Initiative. P. R. was also supported by the Fogarty International Center, National Institutes of Health (NIH), and NIH Grant 1R01AI101155. H. B. was funded by the Intramural Research Group of Fogarty International Center, NIH. D. A. T. C. holds a Career Award at the Scientific Interface from the Burroughs Welcome Fund. NR 46 TC 13 Z9 14 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 JUN 4 PY 2013 VL 110 IS 23 BP 9595 EP 9600 DI 10.1073/pnas.1220908110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165SD UT WOS:000320503000084 PM 23690587 ER PT J AU Dey, B Berger, EA AF Dey, Barna Berger, Edward A. TI Blocking HIV-1 gp120 at the Phe43 Cavity: If the Extension Fits ... SO STRUCTURE LA English DT Editorial Material ID ENVELOPE GLYCOPROTEIN; CD4-BOUND STATE; CD4; MINIPROTEINS; DESIGN; ENTRY; SITE C1 [Dey, Barna; Berger, Edward A.] NIAID, NIH, Lab Viral Dis, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, NIH, Lab Viral Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM eberger@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000538-25] NR 12 TC 1 Z9 1 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN 4 PY 2013 VL 21 IS 6 BP 871 EP 872 DI 10.1016/j.str.2013.05.004 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 168WY UT WOS:000320739800002 PM 23747109 ER PT J AU Acharya, P Luongo, TS Louder, MK McKee, K Yang, YP Kwon, YD Mascola, JR Kessler, P Martin, L Kwong, PD AF Acharya, Priyamvada Luongo, Timothy S. Louder, Mark K. McKee, Krisha Yang, Yongping Kwon, Young Do Mascola, John R. Kessler, Pascal Martin, Loic Kwong, Peter D. TI Structural Basis for Highly Effective HIV-1 Neutralization by CD4-Mimetic Miniproteins Revealed by 1.5 angstrom Cocrystal Structure of gp120 and M48U1 SO STRUCTURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN; RATIONAL DESIGN; POTENT NEUTRALIZATION; RESISTANCE MUTATIONS; CRYSTAL-STRUCTURES; ENTRY INHIBITORS; CD4; BINDING AB The interface between the HIV-1 gp120 envelope glycoprotein and the CD4 receptor contains an unusual interfacial cavity, the "Phe43 cavity", which CD4-mimetic miniproteins with nonnatural extensions can potentially utilize to enhance their neutralization of HIV-1. Here, we report cocrystal structures of HIV-1 gp120 with miniproteins M48U1 and M48U7, which insert cyclohexylmethoxy and 5-hydroxypentylmethoxy extensions, respectively, into the Phe43 cavity. Both inserts displayed flexibility and hydrophobic interactions, but the M48U1 insert showed better shape complementarity with the Phe43 cavity than the M48U7 insert. Subtle alteration in the gp120 conformation played a substantial role in optimizing fit. With M48U1, these translated into a YU2-gp120 affinity of 0.015 nM and neutralization of all 180 circulating HIV-1 strains tested, except clade-A/E isolates with noncanonical Phe43 cavities. Ligand chemistry, shape complementarity, surface burial, and gp120 conformation act in concert to modulate binding of ligands to the gp120-Phe43 cavity and, when optimized, can effect near-pan-neutralization of HIV-1. C1 [Acharya, Priyamvada; Luongo, Timothy S.; Louder, Mark K.; McKee, Krisha; Yang, Yongping; Kwon, Young Do; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kessler, Pascal; Martin, Loic] CEA, IBiTecS, Serv Ingn Mol Prot, F-91191 Gif Sur Yvette, France. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010 FU Intramural AIDS Targeted Anti-retroviral Program (IATAP); Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank members of the Structural Biology Section and Structural Bioinformatics Core at the NIH Vaccine Research Center for comments on the manuscript and J. Stuckey for assistance with figures. sCD4 was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. Amino acid analysis for peptide concentration determination was performed at the Amino Acid Analysis and Protein Sequencing facility at the W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University. Support for this work was provided by the Intramural AIDS Targeted Anti-retroviral Program (IATAP) and the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 38 TC 15 Z9 15 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN 4 PY 2013 VL 21 IS 6 BP 1018 EP 1029 DI 10.1016/j.str.2013.04.015 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 168WY UT WOS:000320739800018 PM 23707685 ER PT J AU Li, SX Ding, XY Guo, F Chen, YC Lapsley, MI Lin, SCS Wang, L McCoy, JP Cameron, CE Huang, TJ AF Li, Sixing Ding, Xiaoyun Guo, Feng Chen, Yuchao Lapsley, Michael Ian Lin, Sz-Chin Steven Wang, Lin McCoy, J. Philip Cameron, Craig E. Huang, Tony Jun TI An On-Chip, Multichannel Droplet Sorter Using Standing Surface Acoustic Waves SO ANALYTICAL CHEMISTRY LA English DT Article ID MICROFLUIDIC DEVICE; HIGH-THROUGHPUT; PARTICLE; MANIPULATION; SEPARATION; CELLS; MICROPARTICLES; MICRODROPLETS; DRIVEN; SSAW AB The emerging field of droplet microfluidics requires effective on-chip handling and sorting of droplets. In this work, we demonstrate a microfluidic device that is capable of sorting picoliter water-in-oil droplets into multiple outputs using standing surface acoustic waves (SSAW). This device integrates a single-layer microfluidic channel with interdigital transducers' (IDTs) to achieve on-chip droplet generation and sorting. Within the SSAW field, water-in-oil droplets experience an acoustic radiation force and are pushed toward the acoustic pressure node. As a result, by tuning the frequency of the SSAW excitation, the position of the pressure nodes can be changed and droplets can be sorted to different outlets at rates up to 222 droplets s(-1). With its advantages in simplicity, controllability, versatility, noninvasiveness, and capability to be integrated with other on-chip components such as droplet manipulation and optical detection units, the technique presented here could be valuable for the development of droplet-based micro total analysis systems (mu TAS). C1 [Li, Sixing; Ding, Xiaoyun; Guo, Feng; Chen, Yuchao; Lapsley, Michael Ian; Lin, Sz-Chin Steven; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, University Pk, PA 16802 USA. [Li, Sixing; Cameron, Craig E.; Huang, Tony Jun] Penn State Univ, Cell & Dev Biol CDB Grad Program, Huck Inst Life Sci, University Pk, PA 16802 USA. [Wang, Lin] Ascent Bionano Technol Inc, State Coll, PA 16801 USA. [McCoy, J. Philip] NHLBI, NIH, Bethesda, MD 20892 USA. [Cameron, Craig E.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. EM junhuang@psu.edu RI Li, Sixing/F-2383-2013; Guo, Feng/B-6860-2012; Ding, Xiaoyun/F-3695-2012; Chen, Yuchao/I-6237-2012; Huang, Tony/A-1546-2009 OI Guo, Feng/0000-0001-9103-3235; Ding, Xiaoyun/0000-0003-4252-9335; FU National Institutes of Health (NIH) [1DP2OD007209-01]; National Science Foundation; Penn State Center for Nanoscale Science (MRSEC) [DMR-0820404]; NIAID, NIH [AI45818]; NSF FX We thank Joey Rufo for the help in preparing the manuscript and ChemPoint for providing DuPont Krytox 157 FS surfactant. This research was supported by the National Institutes of Health (NIH) Director's New Innovator Award (1DP2OD007209-01), the National Science Foundation, and the Penn State Center for Nanoscale Science (MRSEC) under Grant DMR-0820404. S.L. and C.E.C. were funded in part by grant AI45818 from NIAID, NIH. Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network (NNIN). NR 75 TC 53 Z9 53 U1 7 U2 121 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUN 4 PY 2013 VL 85 IS 11 BP 5468 EP 5474 DI 10.1021/ac400548d PG 7 WC Chemistry, Analytical SC Chemistry GA 160DJ UT WOS:000320096900028 PM 23647057 ER PT J AU Huang, YH Terabe, M Pendleton, CD Khursigara, DS Bera, TK Pastan, I Berzofsky, JA AF Huang, Yi-Hsiang Terabe, Masaki Pendleton, C. David Khursigara, Deborah Stewart Bera, Tapan K. Pastan, Ira Berzofsky, Jay A. TI Identification and Enhancement of HLA-A2.1-Restricted CTL Epitopes in a New Human Cancer Antigen-POTE SO PLOS ONE LA English DT Article ID CLASS-I MOLECULES; PROSTATE-CANCER; T-LYMPHOCYTES; INDEPENDENT BINDING; PEPTIDE MOTIFS; SIPULEUCEL-T; IMMUNOTHERAPY; HLA-A2.1; VACCINES; MICE AB Identification of CD8(+) T cell epitopes that can induce T cells to kill tumor cells is a fundamental step for development of a peptide cancer vaccine. POTE protein is a newly identified cancer antigen that was found to be expressed in a wide variety of human cancers, including prostate, colon, lung, breast, ovary and pancreas. Here, we determined HLA-A2.1-restricted cytotoxic T lymphocyte (CTL) epitopes in the POTE protein, and also designed enhanced epitopes by amino acid (AA) substitutions. Five 9-mer peptides were first selected and their binding affinity to HLA-A2 molecules was measured by the T2 binding assay. POTE 272-280 and POTE 323-331 showed the strongest HLA-A2 binding affinity. AA substituted peptides POTE 252-9V (with valine at position 9), POTE 553-1Y (with tyrosine at position 1) and POTE 323-3F (with phenylalanine at position 3) conferred higher affinity for HLA-A2, and induced CTL responses cross-reactive with wild type antigens. While POTE 252-9V was the strongest in this respect, POTE 323-3F had the greatest increase in immunogenicity compared to wild type. Importantly, two modified epitopes (POTE-553-1Y and POTE-323-3F) induced CTLs that killed NCI-H522, a POTE-expressing HLA-A2(+) human non-small cell lung cancer cell line, indicating natural endogenous processing of these epitopes. In conclusion, the immunogenicity of POTE epitopes can be enhanced by peptide modification to induce T cells that kill human cancer cells. A combination of POTE 553-1Y and POTE 323-3F epitopes might be an attractive vaccine strategy for HLA-A2 cancer patients to overcome tolerance induced by tumors and prevent escape. C1 [Huang, Yi-Hsiang] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Div Gastroenterol, Infect & Immun Res Ctr,Inst Clin Med, Taipei 112, Taiwan. [Huang, Yi-Hsiang; Terabe, Masaki; Pendleton, C. David; Khursigara, Deborah Stewart; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bera, Tapan K.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Terabe, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov; berzofsk@helix.nih.gov FU Taiwan Merit Scholarship [TMS-094-2-B-015]; NCI intramural funding from the NCI Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA; Taipei Veterans General Hospital [V97S5-002, V100C-104, V101C-147] FX Dr. Yi-Hsiang Huang was supported by Taiwan Merit Scholarship (TMS-094-2-B-015) and NCI intramural funding from the NCI Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA; and by funding from Taipei Veterans General Hospital (V97S5-002, V100C-104 and V101C-147). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 5 Z9 8 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2013 VL 8 IS 6 AR e64365 DI 10.1371/journal.pone.0064365 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158IE UT WOS:000319961900010 PM 23750208 ER PT J AU Zelazny, AM Ding, L Goldberg, JB Mijares, LA Conlan, S Conville, PS Stock, F Ballentine, SJ Olivier, KN Sampaio, EP Murray, PR Holland, SM AF Zelazny, Adrian M. Ding, Li Goldberg, Joanna B. Mijares, Lilia A. Conlan, Sean Conville, Patricia S. Stock, Frida Ballentine, Samuel J. Olivier, Kenneth N. Sampaio, Elizabeth P. Murray, Patrick R. Holland, Steven M. TI Adaptability and Persistence of the Emerging Pathogen Bordetella petrii SO PLOS ONE LA English DT Article ID O-ANTIGEN BIOSYNTHESIS; CYSTIC-FIBROSIS; GENE-TRANSFER; SP NOV.; IDENTIFICATION; INFECTIONS; PERTUSSIS; STRAINS AB The first described, environmentally isolated, Bordetella petrii was shown to undergo massive genomic rearrangements in vitro. More recently, B. petrii was isolated from clinical samples associated with jaw, ear bone, cystic fibrosis and chronic pulmonary disease. However, the in vivo consequences of B. petrii genome plasticity and its pathogenicity remain obscure. B. petrii was identified from four sequential respiratory samples and a post-mortem spleen sample of a woman presenting with bronchiectasis and cavitary lung disease associated with nontuberculous mycobacterial infection. Strains were compared genetically, phenotypically and by antibody recognition from the patient and from inoculated mice. The successive B. petrii strains exhibited differences in growth, antibiotic susceptibility and recognition by the patient's antibodies. Antibodies from mice inoculated with these strains recapitulated the specificity and strain dependent response that was seen with the patient's serum. Finally, we characterize one strain that was poorly recognized by the patient's antibodies, due to a defect in the lipopolysaccharide O-antigen, and identify a mutation associated with this phenotype. We propose that B. petrii is remarkably adaptable in vivo, providing a possible connection between immune response and bacterial evasion and supporting infection persistence. C1 [Zelazny, Adrian M.; Ding, Li; Ballentine, Samuel J.; Olivier, Kenneth N.; Sampaio, Elizabeth P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Zelazny, Adrian M.; Mijares, Lilia A.; Conville, Patricia S.; Stock, Frida; Murray, Patrick R.] NIH, Microbiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Goldberg, Joanna B.] Univ Virginia Hlth Syst, Dept Microbiol, Charlottesville, VA USA. [Conlan, Sean] NHGRI, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov RI Conlan, Sean/B-4401-2008 OI Conlan, Sean/0000-0001-6848-3465 FU Division of Intramural Research; National Human Genome Research Institute; Clinical Center at the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This work was financially supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute and Clinical Center at the 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 30 TC 6 Z9 6 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2013 VL 8 IS 6 AR e65102 DI 10.1371/journal.pone.0065102 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158IE UT WOS:000319961900037 PM 23750235 ER PT J AU Ascierto, PA Grimaldi, AM Acquavella, N Borgognoni, L Calabro, L Cascinelli, N Cesano, A Del Vecchio, M Eggermont, AM Faries, M Ferrone, S Fox, BA Gajewski, TF Galon, J Gnjatic, S Gogas, H Kashani-Sabet, M Kaufman, HL Larkin, J Lo, RS Mantovani, A Margolin, K Melief, C McArthur, G Palmieri, G Puzanov, I Ribas, A Seliger, B Sosman, J Suenaert, P Tarhini, AA Trinchieri, G Vidal-Vanaclocha, F Wang, E Ciliberto, G Mozzillo, N Marincola, FM Thurin, M AF Ascierto, Paolo A. Grimaldi, Antonio M. Acquavella, Nicolas Borgognoni, Lorenzo Calabro, Luana Cascinelli, Natale Cesano, Alessandra Del Vecchio, Michele Eggermont, Alexander M. Faries, Mark Ferrone, Soldano Fox, Bernard A. Gajewski, Thomas F. Galon, Jerome Gnjatic, Sacha Gogas, Helen Kashani-Sabet, Mohammed Kaufman, Howard L. Larkin, James Lo, Roger S. Mantovani, Alberto Margolin, Kim Melief, Cornelis McArthur, Grant Palmieri, Giuseppe Puzanov, Igor Ribas, Antoni Seliger, Barbara Sosman, Jeff Suenaert, Peter Tarhini, Ahmad A. Trinchieri, Giorgio Vidal-Vanaclocha, Fernando Wang, Ena Ciliberto, Gennaro Mozzillo, Nicola Marincola, Francesco M. Thurin, Magdalena TI Future perspectives in melanoma research. Meeting report from the "Melanoma Bridge. Napoli, December 2nd-4th 2012" SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID ADJUVANT INTERFERON THERAPY; SENTINEL LYMPH-NODES; HIGH-RISK MELANOMA; RANDOMIZED CONTROLLED-TRIAL; STAGE-III MELANOMA; T-CELL RESPONSES; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; PEGYLATED INTERFERON-ALPHA-2B; BRAF(V600E) INHIBITION AB Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third "Melanoma Research: " A bridge from Naples to the World" meeting, shortened as " Bridge Melanoma Meeting" took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients. C1 [Ascierto, Paolo A.; Grimaldi, Antonio M.; Ciliberto, Gennaro; Mozzillo, Nicola] Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. [Acquavella, Nicolas] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Borgognoni, Lorenzo] SM Annunziata Hosp, Reg Melanoma Refferral Ctr, Florence, Italy. [Calabro, Luana] Univ Hosp Siena, Ist Toscano Tumori, Siena, Italy. [Cascinelli, Natale] WHO, Melanoma Program, Milan, Italy. [Cesano, Alessandra] Nodality Inc, San Francisco, CA USA. [Del Vecchio, Michele] Ist Nazl Tumori, Fdn IRCCS, Dept Med Oncol, I-20133 Milan, Italy. [Eggermont, Alexander M.] Canc Inst Gustave Roussy, Paris, France. [Faries, Mark] John Wayne Canc Inst, Santa Monica, CA USA. [Ferrone, Soldano] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Fox, Bernard A.] Providence Portland Med Ctr, Robert W Franz Canc Ctr, Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [Galon, Jerome] INSERM, Lab Integrat Canc Immunol, U872, F-75006 Paris, France. [Galon, Jerome] Univ Paris 05, Paris, France. [Galon, Jerome] Univ Paris 06, Ctr Rech Cordeliers, Paris, France. [Gnjatic, Sacha] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY USA. [Gogas, Helen] Univ Athens, Sch Med, Dept Med 1, GR-11527 Athens, Greece. [Kashani-Sabet, Mohammed] Calif Pacific Med Ctr, Res Inst, Ctr Melanoma Res & Treatment, San Francisco, CA USA. [Kaufman, Howard L.] Rush Univ, Chicago, IL 60612 USA. [Larkin, James] Royal Marsden NHS Fdn Trust, London, England. [Lo, Roger S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lo, Roger S.] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Mantovani, Alberto] Humanitas Clin & Res Inst, Rozzano, Italy. [Margolin, Kim] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Melief, Cornelis] Leiden Univ, Med Ctr, Leiden, Netherlands. [Melief, Cornelis] ISA Pharmaceut, Leiden, Netherlands. [McArthur, Grant] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Puzanov, Igor] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ribas, Antoni] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Tumor Immunol Programme, Los Angeles, CA 90095 USA. [Seliger, Barbara] Univ Halle Wittenberg, Inst Med Immunol, D-06108 Halle, Germany. [Sosman, Jeff] Vanderbilt Ingram Comprehens Canc Ctr, Nashville, TN USA. [Suenaert, Peter] GlaxoSmithKline Vaccines, Global Early Clin Dev, Clin Immunotherapeut, Immunotherapeut, Rixensart, Belgium. [Tarhini, Ahmad A.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Vidal-Vanaclocha, Fernando] CEU San Pablo Univ, Inst Appl Mol Med IMMA, Madrid 28668, Spain. [Vidal-Vanaclocha, Fernando] HM Hosp, Sch Med, Madrid 28668, Spain. [Wang, Ena] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. RP Ascierto, PA (reprint author), Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. EM paolo.ascierto@gmail.com RI Del Vecchio, Michele/K-1584-2016; OI Palmieri, Giuseppe/0000-0002-4350-2276; Del Vecchio, Michele/0000-0001-9060-2512; Ciliberto, Gennaro/0000-0003-2851-8605; Mantovani, Alberto/0000-0001-5578-236X FU Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to 3P Solution of Napoli for their support and cooperation in organizing the meeting and to Michael Hoetzel for providing us with the group picture from the meeting. Sacha Gnjatic would like to acknowledge the Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative for grant support. All Authors would like to dedicate this manuscript to the memory of Natale Cascinelli who devoted his life to the research and care of melanoma patients and was an example for all of us. NR 115 TC 12 Z9 12 U1 0 U2 11 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 JUN 3 PY 2013 VL 11 AR 137 DI 10.1186/1479-5876-11-137 PG 28 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 162ZQ UT WOS:000320305200001 PM 23731854 ER PT J AU Price, JC Pollock, LM Rudd, ML Fogoros, SK Mohamed, H Hanigan, CL Le Gallo, M Zhang, SY Cruz, P Cherukuri, PF Hansen, NF McManus, KJ Godwin, AK Sgroi, DC Mullikin, JC Merino, MJ Hieter, P Bell, DW AF Price, Jessica C. Pollock, Lana M. Rudd, Meghan L. Fogoros, Sarah K. Mohamed, Hassan Hanigan, Christin L. Le Gallo, Matthieu Zhang, Suiyuan Cruz, Pedro Cherukuri, Praveen F. Hansen, Nancy F. McManus, Kirk J. Godwin, Andrew K. Sgroi, Dennis C. Mullikin, James C. Merino, Maria J. Hieter, Philip Bell, Daphne W. CA NIH Intramural Sequencing Ctr NISC TI Sequencing of Candidate Chromosome Instability Genes in Endometrial Cancers Cancers Reveals Somatic Mutations in ESCO1, CHTF18, and MRE11A SO PLOS ONE LA English DT Article ID SISTER-CHROMATID COHESION; CTF18-REPLICATION FACTOR-C; ANTIGEN LOADER COMPLEX; DNA MISMATCH REPAIR; MICROSATELLITE INSTABILITY; S-PHASE; SACCHAROMYCES-CEREVISIAE; COLORECTAL CANCERS; CONSERVED PROTEIN; HUMAN-CELLS AB Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer. C1 [Price, Jessica C.; Pollock, Lana M.; Rudd, Meghan L.; Fogoros, Sarah K.; Mohamed, Hassan; Hanigan, Christin L.; Le Gallo, Matthieu; Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NIH Intramural Sequencing Ctr NISC] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Zhang, Suiyuan; Cruz, Pedro; Cherukuri, Praveen F.; Hansen, Nancy F.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [McManus, Kirk J.] Univ Manitoba, Manitoba Inst Cell Biol, Dept Biochem & Med Genet, Winnipeg, MB, Canada. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Ctr Canc, Kansas City, KS 66103 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Merino, Maria J.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hieter, Philip] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU National Human Genome Research Institute at NIH; NIH [CA016519, RO1-1CA112021-01]; Canadian Institutes of Health Research (CIHR) [MOP-38096]; Manitoba Health Research Council (MHRC); CIHR/MHRC RPP New Investigator award; NCI SPORE in breast cancer at Massachusetts General Hospital; Avon Foundation; [U01 CA113916]; [R01 CA140323] FX This work was funded, in part, by the Intramural Research Program of the National Human Genome Research Institute at NIH (DWB, JCM); NIH grant CA016519 (PH); Canadian Institutes of Health Research (CIHR) grant MOP-38096 (PH); Manitoba Health Research Council (MHRC) grant (KJM); CIHR/MHRC RPP New Investigator award (KJM); U01 CA113916 and R01 CA140323 (AKG); NIH RO1-1CA112021-01 (DCS); the NCI SPORE in breast cancer at Massachusetts General Hospital (DCS); and the Avon Foundation (DCS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 7 Z9 7 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2013 VL 8 IS 6 AR e63313 DI 10.1371/journal.pone.0063313 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 157CD UT WOS:000319872300008 ER PT J AU Toyang, NJ Krause, MA Fairhurst, RM Tane, P Bryant, J Verpoorte, R AF Toyang, Ngeh J. Krause, Michael A. Fairhurst, Rick M. Tane, Pierre Bryant, Joseph Verpoorte, Rob TI Antiplasmodial activity of sesquiterpene lactones and a sucrose ester from Vernonia guineensis Benth. (Asteraceae) SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Vernonia guineensis; Antiplasmodial activity; Sesquiterpene lactone; Sucrose ester; Cameroon ID STIGMASTANE DERIVATIVES; ANTIMALARIAL-DRUGS; MEDICINAL-PLANTS; MALARIA; EXTRACTS AB Ethnopharmacological relevance: Aqueous preparations of Vernonia guineensis Benth. (Asteraceae) are used in Cameroonian folk medicine as a general stimulant and to treat various illnesses and conditions including malaria, bacterial infections and helminthic infestations. Materials and methods: Ten gram samples of the leaf and tuber powders of Vernonia guineensis were extracted separately using dichloromethane, methanol and distilled water. The extracts were dried in vacua and used in bioassays. These extracts and three compounds previously isolated from Vernonia guineensis [vernopicrin (1), vernomelitensin (2) and pentaisovalerylsucrose (3)] were screened for antiplasmodial activity against chloroquine (CQ)-sensitive (Hb3) and CQ-resistant (Dd2) Plasmodium falciparum lines. Results: Crude extracts and pure compounds from Vernonia guineensis showed antiplasmodial activity against both Hb3 and Dd2. The IC50 values of extracts ranged from 1.64 to 272 mu g/ml for Hb3 and 1.82-30.0 mu g/ml for Dd2; those for compounds 1,2 and 3 ranged from 0.47 to 1.62 mu g/ml (1364-1774 nM) for Hb3 and 0.57-1.50 mu g/ml (1644-2332 nM) for Dd2. None of the crude extracts or pure compounds was observed to exert toxic effects on the erythrocytes used to cultivate the Plasmodium falciparum lines. Conclusion: In Cameroonian folk medicine, Vernonia guineensis may be used to treat malaria in part due to the antiplasmodial activity of sesquiterpene lactones (1, 2), a sucrose ester (3) and perhaps other compounds present in crude plant extracts. Exploring the safety and antiplasmodial efficacy of these compounds in vivo requires further study. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Toyang, Ngeh J.] Virgin Bot & Biotech Inc, Columbia, MD USA. [Toyang, Ngeh J.; Bryant, Joseph] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Krause, Michael A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Tane, Pierre] Univ Dschang, Dept Chem, Fac Sci, Dschang, Cameroon. [Verpoorte, Rob] Leiden Univ, Nat Prod Lab, IBL, Leiden, Netherlands. RP Toyang, NJ (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 West Lombard St,Room S421, Baltimore, MD 21201 USA. EM ntoyang@som.umaryland.edu FU Intramural Research Program of the NIAID, NIH FX This study was supported in part by the Intramural Research Program of the NIAID, NIH. The authors are grateful to Alosyius N. Toyang, Valentine Lah and Therese Toyeng for assisting with the collection and processing of the plant material. We also acknowledge Harry Davis, Dr. Eugene Ateh and Dr. Valentina Turri for useful contributions to this study. NR 23 TC 4 Z9 4 U1 0 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD JUN 3 PY 2013 VL 147 IS 3 BP 618 EP 621 DI 10.1016/j.jep.2013.03.051 PG 4 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 157JG UT WOS:000319891800008 PM 23542146 ER PT J AU Tran, E Chinnasamy, D Yu, ZY Morgan, RA Lee, CCR Restifo, NP Rosenberg, SA AF Tran, Eric Chinnasamy, Dhanalakshmi Yu, Zhiya Morgan, Richard A. Lee, Chyi-Chia Richard Restifo, Nicholas P. Rosenberg, Steven A. TI Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MESENCHYMAL STEM-CELLS; PHASE-II TRIAL; METASTATIC COLORECTAL-CANCER; TUMOR-ASSOCIATED FIBROBLASTS; MONOCLONAL-ANTIBODY; COLON-CANCER; MICROENVIRONMENT; ALPHA; TALABOSTAT; TISSUES AB Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immuno-suppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines. However, adoptive transfer of FAP-reactive T cells into mice bearing a variety of subcutaneous tumors mediated limited antitumor effects and induced significant cachexia and lethal bone toxicities in two mouse strains. We found that FAP was robustly expressed on PDGFR-alpha(+), Sca-1(+) multipotent bone marrow stromal cells (BMSCs) in mice, as well as on well-characterized, clinical-grade multipotent human BMSCs. Accordingly, both mouse and human multipotent BMSCs were recognized by FAP-reactive T cells. The lethal bone toxicity and cachexia observed after cell-based immuno-therapy targeting FAP cautions against its use as a universal target. Moreover, the expression of FAP by multipotent BMSCs may point toward the cellular origins of tumor stromal fibroblasts. C1 [Tran, Eric; Chinnasamy, Dhanalakshmi; Yu, Zhiya; Morgan, Richard A.; Restifo, Nicholas P.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA. RP Tran, E (reprint author), NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. EM eric.tran@nih.gov; SAR@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural Research Program of the NIH; NCI FX This research was supported by the Intramural Research Program of the NIH and NCI. NR 30 TC 63 Z9 68 U1 0 U2 9 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 JUN 3 PY 2013 VL 210 IS 6 BP 1125 EP 1135 DI 10.1084/jem.20130110 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 156FS UT WOS:000319807800008 PM 23712432 ER PT J AU Whidbey, C Harrell, MI Burnside, K Ngo, L Becraft, AK Iyer, LM Aravind, L Hitti, J Waldorf, KMA Rajagopal, L AF Whidbey, Christopher Harrell, Maria Isabel Burnside, Kellie Ngo, Lisa Becraft, Alexis K. Iyer, Lakshminarayan M. Aravind, L. Hitti, Jane Waldorf, Kristina M. Adams Rajagopal, Lakshmi TI A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID BLOOD-BRAIN-BARRIER; INVASIVE NEONATAL DISEASE; LUNG EPITHELIAL-CELLS; TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID; PRETERM LABOR; BETA-HEMOLYSIN/CYTOLYSIN; INTRAAMNIOTIC INFECTION; INTACT MEMBRANES; MAMMALIAN-CELLS AB Microbial infection of the amniotic fluid is a significant cause of fetal injury, preterm birth, and newborn infections. Group B Streptococcus (GBS) is an important human bacterial pathogen associated with preterm birth, fetal injury, and neonatal mortality. Although GBS has been isolated from amniotic fluid of women in preterm labor, mechanisms of in utero infection remain unknown. Previous studies indicated that GBS are unable to invade human amniotic epithelial cells (hAECs), which represent the last barrier to the amniotic cavity and fetus. We show that GBS invades hAECs and strains lacking the hemolysin repressor CovR/S accelerate amniotic barrier failure and penetrate chorioamniotic membranes in a hemolysin-dependent manner. Clinical GBS isolates obtained from women in preterm labor are hyperhemolytic and some are associated with covR/S mutations. We demonstrate for the first time that hemolytic and cytolytic activity of GBS is due to the ornithine rhamnolipid pigment and not due to a pore-forming protein toxin. Our studies emphasize the importance of the hemolytic GBS pigment in ascending infection and fetal injury. C1 [Whidbey, Christopher; Burnside, Kellie; Rajagopal, Lakshmi] Univ Washington, Sch Med, Dept Pediat Infect Dis, Seattle, WA 98195 USA. [Hitti, Jane; Waldorf, Kristina M. Adams] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Whidbey, Christopher; Harrell, Maria Isabel; Ngo, Lisa; Becraft, Alexis K.; Rajagopal, Lakshmi] Seattle Childrens Hosp Res Inst, Ctr Childhood Infect & Prematur Res, Seattle, WA 98101 USA. [Whidbey, Christopher; Rajagopal, Lakshmi] Univ Washington, Sch Publ Hlth, Dept Global Hlth, Seattle, WA 98195 USA. [Iyer, Lakshminarayan M.; Aravind, L.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Waldorf, KMA (reprint author), Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. EM adamsk@u.washington.edu; lakshmi.rajagopal@seattlechildrens.org FU National Institutes of Health (NIH) [R01AI100989, R01AI070749, K08AI067910]; March of Dimes grant [21-FY08-562, 21-FY06-77]; NIH [5 T32 HD007233-29, T32 AI07509]; NLM, NIH; Cuyamaca Foundation; [R01AI31871] FX This work was supported by funding from the National Institutes of Health (NIH) grants R01AI100989 to L. Rajagopal and K. M. Adams Waldorf, R01AI070749 to L. Rajagopal, and K08AI067910 to K.M. Adams Waldorf. This work was also supported by funding from the March of Dimes grant 21-FY08-562 and 21-FY06-77 to K.M. Adams Waldorf. Support for K. Burnside was provided by the NIH training grant (5 T32 HD007233-29, PI: Lisa Frenkel). Support for C. Whidbey was provided by the NIH training grant (T32 AI07509, PI: Lee Ann Campbell). L.M. Iyer and L. Aravind are supported by intramural funds from NLM, NIH. The Cuyamaca Foundation also provided support for this work. We are grateful to the human subjects who participated in these studies. The study on women in preterm labor from where GBS clinical isolates were obtained was funded by R01AI31871. NR 78 TC 31 Z9 32 U1 0 U2 8 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 JUN 3 PY 2013 VL 210 IS 6 BP 1265 EP 1281 DI 10.1084/jem.20122753 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 156FS UT WOS:000319807800018 PM 23712433 ER PT J AU Rothman, SM Mattson, MP AF Rothman, S. M. Mattson, M. P. TI ACTIVITY-DEPENDENT, STRESS-RESPONSIVE BDNF SIGNALING AND THE QUEST FOR OPTIMAL BRAIN HEALTH AND RESILIENCE THROUGHOUT THE LIFESPAN SO NEUROSCIENCE LA English DT Review DE BDNF; caloric restriction; exercise; glucocorticoid; LTP; synaptic plasticity ID NEUROTROPHIC FACTOR EXPRESSION; MESSENGER-RNA EXPRESSION; LONG-TERM POTENTIATION; CULTURED HIPPOCAMPAL-NEURONS; ELEMENT-BINDING PROTEIN; SPINAL-CORD-INJURY; RAT HIPPOCAMPUS; CALORIC RESTRICTION; ALZHEIMERS-DISEASE; GENE-EXPRESSION AB During development of the nervous system, the formation of connections (synapses) between neurons is dependent upon electrical activity in those neurons, and neurotrophic factors produced by target cells play a pivotal role in such activity-dependent sculpting of the neural networks. A similar interplay between neurotransmitter and neurotrophic factor signaling pathways mediates adaptive responses of neural networks to environmental demands in adult mammals, with the excitatory neurotransmitter glutamate and brain-derived neurotrophic factor (BDNF) being particularly prominent regulators of synaptic plasticity throughout the central nervous system. Optimal brain health throughout the lifespan is promoted by intermittent challenges such as exercise, cognitive stimulation and dietary energy restriction, that subject neurons to activity-related metabolic stress. At the molecular level, such challenges to neurons result in the production of proteins involved in neurogenesis, learning and memory and neuronal survival; examples include proteins that regulate mitochondrial biogenesis, protein quality control, and resistance of cells to oxidative, metabolic and proteotoxic stress. BDNF signaling mediates up-regulation of several such proteins including the protein chaperone GRP-78, antioxidant enzymes, the cell survival protein Bcl-2, and the DNA repair enzyme APEL Insufficient exposure to such challenges, genetic factors may conspire to impair BDNF production and/or signaling resulting in the vulnerability of the brain to injury and neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Further, BDNF signaling is negatively regulated by glucocorticoids. Glucocorticoids impair synaptic plasticity in the brain by negatively regulating spine density, neurogenesis and long-term potentiation, effects that are potentially linked to glucocorticoid regulation of BDNF. Findings suggest that BDNF signaling in specific brain regions mediates some of the beneficial effects of exercise and energy restriction on peripheral energy metabolism and the cardiovascular system. Collectively, the findings described in this article suggest the possibility of developing prescriptions for optimal brain health based on activity-dependent BDNF signaling. This article is part of a Special Issue entitled: Steroid hormone actions in the CNS: the role of BDNF. Published by Elsevier Ltd. on behalf of IBRO. C1 [Rothman, S. M.; Mattson, M. P.] NIA, Neurosci Lab, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Rothman, SM (reprint author), NIA, Neurosci Lab, NIH, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rothmansm@mail.nih.gov FU intramural research program of the National institute on Aging FX This work was supported by the intramural research program of the National institute on Aging. NR 178 TC 39 Z9 41 U1 5 U2 82 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD JUN 3 PY 2013 VL 239 SI SI BP 228 EP 240 DI 10.1016/j.neuroscience.2012.10.014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 134KO UT WOS:000318209300018 PM 23079624 ER PT J AU Koulaouzidis, A Karargyris, A Rondonotti, E Plevris, JN AF Koulaouzidis, A. Karargyris, A. Rondonotti, E. Plevris, J. N. TI 3D RECONSTRUCTION IN CAPSULE ENDOSCOPY; A FEASIBILITY STUDY SO GUT LA English DT Meeting Abstract CT Annual General Meeting of the British-Society-of-Gastroenterology CY JUN 24-27, 2013 CL Glasgow, SCOTLAND SP British Soc Gastroenterol C1 [Koulaouzidis, A.; Plevris, J. N.] Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Edinburgh, Midlothian, Scotland. [Karargyris, A.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Rondonotti, E.] Osped Valduce, Gastroenterol Unit, Como, Italy. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD JUN PY 2013 VL 62 SU 1 BP A50 EP A51 DI 10.1136/gutjnl-2013-304907.114 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AA6SF UT WOS:000331227600100 ER PT J AU Edelman, EJ Gordon, KS Hogben, M Crystal, S Bryant, K Justice, AC Fiellin, DA AF Edelman, E. J. Gordon, Kirsha S. Hogben, Matthew Crystal, Stephen Bryant, Kendall Justice, Amy C. Fiellin, David A. TI PARTNER NOTIFICATION PRACTICES AMONG HIV-INFECTED MEN SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 [Edelman, E. J.; Justice, Amy C.; Fiellin, David A.] Yale Univ, New Haven, CT USA. [Gordon, Kirsha S.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Hogben, Matthew] Ctr Dis Control & Prevent, Atlanta, GA USA. [Crystal, Stephen] Rutgers, New Brunswick, NJ USA. [Bryant, Kendall] NIAAA, Potomac, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S134 EP S135 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939301079 ER PT J AU Goold, SD Tilburt, JC Wynia, M James, KM Sheeler, R Egginton, J Liebow, M Thorsteinsdottir, B Danis, M AF Goold, Susan D. Tilburt, Jon C. Wynia, Matthew James, Katherine M. Sheeler, Robert Egginton, Jason Liebow, Mark Thorsteinsdottir, Bjorg Danis, Marion TI PHYSICIAN VIEWS OF COST-CONTAINMENT STRATEGIES SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 [Goold, Susan D.; Liebow, Mark] Univ Michigan, Ann Arbor, MI 48109 USA. [Tilburt, Jon C.; James, Katherine M.; Sheeler, Robert; Egginton, Jason; Liebow, Mark; Thorsteinsdottir, Bjorg] Mayo Clin, Rochester, MN USA. [Wynia, Matthew] Amer Med Assoc, Chicago, IL 60610 USA. [Danis, Marion] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S146 EP S147 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939301107 ER PT J AU Justice, AC Tate, JP Brown, ST Gibert, C Rodriguez-Barradas, M Rimland, D Akgun, KM Bryant, K AF Justice, Amy C. Tate, Janet P. Brown, Sheldon T. Gibert, Cynthia Rodriguez-Barradas, Maria Rimland, David Akguen, Kathleen M. Bryant, Kendall TI CAN THE VETERANS AGING COHORT STUDY INDEX IMPROVE CLINICAL JUDGMENT FOR BOTH HIV INFECTED AND UNINFECTED VETERANS? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 [Justice, Amy C.; Tate, Janet P.; Akguen, Kathleen M.] Yale Univ, West Haven, CT USA. [Justice, Amy C.; Tate, Janet P.; Akguen, Kathleen M.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Brown, Sheldon T.] James J Peters VA Med Ctr, New York, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. [Gibert, Cynthia] George Washington Univ, Sch Med, Washington, DC USA. [Gibert, Cynthia] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Rodriguez-Barradas, Maria] Baylor Coll Med, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rimland, David] Emory Sch Med, Atlanta, GA USA. [Rimland, David] Atlanta Vet Affairs Med Ctr, Atlanta, GA USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S39 EP S39 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939300093 ER PT J AU Kwon, D Tisnado, D Adams, J Rastegar, A Klabunde, C Hornbrook, MC Keating, NL Kahn, KL AF Kwon, Daniel Tisnado, Diana Adams, John Rastegar, Afshin Klabunde, Carrie Hornbrook, Mark C. Keating, Nancy L. Kahn, Katherine L. TI ARE PHYSICIAN-REPORTED BARRIERS TO SPECIALIST REFERRAL AN IMPORTANT PREDICTOR OF CAREER SATISFACTION AMONG PHYSICIANS CARING FOR CANCER PATIENTS? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 [Kwon, Daniel] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Tisnado, Diana; Kahn, Katherine L.] Univ Calif Los Angeles, Los Angeles, CA USA. [Adams, John; Rastegar, Afshin; Kahn, Katherine L.] RAND Corp, Santa Monica, CA USA. [Hornbrook, Mark C.] Kaiser Permanente Ctr Hlth Res, Los Angeles, CA USA. [Keating, Nancy L.] Brigham & Womens Hosp, Boston, MA USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Boston, MA USA. [Klabunde, Carrie] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S23 EP S24 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939300055 ER PT J AU Sayanlar, J AF Sayanlar, Jason TI EOSINOPHILIC CARDIOMYOPATHY WITH ENDOMYOCARDIAL FIBROSIS SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 Georgetown Univ Hosp, Washington, DC 20007 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S323 EP S323 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939302067 ER PT J AU Tetrault, JM Tate, JP Edelman, J Gordon, A Lo Re, V Fiellin, LE Bryant, K Justice, AC Fiellin, DA AF Tetrault, Jeanette M. Tate, Janet P. Edelman, Jennifer Gordon, Adam Lo Re, Vincent Fiellin, Lynn E. Bryant, Kendall Justice, Amy C. Fiellin, David A. TI USE AND SAFETY OF BUPRENORPHINE IN HIV-INFECTED AND UNINFECTED OPIOID DEPENDENT PATIENTS SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 24-27, 2013 CL Denver, CO SP Soc Gen Internal Med C1 [Tetrault, Jeanette M.; Edelman, Jennifer; Fiellin, Lynn E.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, New Haven, CT USA. [Tate, Janet P.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Gordon, Adam] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Lo Re, Vincent; Bryant, Kendall] NIAAA, Rockville, MD 20852 USA. RI Lo Re, Vincent/N-7817-2015 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 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2013 VL 28 SU 1 BP S233 EP S234 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AB6ZP UT WOS:000331939301311 ER PT J AU Elmore, SA Hoenerhoff, M Katsuta, O Kokoshima, H Maronpot, R Nagai, H Satoh, H Tanaka, Y Tochitani, T Tsuchiya, S Yoshizawa, K AF Elmore, Susan A. Hoenerhoff, Mark Katsuta, Osamu Kokoshima, Hiroko Maronpot, Robert Nagai, Hiroaki Satoh, Hiroshi Tanaka, Yasuhiro Tochitani, Tomoaki Tsuchiya, Seiichiro Yoshizawa, Katsuhiko TI Proceedings of the 2013 Joint JSTP/NTP Satellite Symposium SO JOURNAL OF TOXICOLOGIC PATHOLOGY LA English DT Article DE JSTP/NTP Satellite Symposium; atypical foci of cellular alteration; cholangiocarcinoma; cholangiofibrosis; congenital hepatic fibrosis; eosinophilic crystalline pneumonia; eosinophilic substance; epithelioid type of malignant schwannoma; hyaline glomerulopathy; intrahepatocytic erythrocytes; middle ear adenocarcinoma; nasal septum hyalinosis; pancreatic ductal cell adenoma; subendothelial hepatocytes; thyroid follicular cell vacuolar degeneration; ventriculoencephalitis ID ACIDOPHILIC MACROPHAGE PNEUMONIA; CONGENITAL HEPATIC-FIBROSIS; MOUSE NASAL-SEPTUM; YOLK-SAC TUMOR; NONPROLIFERATIVE LESIONS; EOSINOPHILIC SUBSTANCE; RESPIRATORY-TRACT; THYROID-GLAND; BILE-DUCTS; MICE AB The first joint Japanese Society of Toxicologic Pathology (JSTP) and National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held on January 29th at Okura Frontier Hotel in Tsukuba, Ibaraki, Japan, in advance of the JSTP's 29th Annual Meeting. The goal of this Symposium was to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, select images that were used for audience voting or discussion, and the voting results. Some lesions and topics covered during the symposium include: treatment-related atypical hepatocellular foci of cellular alteration in B6C3F1 mice; purulent ventriculoencephalitis in a young BALB/c mouse; a subcutaneous malignant schwannoma in a RccHan:WIST rat; spontaneous nasal septum hyalinosis/eosinophilic substance in B6C3F1 mice; a rare pancreatic ductal cell adenoma in a young Lewis rat; eosinophilic crystalline pneumonia in a transgenic mouse model; hyaline glomerulopathy in two female ddY mice; treatment-related intrahepatic erythrocytes in B6C3F1 mice; treatment-related subendothelial hepatocytes in B6C3F1 mice; spontaneous thyroid follicular cell vacuolar degeneration in a cynomolgus monkey; congenital hepatic fibrosis in a 1-year-old cat; a spontaneous adenocarcinoma of the middle ear in a young Crl:CD(SD) rat; and finally a series of cases illustrating some differences between cholangiofibrosis and cholangiocarcinoma in Sprague Dawley and F344 rats. C1 [Elmore, Susan A.; Hoenerhoff, Mark] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Katsuta, Osamu] Santen Pharmaceut Co Ltd, Nara 6300101, Japan. [Kokoshima, Hiroko] Mitsubishi Chem Medience Corp, Kamisu, Ibaraki 3140255, Japan. [Maronpot, Robert] Maronpot Consulting LLC, Raleigh, NC USA. [Nagai, Hiroaki] Nihon Nohyaku Co Ltd, Osaka 5860094, Japan. [Satoh, Hiroshi] Fujifilm Corp, Safety Evaluat Ctr, Minamiashigara, Kanagawa 2500193, Japan. [Tanaka, Yasuhiro] Setsunan Univ, Fac Pharmaceut Sci, Hirakata, Osaka 5730101, Japan. [Tochitani, Tomoaki] Dainippon Sumitomo Pharma Co Ltd, Konohana Ku, Osaka 5540022, Japan. [Tsuchiya, Seiichiro] Ishihara Sangyo Kaisha Ltd, Kusatsu, Shiga 5250025, Japan. [Yoshizawa, Katsuhiko] Kansai Med Univ, Hirakata, Osaka 5731010, Japan. RP Elmore, SA (reprint author), NIEHS, Natl Toxicol Program, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); JSTP FX This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). This article may be the work product of an employee or group of employees of the NIEHS, NIH; however, the statements, opinions or conclusions contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH or United States government. We also express our thanks for the financial support of the JSTP for publication of these proceedings in the Journal of Toxicologic Pathology. NR 81 TC 0 Z9 0 U1 0 U2 3 PU JAPANESE SOC TOXICOLOGIC PATHOLOGY PI TOKYO PA DEPT ACAD SOC, MEDICAL TRIBUNE INC, ITALIAN CULTURAL INST BLDG 8F 2-1-30, KUDAN MINAMI, CHIYODA, TOKYO, 102-0074, JAPAN SN 0914-9198 EI 1881-915X J9 J TOXICOL PATHOL JI J. Toxicol. Pathol. PD SUM PY 2013 VL 26 IS 2 BP 231 EP 257 DI 10.1293/tox.26.231 PG 27 WC Pathology; Toxicology SC Pathology; Toxicology GA 193JH UT WOS:000322555600018 PM 23914068 ER PT J AU Haddad, MR Donsante, A Zerfas, P Kaler, SG AF Haddad, Marie Reine Donsante, Anthony Zerfas, Patricia Kaler, Stephen G. TI Fetal Brain-directed AAV Gene Therapy Results in Rapid, Robust, and Persistent Transduction of Mouse Choroid Plexus Epithelia SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE blood-cerebrospinal fluid barrier; choroid plexus; in utero gene therapy; rAAV5; rAAV9; survival surgery ID CEREBROSPINAL-FLUID; IMPROVES SURVIVAL; NERVOUS-SYSTEM; KRABBE DISEASE; MODEL; MICE; EXPRESSION; INJECTION; VECTORS; WIDESPREAD AB Fetal brain-directed gene addition represents an under-appreciated tool for investigating novel therapeutic approaches in animal models of central nervous system diseases with early prenatal onset. Choroid plexuses (CPs) are specialized neuroectoderm-derived structures that project into the brain's ventricles, produce cerebrospinal fluid (CSF), and regulate CSF biochemical composition. Targeting the CP may be advantageous for adeno-associated viral (AAV) gene therapy for central nervous system disorders due to its immunoprivileged location and slow rate of epithelial turnover. Yet the capacity of AAV vectors to transduce CP has not been delineated precisely. We performed intracerebroventricular injections of recombinant AAV serotype 5-green fluorescent protein (rAAV5-GFP) or rAAV9-GFP in embryonic day 15 (E15) embryos of CD-1 and C57BL/6 pregnant mice and quantified the percentages of GFP expression in CP epithelia (CPE) from lateral and fourth ventricles on E17, postnatal day 2 (P2), and P22. AAV5 was selective for CPE and showed significantly higher transduction efficiency in C57BL/6 mice (P = 0.0128). AAV9 transduced neurons and glial cells in both the mouse strains, in addition to CPE. We documented GFP expression in CPE on E17, within just 48 hours of rAAV administration to the fetal lateral ventricle, and expression by both the serotypes persisted at P130. Our results indicate that prenatal administration of rAAV5 and rAAV9 enables rapid, robust, and sustained transduction of mouse CPE and buttress the rationale for experimental therapeutics targeting the CP. C1 [Haddad, Marie Reine; Donsante, Anthony; Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Unit Human Copper Metab, Bethesda, MD USA. [Zerfas, Patricia] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), NIH, Bldg 10 Room 10N313,10 Ctr Dr MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov NR 36 TC 6 Z9 6 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD JUN PY 2013 VL 2 AR e101 DI 10.1038/mtna.2013.27 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC4BV UT WOS:000332466500006 PM 23799375 ER PT J AU Gamaleddin, I Guranda, M Scherma, M Fratta, W Makriyannis, A Vadivel, SK Goldberg, SR Le Foll, B AF Gamaleddin, Islam Guranda, Mihail Scherma, Maria Fratta, Walter Makriyannis, Alexandros Vadivel, Subramanian K. Goldberg, Steven R. Le Foll, Bernard TI AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Nicotine; nicotine taking; nicotine seeking; endocannabinoids; AM404 ID ANANDAMIDE TRANSPORT INHIBITOR; ACID AMIDE HYDROLASE; CANNABINOID RECEPTORS; CELLULAR UPTAKE; ESTER URB597; RATS; HYDROLYSIS; ANTAGONIST; BLOCKS; 2-ARACHIDONOYLGLYCEROL AB Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors. Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming. Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers. C1 [Gamaleddin, Islam; Guranda, Mihail; Le Foll, Bernard] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Gamaleddin, Islam; Le Foll, Bernard] Ctr Addict & Mental Hlth, Addict Program, Toronto, ON M5S 2S1, Canada. [Gamaleddin, Islam] Ain Shams Univ, Inst Environm Studies & Res, Dept Med Sci, Cairo, Egypt. [Scherma, Maria; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Baltimore, MD USA. [Scherma, Maria; Fratta, Walter] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Makriyannis, Alexandros; Vadivel, Subramanian K.] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Le Foll, Bernard] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Dept Toxicol, Toronto, ON, Canada. RP Gamaleddin, I (reprint author), Ctr Addict & Mental Hlth, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM islam.gamaleddin@mail.utoronto.ca RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Pfizer Inc.; Pfizer Cardiovascular Research Award, Canada, Inc [WS 455595]; Intramural Research Program of NIDA, NIH, DHHS; Italian Ministry of University and Scientific Research FX Dr Le Foll has received grant and salary support from Pfizer Inc. and is a consultant for Richter Pharmaceuticals, Lundbeck, Mylan, Ethypharm and Pfizer.; This research was supported by a grant from Pfizer Cardiovascular Research Award, Canada, Inc, # WS 455595, by the Intramural Research Program of NIDA, NIH, DHHS and in part by the Italian Ministry of University and Scientific Research. AM404 was synthesized and generously provided by Alexandros Makriyannis. NR 40 TC 11 Z9 11 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JUN PY 2013 VL 27 IS 6 BP 564 EP 571 DI 10.1177/0269881113477710 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 145JF UT WOS:000319010800010 PM 23427192 ER PT J AU Remmers, EF AF Remmers, E. F. TI THE EXPANDING SPECTRUM OF AUTOINFLAMMATION SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Remmers, E. F.] NHGRI, MGB Inflammatory Dis Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 3 EP 4 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901009 ER PT J AU Lessard, CJ Li, H Ice, JA Adrianto, I Jonsson, R Illei, GG Rischmueller, M Nordmark, G Mariette, X Miceli-Richard, C Herlenius, MW Witte, T Brennan, M Omdal, R Gaffney, PM Lessard, JA Ronnblom, L Ng, WF Rhodus, N Segal, B Scofield, RH James, JA Anaya, JM Montgomery, CG Harley, JB Sivils, KM AF Lessard, C. J. Li, H. Ice, J. A. Adrianto, I. Jonsson, R. Illei, G. G. Rischmueller, M. Nordmark, G. Mariette, X. Miceli-Richard, C. Herlenius, M. Wahren Witte, T. Brennan, M. Omdal, R. Gaffney, P. M. Lessard, J. A. Ronnblom, L. Ng, W. -F. Rhodus, N. Segal, B. Scofield, R. H. James, J. A. Anaya, J. -M. Montgomery, C. G. Harley, J. B. Sivils, K. Moser TI IDENTIFICATION OF MULTIPLE SJOGREN'S SYNDROME SUSCEPTIBILITY LOCI SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Lessard, C. J.; Li, H.; James, J. A.; Sivils, K. Moser] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Lessard, C. J.; Li, H.; Ice, J. A.; Adrianto, I.; Gaffney, P. M.; Scofield, R. H.; James, J. A.; Montgomery, C. G.; Sivils, K. Moser] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Jonsson, R.; Omdal, R.] Univ Bergen, Bergen, Norway. [Illei, G. G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Rischmueller, M.] Queen Elizabeth Hosp & Hlth Serv, Adelaide, SA, Australia. [Nordmark, G.; Ronnblom, L.] Uppsala Univ, Uppsala, Sweden. [Mariette, X.; Miceli-Richard, C.] Univ Paris 11, Paris, France. [Herlenius, M. Wahren] Karolinska Inst, Dept Med, Stockholm, Sweden. [Witte, T.] Hannover Med Sch, Hannover, Germany. [Brennan, M.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Lessard, J. A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Ng, W. -F.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Rhodus, N.] Univ Minnesota, Minneapolis, MN USA. [Segal, B.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Scofield, R. H.] US Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. [Scofield, R. H.; James, J. A.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Anaya, J. -M.] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia. [Harley, J. B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RI Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016 OI Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 2 Z9 2 U1 2 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 54 EP 55 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901223 ER PT J AU Tjarnlund, A Bottai, M Rider, LG Werth, VP Pilkington, C de Visser, M Alfredsson, L Amato, AA Barohn, RJ Liang, MH Singh, JA Miller, FW Lundberg, IE AF Tjarnlund, A. Bottai, M. Rider, L. G. Werth, V. P. Pilkington, C. de Visser, M. Alfredsson, L. Amato, A. A. Barohn, R. J. Liang, M. H. Singh, J. A. Miller, F. W. Lundberg, I. E. CA Int Myositis Classification Criter TI PROGRESS REPORT ON THE DEVELOPMENT OF NEW CLASSIFICATION CRITERIA FOR ADULT AND JUVENILE IDIOPATHIC INFLAMMATORY MYOPATHIES SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Tjarnlund, A.; Lundberg, I. E.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Solna, Sweden. [Bottai, M.; Alfredsson, L.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Rider, L. G.; Miller, F. W.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept HHS, Bethesda, MD USA. [Werth, V. P.] Philadelphia VAMC, Dept Dermatol, Philadelphia, PA USA. [Werth, V. P.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Pilkington, C.] Great Ormond St Hosp Sick Children, Dept Rheumatol, London WC1N 3JH, England. [de Visser, M.] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Amato, A. A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Barohn, R. J.] Univ Kansas, Med Ctr, Dept Neurol, Lawrence, KS 66045 USA. [Liang, M. H.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Singh, J. A.] Univ Alabama Birmingham, Birmingham, AL USA. [Singh, J. A.] VA Med Ctr, Birmingham, AL USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 60 EP 60 PG 1 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901238 ER PT J AU Olivecrona, H Raboisson, MA Soderberg, K Hallen, B Leinonen, M Sibley, C Plass, N Brewer, C King, K Zalewski, C Kim, J Bishop, R Hill, S Paul, S Stone, D Chapelle, D Butman, J Goldbach-Mansky, R AF Olivecrona, H. Raboisson, M. Alden Soderberg, K. Hallen, B. Leinonen, M. Sibley, C. Plass, N. Brewer, C. King, K. Zalewski, C. Kim, J. Bishop, R. Hill, S. Paul, S. Stone, D. Chapelle, D. Butman, J. Goldbach-Mansky, R. TI KINERET (R) (ANAKINRA) CONTROLS DISEASE SYMPTOMS IN PATIENTS WITH SEVERE CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS): UP TO 5-YEAR FOLLOW-UP DATA SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract ID ANTAGONIST; PREVENTION C1 [Olivecrona, H.; Raboisson, M. Alden; Soderberg, K.; Hallen, B.] Swedish Orphan Biovitrum, Stockholm, Sweden. [Leinonen, M.] 4Pharma AB, Stockholm, Sweden. [Sibley, C.; Plass, N.; Stone, D.; Chapelle, D.; Goldbach-Mansky, R.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Brewer, C.; King, K.; Zalewski, C.; Kim, J.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Bishop, R.] NEI, Bethesda, MD 20892 USA. [Hill, S.; Paul, S.; Butman, J.] NIH Clin Ctr, Bethesda, MD USA. NR 4 TC 2 Z9 2 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 70 EP 71 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901264 ER PT J AU Daridon, C Loddenkemper, C Spieckermann, S Kuhl, AA Salama, A Burmester, GR Lipsky, PE Thomas, D AF Daridon, C. Loddenkemper, C. Spieckermann, S. Kuehl, A. A. Salama, A. Burmester, G. R. Lipsky, P. E. Thomas, D. TI PROLIFERATIVE LYMPHOID NODULES AND NOT GERMINAL CENTERS ARE THE SITES OF AUTOANTIGEN STIMULATION IN HUMAN SPLEEN SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Daridon, C.; Burmester, G. R.; Thomas, D.] Charite, Dept Med Rheumatol & Clin Immunol, CC12, D-13353 Berlin, Germany. [Daridon, C.; Thomas, D.] Charite, German Rheumatism Res Ctr DRFZ, D-13353 Berlin, Germany. [Loddenkemper, C.; Spieckermann, S.; Kuehl, A. A.] Charite, Dept Gastroenterol Infectiol & Rheumatol, CC13, D-13353 Berlin, Germany. [Kuehl, A. A.] Charite, Res Ctr ImmunoSci RCIS, D-13353 Berlin, Germany. [Salama, A.] Charite, Inst Transfus Med CC14, D-13353 Berlin, Germany. [Lipsky, P. E.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 119 EP 119 PG 1 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901401 ER PT J AU Ciccia, F Accardo-Palumbo, A Rizzo, A Guggino, G Raimondo, S Giardina, A Peralta, M Colbert, R Alessandro, R Triolo, G AF Ciccia, F. Accardo-Palumbo, A. Rizzo, A. Guggino, G. Raimondo, S. Giardina, A. Peralta, M. Colbert, R. Alessandro, R. Triolo, G. TI AUTOPHAGY, BUT NOT THE UNFOLDED PROTEIN RESPONSE, REGULATES THE EXPRESSION OF IL-23 IN THE GUT OF PATIENTS WITH ANKYLOSING SPONDYLITIS AND SUBCLINICAL GUT INFLAMMATION SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Ciccia, F.; Guggino, G.] Uniivers Palermo, Sez Reumatol Sperimentale, Dipartimento Biomed Med Interna & Specialist, Palermo, Italy. [Accardo-Palumbo, A.; Rizzo, A.] Univ Palermo, Osped Riuniti Villa Sofia Cervello, Palermo, Italy. [Raimondo, S.; Alessandro, R.] Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, Palermo, Italy. [Giardina, A.; Peralta, M.; Triolo, G.] Univ Palermo, Sez Reumatol Sperimentale, Dipartimento Biomed Med Interna & Specialist, Palermo, Italy. [Colbert, R.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 148 EP 148 PG 1 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587901481 ER PT J AU Baldini, C Martini, D Sernissi, F Gallo, A Rossi, C Mosca, M Santini, E Pepe, P Solini, A Perez, P Alevizos, I Bombardieri, S AF Baldini, C. Martini, D. Sernissi, F. Gallo, A. Rossi, C. Mosca, M. Santini, E. Pepe, P. Solini, A. Perez, P. Alevizos, I. Bombardieri, S. TI GROSS CYSTIC DISEASE FLUID PROTEIN-15(GCDFP-15)/PROLACTIN-INDUCIBLE PROTEIN (PIP): A FUNCTIONAL SALIVARY BIOMARKER FOR PRIMARY SJOGREN'S SYNDROME? SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Baldini, C.; Martini, D.; Sernissi, F.; Mosca, M.; Pepe, P.; Bombardieri, S.] Univ Pisa, Rheumatol Unit, Pisa, Italy. [Gallo, A.; Perez, P.; Alevizos, I.] NIDCR, NIH, Bethesda, MD USA. [Rossi, C.; Santini, E.; Solini, A.] Univ Pisa, Pisa, Italy. NR 0 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 268 EP 269 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587902223 ER PT J AU Gensler, LS Haroon, N Reveille, JD Learch, TJ Brown, MA Weisman, MH Inman, RD Ward, MM AF Gensler, L. S. Haroon, N. Reveille, J. D. Learch, T. J. Brown, M. A. Weisman, M. H. Inman, R. D. Ward, M. M. TI SOCIOECONOMIC STATUS PREDICTS RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Gensler, L. S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Haroon, N.; Inman, R. D.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Reveille, J. D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Learch, T. J.; Weisman, M. H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Brown, M. A.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Ward, M. M.] NIAMSD, NIH, Bethesda, MD 20892 USA. OI Brown, Matthew A/0000-0003-0538-8211 NR 1 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 533 EP 533 PG 1 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587903360 ER EF