FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Spitz, MR Amos, CI Bierut, LJ Caporaso, NE AF Spitz, Margaret R. Amos, Christopher I. Bierut, Laura J. Caporaso, Neil E. TI Cotinine Conundrum-A Step Forward but Questions Remain SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RECEPTOR SUBUNIT GENES; LUNG-CANCER; NICOTINE DEPENDENCE; SUSCEPTIBILITY LOCUS; RISK; ASSOCIATION; SMOKERS; CARCINOGEN; VARIANTS; SMOKING C1 [Spitz, Margaret R.] Baylor Coll Med, Dept Mol & Cellular Biol, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Bierut, Laura J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Spitz, MR (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Dan L Duncan Canc Ctr, 1 Baylor Plaza,MS BCM305,Ste 450A8,Cullen Bldg, Houston, TX 77030 USA. EM spitz@bcm.edu FU NCI NIH HHS [U19 CA148127, R01CA121197, P50 CA70907, P50 CA070907, P01CA089392, R01CA127219]; NHGRI NIH HHS [U01 HG004422] NR 19 TC 6 Z9 6 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 10 BP 720 EP 722 DI 10.1093/jnci/djs211 PG 3 WC Oncology SC Oncology GA 944KH UT WOS:000304199600001 PM 22534783 ER PT J AU Prorok, PC Miller, AB Kramer, BS AF Prorok, Philip C. Miller, Anthony B. Kramer, Barnett S. TI Re: Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Prorok, Philip C.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Kramer, Barnett S.] NCI, Off Director, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Prorok, PC (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, NIH, 6130 Execut Blvd,Ste 3132, Bethesda, MD 20892 USA. EM prorokp@mail.nih.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 10 BP 793 EP 794 DI 10.1093/jnci/djs206 PG 2 WC Oncology SC Oncology GA 944KH UT WOS:000304199600014 ER PT J AU Rao, E Jiang, C Ji, M Huang, X Iqbal, J Lenz, G Wright, G Staudt, LM Zhao, Y McKeithan, TW Chan, WC Fu, K AF Rao, E. Jiang, C. Ji, M. Huang, X. Iqbal, J. Lenz, G. Wright, G. Staudt, L. M. Zhao, Y. McKeithan, T. W. Chan, W. C. Fu, K. TI The miRNA-17 similar to 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation SO LEUKEMIA LA English DT Article DE miR-17 similar to 92 cluster; mantle cell lymphoma; PHLPP2; PTEN; PI3K/AKT pathway ID MICRORNA CLUSTER; MALIGNANT-LYMPHOMA; EXPRESSION; GENE; PROLIFERATION; MIR-17-92; BIM; PROMOTES; IDENTIFICATION; AMPLIFICATION AB The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17 similar to 92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P = 0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17 similar to 92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17 similar to 92 cluster. Overexpression of miR-17 similar to 92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17 similar to 92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17 similar to 92 cluster may therefore provide a novel therapeutic approach for patients with MCL. C1 [Rao, E.; Jiang, C.; Ji, M.; Huang, X.; Iqbal, J.; McKeithan, T. W.; Chan, W. C.; Fu, K.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Rao, E.; Jiang, C.; Ji, M.; Huang, X.; Iqbal, J.; McKeithan, T. W.; Chan, W. C.; Fu, K.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE 68198 USA. [Rao, E.; Zhao, Y.] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Transplantat Biol Res Div, Beijing, Peoples R China. [Rao, E.] Chinese Acad Sci, Grad Sch, Beijing, Peoples R China. [Lenz, G.] Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany. [Lenz, G.; Staudt, L. M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wright, G.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Fu, K (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. EM kfu@unmc.edu RI Lenz, Georg/I-6844-2012; Huang, Xin/P-8103-2014; OI Huang, Xin/0000-0001-6778-8849; McKeithan, Timothy/0000-0003-2242-3074 FU National Institutes of Health [U01 CA114778]; Lymphoma Research Foundation/Millennium Pharmaceuticals, Inc.; UNMC Eppley Cancer Center; China Scholarship Council FX This work was supported in part by the National Institutes of Health grant U01 CA114778 to WCC; the Lymphoma Research Foundation/Millennium Pharmaceuticals, Inc. Clinical Investigator Career Development Award to KF; and UNMC Eppley Cancer Center Pilot Grant to KF; MJ and XH are supported by a scholarship from the China Scholarship Council. NR 51 TC 80 Z9 85 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2012 VL 26 IS 5 BP 1064 EP 1072 DI 10.1038/leu.2011.305 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 940IP UT WOS:000303883500026 PM 22116552 ER PT J AU Moore, CR Liu, Y Shao, C Covey, LR Morse, HC Xie, P AF Moore, C. R. Liu, Y. Shao, C. Covey, L. R. Morse, H. C., III Xie, P. TI Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in mice SO LEUKEMIA LA English DT Letter ID MULTIPLE-MYELOMA; CELL HOMEOSTASIS; PATHWAYS; ABNORMALITIES; MUTATIONS; SURVIVAL; RECEPTOR; KINASE; NIK C1 [Moore, C. R.; Liu, Y.; Covey, L. R.; Xie, P.] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. [Shao, C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Morse, H. C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. RP Moore, CR (reprint author), Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. EM xiep@rci.rutgers.edu OI Morse, Herbert/0000-0002-9331-3705; Shao, Changshun/0000-0003-2618-9342 FU Intramural NIH HHS [ZIA AI000858-12]; NCI NIH HHS [R01 CA158402, P30 CA072720, P30CA072720] NR 15 TC 16 Z9 18 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2012 VL 26 IS 5 BP 1122 EP 1127 DI 10.1038/leu.2011.309 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 940IP UT WOS:000303883500037 PM 22033491 ER PT J AU Burd, CJ Ward, JM Crusselle-Davis, VJ Kissling, GE Phadke, D Shah, RR Archer, TK AF Burd, Craig J. Ward, James M. Crusselle-Davis, Valerie J. Kissling, Grace E. Phadke, Dhiral Shah, Ruchir R. Archer, Trevor K. TI Analysis of Chromatin Dynamics during Glucocorticoid Receptor Activation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTORS; IN-VIVO; REGULATORY ELEMENTS; NUCLEAR RECEPTORS; BREAST-CANCER; MMTV PROMOTER; GENE; COACTIVATORS; COMPLEX; BINDING AB Steroid hormone receptors initiate a genetic program tightly regulated by the chromatin environment of the responsive regions. Using the glucocorticoid receptor (GR) as a model factor for transcriptional initiation, we classified chromatin structure through formaldehyde-assisted isolation of regulatory elements (FAIRE). We looked at dynamic changes in FAIRE signals during GR activation specifically at regions of receptor interaction. We found a distribution of GR-responsive regions with diverse responses to activation and chromatin modulation. The majority of GR binding regions demonstrate increases in FAIRE signal in response to ligand. However, the majority GR-responsive regions shared a similar FAIRE signal in the basal chromatin state, suggesting a common chromatin structure for GR recruitment. Supporting this notion, global FAIRE sequencing (seq) data indicated an enrichment of signal surrounding the GR binding site prior to activation. Brg-1 knockdown showed response element-specific effects of ATPase-dependent chromatin remodeling. FAIRE induction was universally decreased by Brg-1 depletion, but to varying degrees in a target specific manner. Taken together, these data suggest classes of nuclear receptor response regions that react to activation through different chromatin regulatory events and identify a chromatin structure that classifies the majority of response elements tested. C1 [Burd, Craig J.; Crusselle-Davis, Valerie J.; Archer, Trevor K.] Natl Inst Environm Hlth Sci, Chromatin & Gene Express Grp, Mol Carcinogenesis Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. [Phadke, Dhiral; Shah, Ruchir R.] SRA Int, Durham, NC USA. RP Archer, TK (reprint author), Natl Inst Environm Hlth Sci, Chromatin & Gene Express Grp, Mol Carcinogenesis Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC USA. EM archer1@niehs.nih.gov OI Burd, Craig/0000-0002-6899-6751 FU NIH, National Institute of Environmental Health Sciences [Z01 ES071006-11] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES071006-11). NR 46 TC 20 Z9 20 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2012 VL 32 IS 10 BP 1805 EP 1817 DI 10.1128/MCB.06206-11 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 939TP UT WOS:000303840100004 PM 22451486 ER PT J AU Postnikov, YV Kurahashi, T Zhou, M Bustin, M AF Postnikov, Yuri V. Kurahashi, Toshihiro Zhou, Ming Bustin, Michael TI The Nucleosome Binding Protein HMGN1 Interacts with PCNA and Facilitates Its Binding to Chromatin SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEAR ANTIGEN PCNA; CHROMOSOMAL-PROTEINS; DNA-DAMAGE; HISTONE H1; MISMATCH REPAIR; LIVING CELLS; IN-VIVO; REPLICATION; ACTIVATION; MOBILITY AB Proliferating cell nuclear antigen (PCNA) is a ubiquitous protein that interacts with multiple partners and regulates nuclear activities, including chromatin assembly, histone modifications, replication, and DNA damage repair. The role of specific partners in regulating PCNA activities is not fully understood. Here we identify the nucleosome binding protein HMGN1 as a new PCNA-interacting protein that enhances the binding of PCNA to chromatin but not to purified DNA. Two tetrapeptides in the conservative domain of HMGN1 contain amino acids necessary for the binding of HMGN1 to PCNA. Deletion of both tetrapeptides abolishes the HMGN1-PCNA interaction. PCNA preferentially binds to the linker DNA adjacent to an HMGN-containing nucleosome. In living cells, loss of HMGN1 decreases the rate of PCNA recruitment to damaged DNA sites. Our study identifies a new factor that facilitates the interaction of PCNA with chromatin and provides insights into mechanisms whereby nucleosome binding architectural proteins affect the cellular phenotype. C1 [Postnikov, Yuri V.; Kurahashi, Toshihiro; Bustin, Michael] NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. [Zhou, Ming] NCI, Lab Prote & Analyt Technol, NIH, Frederick, MD 21701 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research, NCI, NIH; NCI, NIH [N01-CO-12400]; JSPS from the Japanese Biomedical and Behavioral Research at NIH FX This project was supported by the Center for Cancer Research, intramural program of the NCI, NIH, by contract number N01-CO-12400 granted by NCI, NIH, and by a JSPS research fellowship from the Japanese Biomedical and Behavioral Research at NIH to T.K. The yeast RFC and human RFC preparations were generous gifts from Paul Modrich (Duke University). NR 48 TC 10 Z9 10 U1 2 U2 6 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 MAY PY 2012 VL 32 IS 10 BP 1844 EP 1854 DI 10.1128/MCB.06429-11 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 939TP UT WOS:000303840100007 PM 22393258 ER PT J AU Bhatt, S Xiao, Z Meng, ZJ Katzenellenbogen, BS AF Bhatt, Shweta Xiao, Zhen Meng, Zhaojing Katzenellenbogen, Benita S. TI Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen Receptor alpha Turnover and Functional Activity via the SCFSkp2 Proteasomal Complex SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BREAST-CANCER-CELLS; HUMAN PROGESTERONE-RECEPTORS; UBIQUITIN LIGASE; TAMOXIFEN RESISTANCE; AROMATASE INHIBITORS; GENE-EXPRESSION; ER-ALPHA; TRANSCRIPTIONAL ACTIVITY; ENDOCRINE RESISTANCE; 26S PROTEASOME AB The nuclear hormone receptor estrogen receptor alpha (ER alpha) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ER alpha in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ER alpha are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK) -mediated phosphorylation of ER alpha at Ser-294 that specifies its turnover by the SCFSkp2 proteasome complex. Consistently, we observed an inverse relationship between ER alpha and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ER alpha regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ER alpha. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ER alpha protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ER alpha-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ER alpha and the responsiveness to endocrine therapy in some endocrine-insensitive ER alpha-negative breast cancers. C1 [Katzenellenbogen, Benita S.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL USA. [Bhatt, Shweta] Univ Illinois, Dept Biochem, Urbana, IL USA. [Xiao, Zhen; Meng, Zhaojing] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Katzenellenbogen, BS (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL USA. EM katzenel@uiuc.edu FU NIH (National Center for Complementary and Alternative Medicines [NCCAM]) [1 P50 AT006268]; NIH (Office of Dietary Supplements [ODS]); NIH (National Cancer Institute [NCI]) [HHSN261200800001E]; Breast Cancer Research Foundation FX This work was supported by a grant from the NIH (1 P50 AT006268 [B.S.K.] from the National Center for Complementary and Alternative Medicines [NCCAM], the Office of Dietary Supplements [ODS], and the National Cancer Institute [NCI]). This work was also supported by a grant from The Breast Cancer Research Foundation (B.S.K.) and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E (Z.X. and Z.M.). NR 59 TC 23 Z9 26 U1 0 U2 4 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 MAY PY 2012 VL 32 IS 10 BP 1928 EP 1943 DI 10.1128/MCB.06561-11 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 939TP UT WOS:000303840100014 PM 22431515 ER PT J AU Gegonne, A Tai, XG Zhang, JH Wu, G Zhu, JJ Yoshimoto, A Hanson, J Cultraro, C Chen, QR Guinter, T Yang, ZH Hathcock, K Singer, A Rodriguez-Canales, J Tessarollo, L Mackem, S Meerzaman, D Buetow, K Singer, DS AF Gegonne, Anne Tai, Xuguang Zhang, Jinghui Wu, Gang Zhu, Jianjian Yoshimoto, Aki Hanson, Jeffrey Cultraro, Constance Chen, Qing-Rong Guinter, Terry Yang, Zhihui Hathcock, Karen Singer, Alfred Rodriguez-Canales, Jaime Tessarollo, Lino Mackem, Susan Meerzaman, Daoud Buetow, Ken Singer, Dinah S. TI The General Transcription Factor TAF7 Is Essential for Embryonic Development but Not Essential for the Survival or Differentiation of Mature T Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; INSERTIONAL MUTAGENESIS; PROMOTER; INITIATION; ZEBRAFISH; COMPLEX; EMBRYOGENESIS; MACHINERY; SIGNALS; BINDING AB TAF7, a component of the TFIID complex that nucleates the assembly of transcription preinitiation complexes, also independently interacts with and regulates the enzymatic activities of other transcription factors, including P-TEFb, TFIIH, and CIITA, ensuring an orderly progression in transcription initiation. Since not all TAFs are required in terminally differentiated cells, we examined the essentiality of TAF7 in cells at different developmental stages in vivo. Germ line disruption of the TAF7 gene is embryonic lethal between 3.5 and 5.5 days postcoitus. Mouse embryonic fibroblasts with TAF7 deleted cease transcription globally and stop proliferating. In contrast, whereas TAF7 is essential for the differentiation and proliferation of immature thymocytes, it is not required for subsequent, proliferation-independent differentiation of lineage committed thymocytes or for their egress into the periphery. TAF7 deletion in peripheral CD4 T cells affects only a small number of transcripts. However, T cells with TAF7 deleted are not able to undergo activation and expansion in response to antigenic stimuli. These findings suggest that TAF7 is essential for proliferation but not for proliferation-independent differentiation. C1 [Gegonne, Anne; Tai, Xuguang; Guinter, Terry; Hathcock, Karen; Singer, Alfred; Singer, Dinah S.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhang, Jinghui; Wu, Gang; Cultraro, Constance; Yang, Zhihui; Meerzaman, Daoud; Buetow, Ken] NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hanson, Jeffrey; Rodriguez-Canales, Jaime] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhu, Jianjian; Yoshimoto, Aki; Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Chen, Qing-Rong] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singerd@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU U.S. National Institutes of Health, the National Cancer Institute and the Center for Cancer Research FX This study was supported by the Intramural Research Program of the U.S. National Institutes of Health, the National Cancer Institute and the Center for Cancer Research. NR 39 TC 14 Z9 14 U1 0 U2 2 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 MAY PY 2012 VL 32 IS 10 BP 1984 EP 1997 DI 10.1128/MCB.06305-11 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 939TP UT WOS:000303840100018 PM 22411629 ER PT J AU Hastings, CE Fisher, CA McCabe, MA AF Hastings, Clare E. Fisher, Cheryl A. McCabe, Margaret A. CA Natl Clin Res Nursing Consortium TI Clinical research nursing: A critical resource in the national research enterprise SO NURSING OUTLOOK LA English DT Article DE Clinical research; Research nursing; Clinical trials; Good Clinical Practice AB Translational clinical research has emerged as an important priority for the national research enterprise, with a clearly stated mandate to more quickly deliver prevention strategies, treatments and cures based on scientific innovations to the public. Within this national effort, a lack of consensus persists concerning the need for clinical nurses with expertise and specialized training in study implementation and the delivery of care to research participants. This paper reviews efforts to define and document the role of practicing nurses in implementing studies and coordinating clinical research in a variety of clinical settings, and differentiates this clinical role from the role of nurses as scientists and principal investigators. We propose an agenda for building evidence that having nurses provide and coordinate study treatments and procedures can potentially improve research efficiency, participant safety, and the quality of research data. We also provide recommendations for the development of the emerging specialty of clinical research nursing. Cite this article: Hastings, C. E., Fisher, C. A., & McCabe, M. A. (2012, JUNE). Clinical research nursing: A critical resource in the national research enterprise. Nursing Outlook, 60(3), 149-156. doi:10.1016/j.outlook.2011.10.003. C1 [Hastings, Clare E.; Fisher, Cheryl A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [McCabe, Margaret A.] Boston Childrens Hosp, Boston, MA USA. RP Hastings, CE (reprint author), NIH, Ctr Clin, Bldg 10,Room 6-1484,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chastings@cc.nih.gov FU Clinical Center, from the National Center for Research Resources, a component of the National Institutes of Health [MO1-RR02172]; Children's Hospital Boston, General Clinical Research Center FX This work was supported in part by the Intramural Research Program of the NIH, Clinical Center (Hastings and Fisher), Grant Number MO1-RR02172, from the National Center for Research Resources, a component of the National Institutes of Health, and the Children's Hospital Boston, General Clinical Research Center (McCabe). NR 0 TC 13 Z9 14 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD MAY-JUN PY 2012 VL 60 IS 3 BP 149 EP 156 DI 10.1016/j.outlook.2011.10.003 PG 8 WC Nursing SC Nursing GA 944DK UT WOS:000304178400008 PM 22172370 ER PT J AU Colburn, NH Bobe, G Mentor-Marcel, R Hartman, TJ Chapkin, R Lanza, E Milner, J Kim, Y Cross, A Young, MR AF Colburn, Nancy H. Bobe, Gerd Mentor-Marcel, Roycelynn Hartman, Terryl J. Chapkin, Robb Lanza, Elaine Milner, John Kim, Young Cross, Amanda Young, Matthew R. TI DIETARY PREVENTION OF COLON CARCINOGENESIS AND DISCOVERY OF PREDICTIVE BIOMARKERS SO PHARMACEUTICAL BIOLOGY LA English DT Meeting Abstract C1 [Colburn, Nancy H.; Bobe, Gerd; Mentor-Marcel, Roycelynn; Young, Matthew R.] NCI, CCR, NIH, Lab Canc Prevent, Frederick, MD 21702 USA. [Bobe, Gerd; Mentor-Marcel, Roycelynn] NCI, Prevent Oncol Program Canc Prevent Fellowship, Rockville, MD USA. [Hartman, Terryl J.] Penn State Univ, State Coll, PA USA. [Chapkin, Robb] Texas A&M Univ, College Stn, TX USA. [Milner, John; Kim, Young] NCI, Canc Prevent Div, Rockville, MD USA. [Cross, Amanda] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM colburna@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD MAY PY 2012 VL 50 IS 5 BP 627 EP 628 PG 2 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 943GN UT WOS:000304108700265 ER PT J AU Hicks, J Luchsinger, S Killday, B Kostikin, P Muhammad, A Arnason, J Berrue, F Kirby, C Knagge, K Zhao, JP Khan, I Goedecke, T Pauli, G Luo, WB Benesi, A Popplewel, W Gustafson, K Karakach, T Burton, I O'Neil-Johnson, M Colson, K AF Hicks, Josh Luchsinger, Sarah Killday, Brian Kostikin, Pavel Muhammad, Asim Arnason, John Berrue, Fabrice Kirby, Chris Knagge, Kevin Zhao, Jianping Khan, Ikhlas Goedecke, Tanja Pauli, Guido Luo, Wenbin Benesi, Alan Popplewel, Wendy Gustafson, Kirk Karakach, Tobias Burton, Ian O'Neil-Johnson, Mark Colson, Kim TI MULTILAB METHOD VALIDATION OF BLUEBERRY LEAF EXTRACT BY NMR: QUALITATIVE AND QUANTITATIVE SO PHARMACEUTICAL BIOLOGY LA English DT Meeting Abstract C1 [Hicks, Josh; Luchsinger, Sarah; Killday, Brian; Kostikin, Pavel; Colson, Kim] Bruker BioSpin, Billerica, MA 01821 USA. [Muhammad, Asim; Arnason, John] U Ottawa, Ottawa, ON K1N 6N5, Canada. [Berrue, Fabrice] U PEI, Charlottetown, PE C1A 4P3, Canada. [Kirby, Chris] Agr & Agri Food Canada, Charlottetown, PE C1A 4N6, Canada. [Knagge, Kevin] Murdock Res Inst, Kannapolis, NC 28081 USA. [Zhao, Jianping; Khan, Ikhlas] U Mississippi, Oxford, MS 38677 USA. [Goedecke, Tanja; Pauli, Guido] U Illinois Chicago, Chicago, IL 60680 USA. [Luo, Wenbin; Benesi, Alan] Penn State U, University Pk, PA 16802 USA. [Popplewel, Wendy; Gustafson, Kirk] NCI, Frederick, MD 21702 USA. [Karakach, Tobias; Burton, Ian] NRC, Halifax, NS B3H 3Z1, Canada. [O'Neil-Johnson, Mark] Sequoia Sci, St Louis, MO 63114 USA. EM kim.colson@bruker-biospin.com NR 0 TC 0 Z9 0 U1 2 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD MAY PY 2012 VL 50 IS 5 BP 641 EP 641 PG 1 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 943GN UT WOS:000304108700306 ER PT J AU Pacher, P AF Pacher, Pal TI NONPSYCHOACTIVE CONSTITUENTS FROM CANNABIS SATIVA (MARIJUANA): THERAPEUTIC POTENTIAL IN INFLAMMATORY DISORDERS AND DIABETES SO PHARMACEUTICAL BIOLOGY LA English DT Meeting Abstract C1 [Pacher, Pal] NIAAA, NIH, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD 20852 USA. EM pacher@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD MAY PY 2012 VL 50 IS 5 BP 643 EP 643 PG 1 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 943GN UT WOS:000304108700312 ER PT J AU Rackley, S Pao, M Seratti, GF Gin, N Rasimas, JJ Alter, BP Savage, SA AF Rackley, Sandra Pao, Maryland Seratti, Guillermo F. Gin, Neelam Rasimas, J. J. Alter, Blanche P. Savage, Sharon A. TI Neuropsychiatric Conditions Among Patients with Dyskeratosis Congenita: A Link with Telomere Biology? SO PSYCHOSOMATICS LA English DT Article ID CELL TRANSPLANTATION; LENGTH; SCHIZOPHRENIA; DISORDERS; MALIGNANCIES; DISEASE; STRESS; CANCER AB Background: Dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), is caused by defects in telomere biology, which result in very short germ line telomeres. Telomeres, long nucleotide repeats and a protein complex at chromosome ends, are essential for chromosomal stability. Several association studies suggest that short telomeres are associated with certain psychiatric disorders, including mood disorders and schizophrenia. There are two cases in the literature of schizophrenia and DC occurring as co-morbid conditions. We noted that many patients with DC in our cohort had neuropsychiatric conditions. Methods: Subjects were participants in NCI's IBMFS prospective cohort study. Psychiatric evaluation was incorporated into our clinical assessment in January 2009. Fourteen DC or DC-like patients, including six children, were evaluated in this study through in person interview by either a psychiatrist specialized in psychosomatic medicine or a child and adolescent psychiatrist. Results: Three of the six pediatric subjects and five of the eight adults had a neuropsychiatric condition such as a mood, anxiety, or adjustment disorder, intellectual disability, attention deficit hyperactivity disorder, or pervasive developmental disorders. The lifetime occurrence of any of these disorders in our study was 83% in pediatric subjects and 88% in adults. Notably, the literature reports neuropsychiatric conditions in 25% and 38% in chronically ill children and adults, respectively. Conclusion: This pilot study suggests that patients with DC may have higher rates of neuropsychiatric conditions than the general population or other chronically ill individuals. This potential link between very short telomeres and neuropsychiatric conditions warrants further study. (Psychosomatics 2012; 53:230-235) C1 [Seratti, Guillermo F.; Gin, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Rackley, Sandra] Childrens Natl Med Ctr, Dept Psychiat & Behav Sci, Washington, DC 20010 USA. [Pao, Maryland] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Rasimas, J. J.] Penn State Coll Med, Dept Psychiat, Hershey, PA USA. [Rasimas, J. J.] NIMH, Expt & Therapeut Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7018, Rockville, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Westat, Inc. (NIH) [N02-CP-11019, N02-CP-65504, N02-CP-65501]; National Cancer Institute; National Institute of Mental Health, National Institutes of Health FX The authors thank the patients and families who have generously contributed to their understanding of dyskeratosis congenita and telomere biology disorders. Lisa Leathwood, RN, Westat, Inc. (NIH contracts N02-CP-11019, N02-CP-65504 and N02-CP-65501) provided outstanding study support. This work was funded by the intramural research programs of the National Cancer Institute and the National Institute of Mental Health, National Institutes of Health. NR 27 TC 8 Z9 9 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAY-JUN PY 2012 VL 53 IS 3 BP 230 EP 235 PG 6 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 941MV UT WOS:000303968200004 PM 22458992 ER PT J AU Wallwork, RS Fortgang, R Hashimoto, R Weinberger, DR Dickinson, D AF Wallwork, R. S. Fortgang, R. Hashimoto, R. Weinberger, D. R. Dickinson, D. TI Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Symptoms; Cognition; PANSS ID CONFIRMATORY FACTOR-ANALYSIS; ONSET SCHIZOPHRENIA; SYMPTOM DIMENSIONS; PANSS; VALIDATION; PSYCHOSIS; STABILITY; VALIDITY; RISK AB Although the developers of the Positive and Negative Syndrome Scale (PANSS) grouped items into three subscales, factor analyses indicate that a five-factor model better characterizes PANSS data. However, lack of consensus on which model to use limits the comparability of PANSS variables across studies. We counted "votes" from published factor analyses to derive consensus models. One of these combined superior fit in our Caucasian sample (n=458, CFI=.970), and in distinct Japanese sample (n=164, CFI=.964), relative to the original three-subscale model, with a sorting of items into factors that was highly consistent across the studies reviewed. Published by Elsevier B.V. C1 [Wallwork, R. S.; Fortgang, R.; Weinberger, D. R.; Dickinson, D.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Hashimoto, R.] Osaka Univ, Dept Psychiat, Grad Sch Med, Osaka, Japan. [Weinberger, D. R.] Japan Sci & Technol Agcy JST, CREST, Saitama, Japan. [Weinberger, D. R.] Johns Hopkins Med Ctr, Lieber Inst Brain Dev, Baltimore, MD USA. RP Dickinson, D (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 7SE-5335, Bethesda, MD 20892 USA. EM Dwight.Dickinson@nih.gov RI Hashimoto, Ryota/P-8572-2014 OI Hashimoto, Ryota/0000-0002-5941-4238 FU National Institute of Mental Health FX Funding for this study was provided by the Intramural Research Program of the National Institute of Mental Health; the NIMH IRP had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 42 TC 122 Z9 124 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAY PY 2012 VL 137 IS 1-3 BP 246 EP 250 DI 10.1016/j.schres.2012.01.031 PG 5 WC Psychiatry SC Psychiatry GA 941AI UT WOS:000303933800040 PM 22356801 ER PT J AU Geldmacher, C Koup, RA AF Geldmacher, Christof Koup, Richard A. TI Pathogen-specific T cell depletion and reactivation of opportunistic pathogens in HIV infection SO TRENDS IN IMMUNOLOGY LA English DT Review ID SIMIAN IMMUNODEFICIENCY VIRUS; MUCOSAL HOMING RECEPTOR; HUMAN LYMPHOID-TISSUE; HUMAN-PAPILLOMAVIRUS; SIV INFECTION; MEMORY CD4(+); INTEGRIN ALPHA(4)BETA(7); ANTIRETROVIRAL THERAPY; GASTROINTESTINAL-TRACT; DISEASE PROGRESSION AB During HIV infection, it is unclear why different opportunistic pathogens cause disease at different CD4 T cell count thresholds. Early work has shown that CD4 T cell depletion is influenced both by cellular activation status and expression of viral entry receptors. More recently, functional characteristics; of the CD4 T cells, such as cytokine and chemokine production, have also been shown to influence cellular susceptibility to HIV. Here, we examine how functional differences in pathogen-specific CD4 T cells could lead to their differential loss during HIV infection. This may have implications for when different opportunistic infections occur, and a better understanding of the mechanisms for functional imprinting of antigen-specific T cells may lead to improvements in design of vaccines against HIV and opportunistic pathogens. C1 [Geldmacher, Christof] Univ Munich LMU, Div Infect Dis & Trop Med, Med Ctr, Munich, Germany. [Geldmacher, Christof] Univ Munich LMU, Natl Ctr Infect Dis Germany, Med Ctr, Munich, Germany. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Geldmacher, C (reprint author), Univ Munich LMU, Div Infect Dis & Trop Med, Med Ctr, Munich, Germany. EM geldmacher@lrz.uni-muenehen.de FU Intramural NIH HHS [ZIA AI005014-10, ZIA AI005015-10] NR 92 TC 14 Z9 14 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD MAY PY 2012 VL 33 IS 5 BP 207 EP 214 DI 10.1016/j.it.2012.01.011 PG 8 WC Immunology SC Immunology GA 942UV UT WOS:000304076400002 PM 22398371 ER PT J AU Manolio, TA Weis, BK Cowie, CC Hoover, RN Hudson, K Kramer, BS Berg, C Collins, R Ewart, W Gaziano, JM Hirschfeld, S Marcus, PM Masys, D McCarty, CA McLaughlin, J Patel, AV Peakman, T Pedersen, NL Schaefer, C Scott, JA Sprosen, T Walport, M Collins, FS AF Manolio, Teri A. Weis, Brenda K. Cowie, Catherine C. Hoover, Robert N. Hudson, Kathy Kramer, Barnett S. Berg, Chris Collins, Rory Ewart, Wendy Gaziano, J. Michael Hirschfeld, Steven Marcus, Pamela M. Masys, Daniel McCarty, Catherine A. McLaughlin, John Patel, Alpa V. Peakman, Tim Pedersen, Nancy L. Schaefer, Catherine Scott, Joan A. Sprosen, Timothy Walport, Mark Collins, Francis S. TI New Models for Large Prospective Studies: Is There a Better Way? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE cohort studies; epidemiology; prospective studies ID GENOME-WIDE ASSOCIATION; PROSPECTIVE COHORT; DESIGN; GENES; FEASIBILITY; RECRUITMENT; ENVIRONMENT; PROSTATE AB Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the "UK Biobank," which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which "process" expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin. C1 [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Weis, Brenda K.; Kramer, Barnett S.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bethesda, MD 20892 USA. [Cowie, Catherine C.] NIDDK, Bethesda, MD USA. [Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hudson, Kathy; Collins, Francis S.] NIH, Off Director, Bethesda, MD 20892 USA. [Berg, Chris] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Collins, Rory] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Collins, Rory] Univ Oxford, Epidemiol Studies Unit, Oxford, England. [Ewart, Wendy] MRC, London, England. [Gaziano, J. Michael] Boston VA Med Ctr, Boston, MA USA. [Hirschfeld, Steven] NICHHD, Bethesda, MD 20892 USA. [Marcus, Pamela M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Masys, Daniel] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [McCarty, Catherine A.] Essentia Inst Hlth Res, Duluth, MN USA. [McLaughlin, John] Canc Care Ontario, Toronto, ON, Canada. [McLaughlin, John] Ontario Inst Canc Res, Toronto, ON, Canada. [Patel, Alpa V.] Amer Canc Soc, Canc Prevent Study 3, Atlanta, GA 30329 USA. [Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Schaefer, Catherine] Kaiser Permanente Program Genes Environm & Hlth, Oakland, CA USA. [Scott, Joan A.] Natl Coalit Hlth Profess Educ Genet, Washington, DC USA. [Sprosen, Timothy] Univ London Imperial Coll Sci Technol & Med, London, England. [Walport, Mark] Wellcome Trust Res Labs, London, England. RP Manolio, TA (reprint author), NHGRI, Off Populat Genom, 5635 Fishers Lane,Suite 3058,MSC 9307, Bethesda, MD 20892 USA. EM manolio@nih.gov RI McLaughlin, John/E-4577-2013; OI Walport, Mark/0000-0001-7220-5273 FU Medical Research Council [MC_QA137853] NR 29 TC 43 Z9 45 U1 1 U2 17 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 MAY 1 PY 2012 VL 175 IS 9 BP 859 EP 866 DI 10.1093/aje/kwr453 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 937IU UT WOS:000303653000001 PM 22411865 ER PT J AU Tsilidis, KK Travis, RC Appleby, PN Allen, NE Lindstrom, S Schumacher, FR Cox, D Hsing, AW Ma, J Severi, G Albanes, D Virtamo, J Boeing, H Bueno-de-Mesquita, HB Johansson, M Quiros, JR Riboli, E Siddiq, A Tjonneland, A Trichopoulos, D Tumino, R Gaziano, JM Giovannucci, E Hunter, DJ Kraft, P Stampfer, MJ Giles, GG Andriole, GL Berndt, SI Chanock, SJ Hayes, RB Key, TJ AF Tsilidis, Konstantinos K. Travis, Ruth C. Appleby, Paul N. Allen, Naomi E. Lindstrom, Sara Schumacher, Fredrick R. Cox, David Hsing, Ann W. Ma, Jing Severi, Gianluca Albanes, Demetrius Virtamo, Jarmo Boeing, Heiner Bueno-de-Mesquita, H. Bas Johansson, Mattias Ramon Quiros, J. Riboli, Elio Siddiq, Afshan Tjonneland, Anne Trichopoulos, Dimitrios Tumino, Rosario Gaziano, J. Michael Giovannucci, Edward Hunter, David J. Kraft, Peter Stampfer, Meir J. Giles, Graham G. Andriole, Gerald L. Berndt, Sonja I. Chanock, Stephen J. Hayes, Richard B. Key, Timothy J. TI Interactions Between Genome-wide Significant Genetic Variants and Circulating Concentrations of Insulin-like Growth Factor 1, Sex Hormones, and Binding Proteins in Relation to Prostate Cancer Risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE gene-environment interaction; gonadal steroid hormones; insulin-like growth factor binding protein 3; insulin-like growth factor I; molecular epidemiology; prostatic neoplasms ID STEROID-HORMONES; FACTOR-I; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS; FREE TESTOSTERONE; SUBSEQUENT RISK; SERUM ANDROGENS; ASSOCIATION; 8Q24; IDENTIFICATION AB Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins. C1 [Tsilidis, Konstantinos K.; Travis, Ruth C.; Appleby, Paul N.; Allen, Naomi E.; Key, Timothy J.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Lindstrom, Sara; Albanes, Demetrius; Giovannucci, Edward; Kraft, Peter; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cox, David] Ctr Leon Berard, Lyon Canc Res Ctr, INSERM U1052, F-69373 Lyon, France. [Cox, David; Riboli, Elio; Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Hsing, Ann W.; Albanes, Demetrius; Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ma, Jing; Giovannucci, Edward; Hunter, David J.; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Ma, Jing; Gaziano, J. Michael; Giovannucci, Edward; Hunter, David J.; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA USA. [Severi, Gianluca; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Severi, Gianluca; Giles, Graham G.] Univ Melbourne, Ctr Mol Genet Environm & Analyt Epidemiol, Melbourne, Vic, Australia. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Boeing, Heiner] German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, Ctr Nutr & Hlth, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Johansson, Mattias] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Ramon Quiros, J.] Publ Hlth & Hlth Planning Directorate, Asturias, Spain. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Tumino, Rosario] Civile MP Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Gaziano, J. Michael] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr, Boston, MA USA. [Gaziano, J. Michael] Boston Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Lindstrom, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Div Epidemiol, Sch Med, New York, NY 10016 USA. RP Tsilidis, KK (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. EM kostas.tsilidis@ceu.ox.ac.uk RI Cox, David/A-2023-2009; Albanes, Demetrius/B-9749-2015 OI Cox, David/0000-0002-2152-9259; FU US National Cancer Institute [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; US National Institutes of Health; Australian National Health and Medical Research Council [209057, 251553, 450104]; Cancer Research UK FX This study was supported by the US National Cancer Institute (grant U01-CA98233-07 to Dr. David J. Hunter, grant U01-CA98710-06 to Dr. Michael J. Thun, grant U01-CA98216-06 to Drs. Elio Riboli and Rudolf Kaaks, and grant U01-CA98758-07 to Dr. Brian E. Henderson) and by a grant from the Intramural Research Program of the US National Institutes of Health. The Melbourne Collaborative Cohort Study was supported by grants 209057, 251553, and 450104 from the Australian National Health and Medical Research Council and by infrastructure provided by Cancer Council Victoria. Dr. Konstantinos K. Tsilidis was supported by Cancer Research UK. NR 42 TC 9 Z9 9 U1 0 U2 10 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 MAY 1 PY 2012 VL 175 IS 9 BP 926 EP 935 DI 10.1093/aje/kwr423 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 937IU UT WOS:000303653000010 PM 22459122 ER PT J AU Williams, PL Seage, GR Van Dyke, RB Siberry, GK Griner, R Tassiopoulos, K Yildirim, C Read, JS Huo, YL Hazra, R Jacobson, DL Mofenson, LM Rich, K AF Williams, Paige L. Seage, George R., III Van Dyke, Russell B. Siberry, George K. Griner, Raymond Tassiopoulos, Katherine Yildirim, Cenk Read, Jennifer S. Huo, Yanling Hazra, Rohan Jacobson, Denise L. Mofenson, Lynne M. Rich, Kenneth CA Pediat HIV AIDS Cohort Study TI A Trigger-based Design for Evaluating the Safety of In Utero Antiretroviral Exposure in Uninfected Children of Human Immunodeficiency Virus-Infected Mothers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE antiretroviral; asymptotic relative efficiency; HIV-exposed; infants; outcome-dependent sampling; safety; surveillance ID PERSISTENT MITOCHONDRIAL DYSFUNCTION; MEDICATION-RELATED HARM; PERINATAL EXPOSURE; UNITED-STATES; HIV; TRANSMISSION; WOMEN; INFANTS; PREGNANCY; DRUGS AB The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites between 2007 and 2011 that was designed to evaluate the safety of in utero antiretroviral drug exposure in children not infected with human immunodeficiency virus who were born to mothers who were infected. This ongoing study uses a "trigger-based" design; that is, initial assessments are conducted on all children, and only those meeting certain thresholds or "triggers" undergo more intensive evaluations to determine whether they have had an adverse event (AE). The authors present the estimated rates of AEs for each domain of interest in the Surveillance Monitoring of ART Toxicities Study. They also evaluated the efficiency of this trigger-based design for estimating AE rates and for testing associations between in utero exposures to antiretroviral drugs and AEs. The authors demonstrate that estimated AE rates from the trigger-based design are unbiased after correction for the sensitivity of the trigger for identifying AEs. Even without correcting for bias based on trigger sensitivity, the trigger approach is generally more efficient for estimating AE rates than is evaluating a random sample of the same size. Minor losses in efficiency when comparing AE rates between persons exposed and unexposed in utero to particular antiretroviral drugs or drug classes were observed under most scenarios. C1 [Williams, Paige L.; Seage, George R., III; Griner, Raymond; Tassiopoulos, Katherine; Yildirim, Cenk; Huo, Yanling; Jacobson, Denise L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Seage, George R., III; Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Van Dyke, Russell B.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Siberry, George K.; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Read, Jennifer S.] Dept Hlth & Human Serv, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Off Secretary, Washington, DC USA. [Rich, Kenneth] Univ Illinois, Chicago, IL USA. RP Williams, PL (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 665 Huntington Ave,FXB-607, Boston, MA 02115 USA. EM paige@sdac.harvard.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism, through Harvard University School of Public Health [U01 HD052102-04]; Tulane University School of Medicine [U01 HD052104-01] FX The Pediatric HIV/AIDS Cohort Study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with co-funding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (U01 HD052104-01) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (Principal Investigator: Julie Davidson). NR 40 TC 17 Z9 17 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 MAY 1 PY 2012 VL 175 IS 9 BP 950 EP 961 DI 10.1093/aje/kwr401 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 937IU UT WOS:000303653000012 PM 22491086 ER PT J AU Avila, N Crocker, M Millo, C Niyyati, M VanRyzin, C Dwyer, A Merke, D AF Avila, N. Crocker, M. Millo, C. Niyyati, M. VanRyzin, C. Dwyer, A. Merke, D. TI Ectopic Adrenal Rest Tissue in Patients With Congenital Adrenal Hyperplasia: Imaging Characteristics and Localization SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Roentgen-Ray-Society CY APR 29-MAY 04, 2012 CL Vancouver, CANADA SP Amer Roentgen Ray Soc C1 [Avila, N.] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Avila, N.] NHLBI, NIH, Bethesda, MD 20892 USA. [Crocker, M.] Childrens Hosp, Boston, MA 02115 USA. [Millo, C.; Niyyati, M.; VanRyzin, C.; Merke, D.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [VanRyzin, C.; Merke, D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM nilo.avila@va.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2012 VL 198 IS 5 SU S PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 937OI UT WOS:000303667400719 ER PT J AU Linguraru, M Sandberg, J Petrick, N Summers, R AF Linguraru, M. Sandberg, J. Petrick, N. Summers, R. TI Hepatic Volumetric Nomograms From Automated Analysis of Abdominal CT SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Roentgen-Ray-Society CY APR 29-MAY 04, 2012 CL Vancouver, CANADA SP Amer Roentgen Ray Soc C1 [Linguraru, M.; Sandberg, J.; Summers, R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, N.] Food & Drug Adm Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM rms@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2012 VL 198 IS 5 SU S PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 937OI UT WOS:000303667400126 ER PT J AU Liu, J Hua, J Yao, J White, J Summers, R AF Liu, J. Hua, J. Yao, J. White, J. Summers, R. TI Computer-Aided Detection of Lymphadenopathy in Contrast-Enhanced Abdominal CT SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Roentgen-Ray-Society CY APR 29-MAY 04, 2012 CL Vancouver, CANADA SP Amer Roentgen Ray Soc C1 [Liu, J.; Hua, J.; Yao, J.; White, J.; Summers, R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM rms@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2012 VL 198 IS 5 SU S PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 937OI UT WOS:000303667400456 ER PT J AU Valle-Onate, R Ward, MM Kerr, GS AF Valle-Onate, Rafael Ward, Michael M. Kerr, Gail S. TI Physical Therapy and Surgery SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT 9th Annual Research and Education Meeting of Spondyloarthritis Research and Treatment Network (SPARTAN) CY JUL 29-30, 2011 CL Portland, OR DE Total hip arthroplasty; Physical therapy; Ankylosing spondylitis ID TOTAL HIP-ARTHROPLASTY; CAUDA-EQUINA SYNDROME; ANKYLOSING-SPONDYLITIS; HETEROTOPIC OSSIFICATION; ECTOPIC OSSIFICATION; REPLACEMENT; INVOLVEMENT; PREVENTION; REHABILITATION; RADIOTHERAPY AB Physical therapy and orthopedic surgery are important components in the treatment of ankylosing spondylitis (AS). Supervised physical therapy is more effective than individual or unsupervised exercise in improving symptoms, but controlled trials suggest that combined inpatient and outpatient therapy provides the greatest improvement. Recommendations for exercise are universal, but the best types and sequence of therapies are not known. Total hip replacement is the surgery most commonly performed for AS, with good long-term implant survival. Heterotopic ossification may occur no more frequently after hip replacement in patients with AS than in patients with other diseases. Corrective spinal surgery is rarely performed and requires specialized centers and experienced surgeons. C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20893 USA. [Valle-Onate, Rafael] Univ Sabana, Mil Hosp Sch Med, Bogota, Colombia. [Kerr, Gail S.] Vet Affairs Med Ctr, Dept Med Serv, Washington, DC 20422 USA. RP Ward, MM (reprint author), NIAMSD, NIH, 9000 Rockville Pike, Bethesda, MD 20893 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-03] NR 42 TC 2 Z9 2 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD MAY PY 2012 VL 343 IS 5 BP 353 EP 356 DI 10.1097/MAJ.0b013e3182514080 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 937OH UT WOS:000303667300004 PM 22543536 ER PT J AU Tse, SML Burgos-Vargas, R Colbert, RA AF Tse, Shirley M. L. Burgos-Vargas, Ruben Colbert, Robert A. TI Juvenile Spondyloarthritis Treatment Recommendations SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT 9th Annual Research and Education Meeting of Spondyloarthritis Research and Treatment Network (SPARTAN) CY JUL 29-30, 2011 CL Portland, OR DE Juvenile spondyloarthritis; Enthesitis-related arthritis; Axial ID SOCIETY CLASSIFICATION CRITERIA; ANTITUMOR NECROSIS FACTOR; PLACEBO-CONTROLLED TRIAL; ANKYLOSING-SPONDYLITIS; DOUBLE-BLIND; RADIOGRAPHIC PROGRESSION; AXIAL SPONDYLOARTHRITIS; RHEUMATOID-ARTHRITIS; IDIOPATHIC ARTHRITIS; RANDOMIZED-TRIAL AB No specific recommendations for the treatment of juvenile spondyloarthritis have been established. Important differences exist in how spondyloarthritis begins and progresses in children and adults, supporting the need for pediatric-specific recommendations. Recently published recommendations for the treatment of juvenile arthritis consider children with sacroiliitis in a separate group and allow for more accelerated institution of a tumor necrosis factor inhibitor depending on disease activity and prognostic factors that derive primarily from studies of other forms of juvenile arthritis. There is a need to develop measures of disease activity and prognosis specific for juvenile spondyloarthritis that reflect spinal disease, as well as other major clinical features, such as enthesitis, before significant progress can be made in this area. C1 [Colbert, Robert A.] NIAMSD, NIH, Bethesda, MD 20893 USA. [Tse, Shirley M. L.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Burgos-Vargas, Ruben] Hosp Gen Mexico City, Mexico City, DF, Mexico. RP Colbert, RA (reprint author), NIAMSD, NIH, 9000 Rockville Pike, Bethesda, MD 20893 USA. EM colbertra@mac.com FU Intramural NIH HHS [ZIA AR041184-02] NR 41 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD MAY PY 2012 VL 343 IS 5 BP 367 EP 370 DI 10.1097/MAJ.0b013e3182514043 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 937OH UT WOS:000303667300008 PM 22543540 ER PT J AU Reveille, JD Ximenes, A Ward, MM AF Reveille, John D. Ximenes, Antonio Ward, Michael M. TI Economic Considerations of the Treatment of Ankylosing Spondylitis SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT 9th Annual Research and Education Meeting of Spondyloarthritis Research and Treatment Network (SPARTAN) CY JUL 29-30, 2011 CL Portland, OR DE Spondyloarthritis; Ankylosing spondylitis; Psoriatic arthritis; Economics; Anti-TNF treatment ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; TOTAL HIP-ARTHROPLASTY; LOW-DOSE INFLIXIMAB; COST-OF-ILLNESS; RHEUMATOID-ARTHRITIS; WORK DISABILITY; RISK-FACTORS; DOUBLE-BLIND; ETANERCEPT AB Ankylosing spondylitis (AS) is associated with both significant direct and indirect costs, which vary by country, and have generally increased dramatically since the introduction of anti-tumor necrosis factor therapy. The cost-effectiveness of biologic agents is controversial, although cost-effectiveness studies need to consider the potential impact of anti-tumor necrosis factor treatments on work ability. Alternatives to reduce costs associated with biologics have been examined, including on-demand dosing and lower dose alternatives. Other treatment measures, such as total hip arthroplasty and physical therapy, are also effective in reducing pain and improving function in patients with AS, although the optimal type or combination of physical therapy treatment modalities, the optimal frequency and duration of treatment and whether therapy is equally effective in stable disease and uncontrolled AS need to be determined. No studies have examined differences in patient outcomes based on subspecialty care. Establishing an evidence base for these questions would help inform policy decisions to design the most cost-effective measures to treat AS. C1 [Reveille, John D.] Univ Texas Houston Hlth Sci Ctr, Div Rheumatol, Houston, TX 77030 USA. [Ximenes, Antonio] Hosp Geral Goiania, Div Rheumatol, Goiania, Go, Brazil. [Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Reveille, JD (reprint author), Univ Texas Houston Hlth Sci Ctr, Div Rheumatol, MSB 5-270,6431 Fannin, Houston, TX 77030 USA. EM john.d.reveille@uth.tmc.edu FU Intramural NIH HHS [ZIA AR041153-07]; NIAID NIH HHS [1U01AI090909-01, U01 AI090909]; NIAMS NIH HHS [P01 AR052915]; PHS HHS [P01-052915-01] NR 42 TC 13 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD MAY PY 2012 VL 343 IS 5 BP 371 EP 374 DI 10.1097/MAJ.0b013e3182514093 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 937OH UT WOS:000303667300009 PM 22543541 ER PT J AU Geller, B Luby, JL Joshi, P Wagner, KD Emslie, G Walkup, JT Axelson, DA Bolhofner, K Robb, A Wolf, DV Riddle, MA Birmaher, B Nusrat, N Ryan, ND Vitiello, B Tillman, R Lavori, P AF Geller, Barbara Luby, Joan L. Joshi, Paramjit Wagner, Karen Dineen Emslie, Graham Walkup, John T. Axelson, David A. Bolhofner, Kristine Robb, Adelaide Wolf, Dwight V. Riddle, Mark A. Birmaher, Boris Nusrat, Nasima Ryan, Neal D. Vitiello, Benedetto Tillman, Rebecca Lavori, Philip TI A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed Phase, in Children and Adolescents SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID SSRI-RESISTANT DEPRESSION; PLACEBO-CONTROLLED TRIAL; GLOBAL ASSESSMENT SCALE; DOUBLE-BLIND; KIDDIE SCHEDULE; RISK; ANTIDEPRESSANTS; SCHIZOPHRENIA; PHENOMENOLOGY; METAANALYSIS AB Context: There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Objective: To investigate which medication to administer first to antimanic medication-naive subjects. Design, Setting, and Participants: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5US sites from 2003 to 2008 into a controlled, randomized, no-patientchoice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. Interventions: Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 mu g/mL), and risperidone (4-6 mg). Main Outcome Measures: Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. Results: There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) mu g/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; chi(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; chi(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (chi(2)(1) = 6.4, P =. 011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F-1,F-212 = 45.5, P < .001; F-1,F-212 = 39.1, P < .001; and F-1,F-213 = 191.4, P < .001, respectively) and vs divalproex sodium (F-1,F-212 = 34.7, P <.001; F-1,F-212 = 45.3, P <.001; and F-1,F-213 = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). Conclusions: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. C1 [Geller, Barbara; Luby, Joan L.; Bolhofner, Kristine; Tillman, Rebecca] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. [Joshi, Paramjit; Robb, Adelaide; Nusrat, Nasima] Childrens Natl Med Ctr, Dept Psychiat & Behav Sci, Washington, DC 20010 USA. [Wagner, Karen Dineen; Wolf, Dwight V.] Univ Texas Med Branch, Dept Psychiat, Galveston, TX USA. [Emslie, Graham] Univ Texas SW, Dept Psychiat, Dallas, TX USA. [Walkup, John T.; Riddle, Mark A.] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Axelson, David A.; Birmaher, Boris; Ryan, Neal D.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Lavori, Philip] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Geller, B (reprint author), Washington Univ, Dept Psychiat, 660 S Euclid, St Louis, MO 63110 USA. EM gellerb@wustl.edu FU NIMH [U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, R01 MH051481]; National Alliance for Research on Schizophrenia and Depression; CHADS; Biobehavioral Diagnostics, Inc; Eli Lilly; Forest; GlaxoSmithKline; Shire; Somerset; Bristol Meyers Squibb; McNeil Pediatrics; Merck Scherring Plough; Janssen; Sepracor; Supernus; Otsuka; Pfizer; Johnson and Johnson; Merck/Scherring Plough FX Dr Geller reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; payment for writing or reviewing the manuscript from NIMH; and provision of writing assistance, equipment, or administrative support from NIMH. Dr Geller also reports the following from outside the submitted work: consultancy for NIMH and the US Food and Drug Administration (FDA) Federal Advisory Committees; employment at Washington University in St Louis, Missouri; grants from NIMH; payment for lectures from Vanderbilt University and the International Review of Bipolar Disorder; payment for manuscript preparation from NIMH; royalties from Guilford Press; travel, accommodations, and meeting expenses from NIMH and FDA for service on Federal Advisory Committees; payment from Massachusetts Medical Society for Journal Watch in Psychiatry Associate Editorship. Dr Luby reports the following for the work under consideration: grant from NIMH and provision of medicines from Abbott. Dr Luby also reports the following from outside the submitted work: employment at Washington University School of Medicine in St Louis, Missouri; grants/grants pending from NIMH, National Alliance for Research on Schizophrenia and Depression, and CHADS; and royalties from Guilford Press. Dr Joshi reports the following from the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; provision of medicines from Abbott. Dr Joshi also reports the following from outside the submitted work: employment at Children's National Medical Center in Washington, DC. Dr Wagner reports the following from the work under consideration: grant from NIMH and provision of medicines from Abbott. Dr Wagner also reports the following from outside the submitted work: consultancy for Forest, American Institute of Biological Sciences, Krog and Partners, and National Institutes of Health; employment at University of Texas Medical Branch in Galveston; payment for lectures from American Psychiatric Association, Letters and Sciences, American Society of Clinical Psychopharmacology, Toledo Hospital, American Academy of Child and Adolescent Psychiatry, Madison Institute of Medicine, Mexican Psychiatric Association, Contemporary Forums, Doctors Hospital at Renaissance, CME LLC, Nevada Psychiatric Association, and Quantia Communications; payment for manuscript preparation from Guilford Publications, Health and Wellness Education Partners, American Psychiatric Publishing Inc, Springer Publishing, CMP Medica, UBM Medica, and Wolters Kluver Health; payment from Physician's Postgraduate Press, Inc, for serving as deputy editor of the Journal of Clinical Psychiatry. Dr Wagner also sits on the Scientific Advisory Board of the Child and Adolescent Bipolar Foundation and on the Scientific Advisory Board of the Depression and Bipolar Support Alliance. Dr Emslie reports the following from the work under consideration: a grant from NIMH and provision of medicines from Abbott. Dr Emslie also reports the following from outside the submitted work: consultancy for Biobehavioral Diagnostics, Inc, Eli Lilly, Forest, GlaxoSmithKline, Pfizer, Shire, Validus, and Wyeth; employment at University of Texas Southwestern Medical Center; grants/grants pending from NIMH, Biobehavioral Diagnostics, Inc, Eli Lilly, Forest, GlaxoSmithKline, Shire, and Somerset; payment for lectures, including service on speakers bureaus from Forest; and receiving payment for manuscript preparation from British Medical Journal Online.; Dr Walkup reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Axelson reports the following for the work under consideration: a grant from NIMH. Ms Bolhofner reports the following for the work under consideration: a grant from NIMH. Ms Bolhofner also reports the following from outside the submitted work: employment at Washington University in St Louis, Missouri, and grants from NIMH. Dr Robb reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; provision of medicines from Abbott; and payment for serving as clinical pharmacologist for the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Robb also reports the following from outside the submitted work: board membership at Lilly, Bristol Myers Squibb, Otsuka, Shinogi, and McNeil Pediatrics; consultancy for Lundbeck; employment at Children's National Medical Center; expert testimony for a case on antipsychotic use; grants/grants pending from Bristol Meyers Squibb, McNeil Pediatrics, Merck Scherring Plough, GlaxoSmithKline, Janssen, Sepracor, Supernus, Otsuka, Pfizer, Johnson and Johnson, and Forest; payment for service on speakers bureaus from Bristol Myers Squibb, Lilly, and McNeil Pediatrics; royalties from Epocrates; payment for development of education presentations from University of Minnesota, American Academy of Child & Adolescent Psychiatry, and American Academy of Pediatrics; stock/stock options from Lilly, Pfizer, Johnson and Johnson, GlaxoSmithKline, and 3M. Dr Robb also sits on the Children and Adults with Attention-Deficit/Hyperactivity Disorder professional advisory board and program committee for the American Psychiatric Association annual meeting, and her husband sits on American Epilepsy Society Board and Scientific Committee for Child Neurology Society. Dr Wolf reports the following for the work under consideration: a grant from NIMH. Dr Riddle reports the following for the work under consideration: a grant from NIMH and provision of medicines from Abbott. Dr Riddle also reports the following from outside the submitted work: employment at Johns Hopkins University; expert testimony for Teva Canada; and receiving aripiprazole for an NIMH study. Dr Birmaher reports the following for the work under consideration: a grant from NIMH. Dr Birmaher also reports the following from outside the submitted work: consultancy for Schering Plough, Dey Pharma, Forest, and Jazz Pharmaceuticals; and royalties from Random House and Lippincott Williams and Wilkins. Dr Nusrat reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Nusrat also reports the following from outside the submitted work: employment at Children's National Medical Center and grants/grants pending from Merck/Scherring Plough, GlaxoSmithKline, Janssen, Sepracor, Supernus, Otsuka, Pfizer, Johnson and Johnson, and Forest. Dr Ryan reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Ryan also reports the following from outside the submitted work: employment at the University of Pittsburgh and the University of Pittsburgh Medical Center. Ms Tillman reports the following for the work under consideration: a grant from NIMH and payment for writing or reviewing the manuscript from NIMH.; Ms Tillman also reports the following from outside the submitted work: employment at Washington University in St Louis and receiving travel/accommodations/meeting expenses from NIMH. Dr Lavori reports the following for the work under consideration: a grant from NIMH.; This work was supported by NIMH grants U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, and R01 MH051481. NR 37 TC 69 Z9 69 U1 5 U2 25 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2012 VL 69 IS 5 BP 515 EP 528 DI 10.1001/archgenpsychiatry.2011.1508 PG 14 WC Psychiatry SC Psychiatry GA 937QB UT WOS:000303672000011 PM 22213771 ER PT J AU Lipsky, LM Iannotti, RJ AF Lipsky, Leah M. Iannotti, Ronald J. TI Associations of Television Viewing With Eating Behaviors in the 2009 Health Behaviour in School-aged Children Study SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID NUTRITION EXAMINATION SURVEY; BODY-MASS INDEX; SOFT DRINK CONSUMPTION; SEDENTARY LIFE-STYLE; FAST-FOOD INTAKE; PHYSICAL-ACTIVITY; UNITED-STATES; NATIONAL-HEALTH; ENERGY-INTAKE; INTERDISCIPLINARY INTERVENTION AB Objective: To examine associations of television viewing with eating behaviors in a representative sample of US adolescents. Design: Cross-sectional survey. Setting: Public and private schools in the United States during the 2009-2010 school year. Participants: A total of 12 642 students in grades 5 to 10 (mean [SD] age, 13.4[0.09] years; 86.5% participation). Main Exposures: Television viewing (hours per day) and snacking while watching television (days per week). Main Outcome Measures: Eating (>= 1 instance per day) fruit, vegetables, sweets, and sugary soft drinks; eating at a fast food restaurant (>= 1 d/wk); and skipping breakfast (>= 1 d/wk). Results: Television viewing was inversely related to intake of fruit (adjusted odds ratio, 0.92; 95% CI, 0.88-0.96) and vegetables (0.95; 0.91-1.00) and positively related to intake of candy (1.18; 1.14-1.23) and fast food (1.14; 1.09-1.19) and skipping breakfast (1.06; 1.02-1.10) after adjustment for socioeconomic factors, computer use, and physical activity. Television snacking was related to increased intake of fruit (adjusted odds ratio, 1.06; 95% CI, 1.02-1.10), candy (1.20; 1.16-1.24), soda (1.15; 1.11-1.18), and fast food (1.09; 1.06-1.13), independent of television viewing. The relationships of television viewing with fruit and vegetable intake and with skipping breakfast were essentially unchanged after adjustment for television snacking; the relationships with intake of candy, soda, and fast food were moderately attenuated. Age and race/ethnicity modified relationships of television viewing with soda and fast food intake and with skipping breakfast. Conclusion: Television viewing was associated with a cluster of unhealthy eating behaviors in US adolescents after adjustment for socioeconomic and behavioral covariates. Arch Pediatr Adolesc Med. 2012; 166(5): 465-472 C1 [Lipsky, Leah M.; Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20852 USA. RP Lipsky, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,Ste 7B13, Bethesda, MD 20852 USA. EM lipskylm@mail.nih.gov OI Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN2672008000009C]; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was funded by grant HHSN2672008000009C from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 68 TC 26 Z9 27 U1 7 U2 40 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAY PY 2012 VL 166 IS 5 SI SI BP 465 EP 472 PG 8 WC Pediatrics SC Pediatrics GA 937PB UT WOS:000303669300011 PM 22566548 ER PT J AU Scott, I Webster, BR Li, JH Sack, MN AF Scott, Iain Webster, Bradley R. Li, Jian H. Sack, Michael N. TI Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1 SO BIOCHEMICAL JOURNAL LA English DT Article DE general control of amino acid synthesis 5 (GCN5)-like 1 (GCN5L1); mitochonclrial metabolism; protein acetylation; sirtuin 3 (SIRT3) ID FATTY-ACID OXIDATION; SIRT3; DEACETYLATION; PROTEIN; ACETYLATION; RESTRICTION; SIRTUINS; BIOLOGY; ENZYME AB SIRT3 (sirtuin 3) modulates respiration via the deacetylation of lysine residues in electron transport chain proteins. Whether mitochondria] protein acetylation is controlled by a counter-regulatory program has remained elusive. In the present study we identify an essential component of this previously undefined mitochondrial acetyltransferase system. We show that GCN5L1 [GCN5 (general control of amino acid synthesis 5)-like 1; also known as Bloc l s1] counters the acetylation and respiratory effects of SIRT3. GCN5L1 is mitochondrial-enriched and displays significant homology with a prokaryotic acetyltransferase. Genetic knockdown of GCN5L1 blunts mitochondrial protein acetylation, and its reconstitution in intact mitochondria restores protein acetylation. GCN5L1 interacts with and promotes acetylation of SIRT3 respiratory chain targets and reverses global SIRT3 effects on mitochondrial protein acetylation, respiration and bioenergetics. The results of the present study identify GCN5L1 as a critical prokaryote-derived component of the mitochondria] acetyltransferase programme. C1 [Scott, Iain; Webster, Bradley R.; Li, Jian H.; Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov RI Li, Jianhua/B-7671-2011 OI Li, Jianhua/0000-0002-5744-3182 FU Division of Intramural Research of the NHLBI (National Heart, Lung and Blood Institute), NIH (National Institutes of Health) FX This work was supported by the Division of Intramural Research of the NHLBI (National Heart, Lung and Blood Institute), NIH (National Institutes of Health). NR 23 TC 69 Z9 74 U1 0 U2 9 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAY 1 PY 2012 VL 443 BP 655 EP 661 DI 10.1042/BJ20120118 PN 3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 941DP UT WOS:000303944200007 PM 22309213 ER PT J AU Freidlin, B Korn, EL AF Freidlin, B. Korn, E. L. TI Assessing causal relationships between treatments and clinical outcomes: always read the fine print SO BONE MARROW TRANSPLANTATION LA English DT Review DE randomized clinical trials; observational studies; causal inference; competing risks; non-randomized comparisons ID HIGH-DOSE CHEMOTHERAPY; RENAL-CELL CARCINOMA; PHASE-III TRIAL; METASTATIC COLORECTAL-CANCER; CORONARY-HEART-DISEASE; INTRACRANIAL ARTERIAL BYPASS; VITAMIN-E CONSUMPTION; BREAST-CANCER; LUNG-CANCER; ARTHROSCOPIC SURGERY AB Changes in clinical practice should be driven by relevant and reliable evidence. Hence, adoption of a new therapy requires demonstrating that it provides (causes) benefit. Such evidence is generally obtained from intent-to-treat analyses of randomized clinical trials (RCTs). In this paper, we review other approaches to assessing the causal relationship between treatments and outcomes: (1) inference from non-randomized (observational) studies, (2) analysis of randomized studies where patients received treatments other than those to which they were randomized and (3) analysis of studies where the outcome of interest is sometimes unobservable because of a competing event (competing risks). We conclude that for the practice-changing demonstration of a favorable benefit-to-risk ratio, the gold standard is the intent-to-treat analysis of RCTs. At the same time, we illustrate how careful application of special statistical methods for assessment of treatment-outcome causation can be instrumental in complementing existing randomized evidence and guiding design of future research. Bone Marrow Transplantation (2012) 47, 626-632; doi:10.1038/bmt.2011.119; published online 30 May 2011 C1 [Freidlin, B.; Korn, E. L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN 8122,Room 8122,6130 Execut Plaza, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 70 TC 2 Z9 2 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 2012 VL 47 IS 5 BP 626 EP 632 DI 10.1038/bmt.2011.119 PG 7 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 940WJ UT WOS:000303923500003 PM 21625225 ER PT J AU Williams, KM Ostrow, LW Loeb, DM Chung, T Cohn, RD Corse, AM Mammen, AL Chen, AR AF Williams, K. M. Ostrow, L. W. Loeb, D. M. Chung, T. Cohn, R. D. Corse, A. M. Mammen, A. L. Chen, A. R. TI Immunohistochemistry of affected tissue may guide cGVHD treatment decisions SO BONE MARROW TRANSPLANTATION LA English DT Article DE cGVHD; rituximab; CD20; myositits ID VERSUS-HOST-DISEASE; POLYMYOSITIS; MUSCLE; RITUXIMAB AB Chronic graft-vs-host disease (cGVHD) myositis is a rare complication of hematopoietic SCT, for which the pathogenesis and optimal therapy are unclear. We performed immunohistochemistry on muscle biopsies from pediatric cGVHD myositis and typical cases of autoimmune dermatomyositis and polymyositis. The immunostaining pattern of cGVHD myositis was distinct from that of typical cases of autoimmunity. There was a high proportion of CD20+ and CD68+ cells, and the best therapeutic response was achieved with rituximab (anti-CD20). These results suggest that cGVHD myositis may be mediated by different leukocytes than similar autoimmune diseases and that treatment may be optimized by targeting the specific cellular infiltrates identified in affected tissue. Bone Marrow Transplantation (2012) 47, 731-733; doi:10.1038/bmt.2011.164; published online 19 September 2011 C1 [Williams, K. M.] NCI, Dept Pediat Hematol Oncol, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Ostrow, L. W.; Loeb, D. M.; Chung, T.; Cohn, R. D.; Corse, A. M.; Mammen, A. L.; Chen, A. R.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Williams, KM (reprint author), NCI, Dept Pediat Hematol Oncol, Expt Transplantat & Immunol Branch, NIH, Bldg 10 CRC,Room 3-3288,10 Ctr Dr, Bethesda, MD 20892 USA. EM williaki@mail.nih.gov FU NCI NIH HHS [P30 CA006973] NR 11 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 2012 VL 47 IS 5 BP 731 EP 733 DI 10.1038/bmt.2011.164 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 940WJ UT WOS:000303923500018 PM 21927032 ER PT J AU Tan, HY Chen, AG Kolachana, B Apud, JA Mattay, VS Callicott, JH Chen, Q Weinberger, DR AF Tan, Hao Yang Chen, Anthony G. Kolachana, Bhaskar Apud, Jose A. Mattay, Venkata S. Callicott, Joseph H. Chen, Qiang Weinberger, Daniel R. TI Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment SO BRAIN LA English DT Article DE antipsychotics; functional MRI; prefrontal cortex; schizophrenia; striatum ID DORSOLATERAL PREFRONTAL CORTEX; CATECHOL-O-METHYLTRANSFERASE; MONOZYGOTIC TWINS DISCORDANT; NEUROPSYCHOLOGICAL DYSFUNCTION; COGNITIVE IMPAIRMENTS; STRIATAL DOPAMINE; GENETIC-VARIATION; BASAL GANGLIA; COMT GENOTYPE; HUMAN BRAIN AB Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical-subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti-dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and corticalsubcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti-dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n = 46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal-parietal and prefrontal-striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal-striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose-response effects of anti-psychotic drugs on cognition in schizophrenia (n = 111). Thus, we suggest that genetic modulation of DRD2-AKT1-related prefrontal-subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment. C1 [Tan, Hao Yang; Chen, Anthony G.; Kolachana, Bhaskar; Apud, Jose A.; Mattay, Venkata S.; Callicott, Joseph H.; Chen, Qiang; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Chen, Qiang; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Tan, HY (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Div Intramural Res Programs, Bethesda, MD 20892 USA. EM haoyangtan@gmail.com; drweinberger@libd.org RI Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 FU National Institute of Mental Health FX This work was funded by the National Institute of Mental Health Intramural Research Program. NR 56 TC 28 Z9 28 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2012 VL 135 BP 1436 EP 1445 DI 10.1093/brain/aws068 PN 5 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 937JE UT WOS:000303654000010 PM 22525159 ER PT J AU Thomas, C Kveraga, K Huberle, E Karnath, HO Bar, M AF Thomas, Cibu Kveraga, Kestutis Huberle, Elisabeth Karnath, Hans-Otto Bar, Moshe TI Enabling global processing in simultanagnosia by psychophysical biasing of visual pathways SO BRAIN LA English DT Article DE brain circuits; cerebral ischaemia; visual system; dorsal stream; neurological disorders ID SPATIAL-FREQUENCY CHANNELS; LATERAL GENICULATE-NUCLEUS; MACAQUE STRIATE CORTEX; TOP-DOWN FACILITATION; FUNCTIONAL-ANATOMY; PARVOCELLULAR CONTRIBUTIONS; DORSAL SIMULTANAGNOSIA; GANGLION-CELLS; EYE-MOVEMENTS; PERCEPTION AB A fundamental aspect of visual cognition is our disposition to see the 'forest before the trees'. However, damage to the posterior parietal cortex, a critical brain region along the dorsal visual pathway, can produce a neurological disorder called simultanagnosia, characterized by a debilitating inability to perceive the 'forest' but not the 'trees' (i.e. impaired global processing despite intact local processing). This impairment in perceiving the global shape persists even though the ventral visual pathway, the primary recognition pathway, is intact in these patients. Here, we enabled global processing in patients with simultanagnosia using a psychophysical technique, which allowed us to bias stimuli such that they are processed predominantly by the intact ventral visual pathway. Our findings reveal that the impairment in global processing that characterizes simultanagnosia stems from a disruption in the processing of low-spatial frequencies through the dorsal pathway. These findings advance our understanding of the relationship between visuospatial attention and perception and reveal the neural mechanism mediating the disposition to see the 'forest before the trees'. C1 [Thomas, Cibu; Kveraga, Kestutis; Bar, Moshe] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Thomas, Cibu; Kveraga, Kestutis; Bar, Moshe] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Huberle, Elisabeth; Karnath, Hans-Otto] Univ Tubingen, Hertie Inst Clin Brain Res, Ctr Neurol, Div Neuropsychol, D-72074 Tubingen, Germany. [Huberle, Elisabeth] Cty Hosp Lucerne, Dept Neurol, CH-6000 Luzern, Switzerland. [Karnath, Hans-Otto] Georgia Inst Technol, Ctr Adv Brain Imaging, Atlanta, GA 30332 USA. [Bar, Moshe] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. RP Thomas, C (reprint author), NIH, 10 Ctr Dr,MSC 1240,Bldg 10,Room 3N228, Bethesda, MD 20892 USA. EM cibu.thomas@nih.gov FU Bundesministerium fur Bildung und Forschung (BMBF-Verbund) [01GW0654]; National Institutes of Health [R01EY019477] FX Bundesministerium fur Bildung und Forschung (BMBF-Verbund Grant Number 01GW0654 to H-O.K.) and by the National Institutes of Health (Grant Number R01EY019477 to M.B.). NR 54 TC 12 Z9 12 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2012 VL 135 BP 1578 EP 1585 DI 10.1093/brain/aws066 PN 5 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 937JE UT WOS:000303654000022 PM 22418740 ER PT J AU Saslow, D Solomon, D Lawson, HW Killackey, M Kulasingam, SL Cain, J Garcia, FAR Moriarty, AT Waxman, AG Wilbur, DC Wentzensen, N Downs, LS Spitzer, M Moscicki, AB Franco, EL Stoler, MH Schiffman, M Castle, PE Myers, ER Comm, AAACCG AF Saslow, Debbie Solomon, Diane Lawson, Herschel W. Killackey, Maureen Kulasingam, Shalini L. Cain, Joanna Garcia, Francisco A. R. Moriarty, Ann T. Waxman, Alan G. Wilbur, David C. Wentzensen, Nicolas Downs, Levi S., Jr. Spitzer, Mark Moscicki, Anna-Barbara Franco, Eduardo L. Stoler, Mark H. Schiffman, Mark Castle, Philip E. Myers, Evan R. Comm, Acs-Asccp-Ascp Cervical Canc Guideline TI American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review ID HUMAN-PAPILLOMAVIRUS DNA; RANDOMIZED CONTROLLED-TRIAL; ATYPICAL SQUAMOUS-CELLS; INTRAEPITHELIAL NEOPLASIA GRADE-2; INTERNATIONAL INCIDENCE RATES; ADENOCARCINOMA IN-SITU; LIQUID-BASED CYTOLOGY; LONG-TERM RISK; WOMEN 30 YEARS; COST-EFFECTIVENESS AB An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. CA Cancer J Clin 2012. (C) 2012 American Cancer Society. C1 [Saslow, Debbie] Amer Canc Soc, Canc Control Sci Dept, Atlanta, GA 30303 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Rockville, MD USA. [Lawson, Herschel W.] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30322 USA. [Killackey, Maureen] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, Reg Network, New York, NY 10021 USA. [Kulasingam, Shalini L.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Cain, Joanna] Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA USA. [Garcia, Francisco A. R.] Univ Arizona, Ctr Excellence Womens Hlth, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Moriarty, Ann T.] AmeriPath Indiana, Dept Esoter Testing, Indianapolis, IN USA. [Waxman, Alan G.] Univ New Mexico, Sch Med, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Wilbur, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Downs, Levi S., Jr.] Univ Minnesota, Sch Med, Masonic Canc Ctr, Dept Obstet Gynecol & Womens Hlth,Div Gynecol Onc, Minneapolis, MN 55455 USA. [Spitzer, Mark] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Moscicki, Anna-Barbara] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Franco, Eduardo L.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Franco, Eduardo L.] McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. [Stoler, Mark H.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. [Schiffman, Mark] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Castle, Philip E.] Amer Soc, Clin Pathol Inst, Washington, DC USA. [Myers, Evan R.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Comm, Acs-Asccp-Ascp Cervical Canc Guideline] Steering Comm, Data Grp, Working Grp 1 2 3A 3B 4 5 6, Valdosta, GA USA. [Saslow, Debbie; Castle, Philip E.; Comm, Acs-Asccp-Ascp Cervical Canc Guideline] Writing Comm, New York, NY USA. [Cain, Joanna] Working Grp 2, Stanford, CA USA. [Waxman, Alan G.] Working Grp 3A, Menlo Pk, CA USA. [Garcia, Francisco A. R.; Moriarty, Ann T.] Working Grp 6, Atlanta, GA USA. RP Saslow, D (reprint author), Amer Canc Soc, Canc Control Sci Dept, 250 Williams St NW,Suite 600, Atlanta, GA 30303 USA. EM debbie.saslow@cancer.org RI Colgan, Terence/J-2339-2016; OI Franco, Eduardo/0000-0002-4409-8084 FU Qiagen; Roche; Gen-Probe, Inc; BD; Abbott Laboratories; Roche Molecular Systems; Merck, Inc; GlaxoSmithKline (GSK), Inc.; National Institute of Allergy and Infectious Diseases FX The following reported no financial relationships or potential conflicts of interest to disclose: D. Saslow, E. Partridge, B. Holladay, W. Kinney, H. Lawson, K. Noller, K. Poole, R. Smith, P. Fontaine, A. Herzig, M. Killackey, S. Kulasingam, D. McCoy, W. Brewster, J. Cain, D. Chelmow, V. King, R. Pretorius, B. Winkler, I. Eltoum, J. Kim, N. Wentzensen, L. Downs, S. Greening, H. Haefner, L. Zephyrin, M. Chevarie-Davis, D. Ekwueme, T. Colgan, M. Henry, S. Massad, K. Simon. P. Castle receives payment for service on the Data Monitoring and Safety Board for Merck Sharp & Dohme and has received free or discounted human papillomavirus tests for research from Qiagen and Roche. C. Cohen serves as a speaker for Merck, Inc, and receives honoraria. M. Edelson's spouse is employed by and receives a salary from Merck and Company. F. Garcia is employed by the University of Arizona, which holds contracts for the performance of research with Roche Pharmaceutical/Roche Molecular; Hologic; Third Wave Technologies; MTM Laboratories; Qiagen; Becton, Dickson and Company (BD); and MediSpectra/LUMA. He also serves on the Speakers' Bureau for Qiagen and receives honoraria. J. Cuzick serves on advisory boards and as an ad hoc consultant for Qiagen; Roche; Gen-Probe, Inc; BD; and Abbott Laboratories, with research funds provided to his institution from Qiagen; Roche; Gen-Probe, Inc; BD; and Abbott Laboratories. P. Gravitt has acted as a member of the Women's Health Advisory Board for Qiagen Corporation and has received research funding from Roche Molecular Systems and Merck, Inc within the last 5 years. E. Myers received research support for investigations for Gen-Probe, Inc, and from GlaxoSmithKline (GSK), Inc. He served as a speaker for and received honoraria from Gen-Probe, Inc, and has served as a consultant for and received honoraria from Gen-Probe, Inc; Merck and Company; and GSK. M. Schiffman holds a research agreement to serve as a medical monitor in the National Cancer Institute (NCI) vaccine trial through GSK; he also receives research support from Qiagen for careHPV research in Nigeria. D. Solomon serves as a medical monitor for the NCI's Costa Rica HPV Vaccine Trial; the trial receives vaccine from GSK. M. Stoler received fees for serving as a consultant to Merck Research Laboratories; Roche; Ventana Medical Systems, Inc; BD; Hologic; MTM Laboratories; and Gen-Probe, Inc. D. Mody conducted lectures and workshops for the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Cytopathology (ASC), for which she received honoraria and/or travel expenses. G. Birdsong's employer receives funding for contracted research performed by him for BD Diagnostics. C. Wheeler is an employee of University of New Mexico, which is contracted by GSK for its vaccine trials and receives equipment/reagents from Roche Molecular Systems, Inc, for human papillomavirus genotyping. D. Wilbur serves on the scientific advisory board for Corista, LLC. T. Darragh received ThinPrep supplies for research from Hologic. She also serves on an advisory board for OncoHealth Corporation and has received stock options as payment and serves on the advisory board of Arbor Vita Corporation. E. Mayeaux serves on the speakers' advisory board for both Merck, Inc, and PharmaDerm and receives honoraria from both companies for his service. M. Spitzer serves as a speaker for both Merck, Inc, and Qiagen and receives honoraria. K.; Ault received clinical research grants from the National Institute of Allergy and Infectious Diseases; Gen-Probe, Inc; Merck, Inc; and Roche and served as a site principal investigator for the research. All grants were provided to his employer, Emory University. E. Franco received honorarium as a Study Steering Committee member for GSK; he also serves on the advisory boards of Merck, Inc; Roche; and Gen-Probe, Inc, from which he receives honoraria and has acted as an ad hoc consultant for Merck, Inc; Roche; Gen-Probe, Inc; and Qiagen, for which honoraria were paid to compensate for time away and work performed. M. Gold received honorarium for serving as a speaker and consultant for Hologic. W. Huh serves as a consultant to Roche; Qiagen; Merck, Inc; and Inovio Pharmaceuticals, Inc and receives honoraria from all 4 companies. A-B. Moscicki received honorarium for serving as a consultant to an advisory board for Merck, Inc. M. Einstein has advised or participated in educational speaking activities, but does not receive an honorarium from any companies. His employer, Montefiore Medical Center, has received payment for his time spent on activities for Merck, Inc; GSK; Roche; Bristol-Myers Squibb; Hologic; Advaxis, Inc; Aura Biosciences, Inc; Inovio Pharmaceuticals, Inc; Photocure ASA; NeoDiagnostix, Inc; and PDS Biotechnology Corporation. Montefiore has received grant funding for research related to the costs of those Merck, GSK, Roche, Advaxis, and Hologic clinical trials for which Dr. Einstein served as the Montefiore principal investigator. A. Moriarty received honorarium as a speaker for ASC. R. Guido has acted as the local principal investigator for a multicenter study (contracted research) for IKONOsys. A. Waxman receives honoraria and expenses for teaching related to the subject matter in this article from nonprofit professional organizations and governmental agencies and contractors. He is on the executive committee of the board of directors of the American Society for Colposcopy and Cervical Pathology; he lectures for them and codirects some of their courses and receives honoraria and expenses for these functions. He also lectures and directs courses for the American College/Congress of Obstetricians and Gynecologists on subjects related to this article and receives honoraria from them. Both organizations are nonprofit professional organizations. He has also received honoraria and expenses from the State of Alaska Department of Health and Social Services and several Alaska Native corporations (Southcentral Foundation, SouthEast Alaska Regional Health Corporation, Arctic Slope Regional Corporation, and Yukon-Kuskokwim Health Corporation) and the Breast Cancer Detection Center of Alaska for lecturing on material related to this article. He also received honoraria from the Center for Health Training, a contractor to Title X agencies for lecturing for the Texas Department of State Health Services. He also received a $200 honorarium from Quadrant HealthCom, Inc for writing an article related to cervical cancer screening for the journal OBG Management. NR 156 TC 357 Z9 378 U1 14 U2 54 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAY-JUN PY 2012 VL 62 IS 3 BP 147 EP 172 DI 10.3322/caac.21139 PG 26 WC Oncology SC Oncology GA 937NO UT WOS:000303665400003 PM 22422631 ER PT J AU Partridge, AH Elmore, JG Saslow, D McCaskill-Stevens, W Schnitt, SJ AF Partridge, Ann H. Elmore, Joann G. Saslow, Debbie McCaskill-Stevens, Worta Schnitt, Stuart J. TI Challenges in ductal carcinoma in situ risk communication and decision-making Report From an American Cancer Society and National Cancer Institute Workshop SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review ID INVASIVE BREAST-CANCER; QUALITY-OF-LIFE; THE-SCIENCE CONFERENCE; PSYCHOLOGICAL MORBIDITY; INFORMED DECISION; RETHINKING TNM; PERCEIVED RISK; NORTH-AMERICA; WOMEN; DIAGNOSIS AB In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS. CA Cancer J Clin 2012. (C) 2012 American Cancer Society. C1 [Partridge, Ann H.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med, Boston, MA 02215 USA. [Elmore, Joann G.] Univ Washington, Harborview Med Ctr, Sch Med, Seattle, WA 98104 USA. [Saslow, Debbie] Amer Canc Soc, Atlanta, GA 30329 USA. [McCaskill-Stevens, Worta] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Schnitt, Stuart J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Partridge, AH (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. EM ann_partridge@dfci.harvard.edu FU NCATS NIH HHS [UL1 TR000423] NR 63 TC 15 Z9 17 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAY-JUN PY 2012 VL 62 IS 3 BP 203 EP 210 DI 10.3322/caac.21140 PG 8 WC Oncology SC Oncology GA 937NO UT WOS:000303665400005 PM 22488610 ER PT J AU Klionsky, DJ Hurley, JH AF Klionsky, Daniel J. Hurley, James H. TI Self-eating with your fingers SO CELL RESEARCH LA English DT Editorial Material ID MEMBRANE CURVATURE; CRYSTAL-STRUCTURE; BECLIN 1; AUTOPHAGY; DOMAIN; BINDING; PHOSPHORYLATION; MACROAUTOPHAGY; PROTEINS; ATG14L AB BECN1 plays a central role in determining cell fate, acting as a balance point in the decision to undergo autophagy or apoptosis. Three distinct structural domains allow BECN1 to interact with several other proteins. Recent crystallographic data provide insight into the nature of the coiled-coil and evolutionarily conserved domains. C1 [Klionsky, Daniel J.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Klionsky, Daniel J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Hurley, James H.] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Klionsky, DJ (reprint author), Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. EM klionsky@umich.edu; hurley@helix.nih.gov FU NIH, NIDDK; NIH [GM53396] FX R Stanley is thanked for discussions. Research in the Hurley lab is supported by the Intramural Program of the NIH, NIDDK. DJK is supported by NIH grant GM53396. NR 20 TC 2 Z9 2 U1 1 U2 11 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD MAY PY 2012 VL 22 IS 5 BP 783 EP 785 DI 10.1038/cr.2012.39 PG 3 WC Cell Biology SC Cell Biology GA 936SY UT WOS:000303611500001 PM 22410794 ER PT J AU O'Connell, ML Birkenkamp, KE Kleiner, DE Folio, LR Holland, SM Olivier, KN AF O'Connell, Meghan L. Birkenkamp, Kate E. Kleiner, David E. Folio, Les R. Holland, Steven M. Olivier, Kenneth N. TI Lung Manifestations in an Autopsy-Based Series of Pulmonary or Disseminated Nontuberculous Mycobacterial Disease SO CHEST LA English DT Article ID AVIUM-INTRACELLULARE; CYSTIC-FIBROSIS; INFECTION; COMPLEX; PREVALENCE; FEATURES AB Background: Comparisons of lung manifestations in primary pulmonary vs disseminated nontuberculous myeobacterial disease have not been well described. The clinical, histopathologic, and radiologic disease manifestations of primary pulmonary or disseminated nontuberculous mycobacterial disease were compared in an autopsy series. Methods: Medical and microbiologic records, autopsy reports, histopathologic slides of the lungs, and chest CT scans were reviewed on patients at the National Institutes of Health with nontuberculous mycobacterial disease who died between 1996 and 2010. Results: The 11 patients with primary pulmonary nontuberculous mycobacterial disease were predominantly female (n = 9), with symptom onset at median 50 (range 35, 71) years and time from onset until death of 12 (3, 34) years. Bronchiectasis with cavity formation and necrotizing bronchocentric granulomatous inflammation predominated but extrapulmonary infection was absent. The five patients with disseminated disease and systemic immune defects were all men with age at onset of 2 (0.33, 33) years and time from onset of disease until death of 9 (1, 31) years. Miliary nodules and/or consolidation with poorly formed granulomatous inflammation were noted in the three disseminated patients with mycobacterial lung involvement. Significant extrapulmonary infection was noted in all five with a relative paucity of lung findings. Conclusions: Nontuberculous mycobacteria can cause progressive, fatal disease. Primary pulmonary disease is bronchocentric and lacks extrathoracic infection consistent with impaired airway surface defenses. In contrast, fatal disseminated infections involving the lung have hematogenous spread, extensive extrathoracic disease, and a distinct pulmonary histopathology consistent with systemic immune dysfunction. CHEST 2012; 141(5):1203-1209 C1 [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Folio, Les R.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM olivierk@niaid.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institutes of Health Clinical Center FX This research was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institutes of Health Clinical Center. NR 25 TC 15 Z9 15 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAY PY 2012 VL 141 IS 5 BP 1203 EP 1209 DI 10.1378/chest.11-0425 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 940PO UT WOS:000303905700017 PM 22194586 ER PT J AU Remaley, AT AF Remaley, Alan T. TI A 54-Year-Old Diabetic Man with Low Serum Cholesterol Commentary SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Dept Lab Med, Bldg 10,Rm 2C-433, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2012 VL 58 IS 5 BP 830 EP 830 DI 10.1373/clinchem.2012.182147 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 937YZ UT WOS:000303701400010 PM 22544858 ER PT J AU Molitoris, BA Okusa, MD Palevsky, PM Kimmel, PL Star, RA AF Molitoris, Bruce A. Okusa, Mark D. Palevsky, Paul M. Kimmel, Paul L. Star, Robert A. TI Designing Clinical Trials in Acute Kidney Injury SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID ACUTE-RENAL-FAILURE; MORTALITY C1 [Kimmel, Paul L.; Star, Robert A.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Molitoris, Bruce A.] Indiana Univ, Dept Med, Indianapolis, IN USA. [Molitoris, Bruce A.] Roudebush VA Med Ctr, Indianapolis, IN USA. [Okusa, Mark D.] Univ Virginia Hlth Syst, Div Nephrol, Charlottesville, VA USA. [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. RP Kimmel, PL (reprint author), NIDDK, Div Kidney Urol & Hematol Dis, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM KimmelP@extra.niddk.nih.gov OI Palevsky, Paul/0000-0002-7334-5400 NR 10 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2012 VL 7 IS 5 BP 842 EP 843 DI 10.2215/CJN.12801211 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 937AZ UT WOS:000303632700021 PM 22442185 ER PT J AU Palevsky, PM Molitoris, BA Okusa, MD Levin, A Waikar, SS Wald, R Chertow, GM Murray, PT Parikh, CR Shaw, AD Go, AS Faubel, SG Kellum, JA Chinchilli, VM Liu, KD Cheung, AK Weisbord, SD Chawla, LS Kaufman, JS Devarajan, P Toto, RM Hsu, CY Greene, T Mehta, RL Stokes, JB Thompson, AM Thompson, BT Westenfelder, CS Tumlin, JA Warnock, DG Shah, SV Xie, YN Duggan, EG Kimmel, PL Star, RA AF Palevsky, Paul M. Molitoris, Bruce A. Okusa, Mark D. Levin, Adeera Waikar, Sushrut S. Wald, Ron Chertow, Glenn M. Murray, Patrick T. Parikh, Chirag R. Shaw, Andrew D. Go, Alan S. Faubel, Sarah G. Kellum, John A. Chinchilli, Vernon M. Liu, Kathleen D. Cheung, Alfred K. Weisbord, Steven D. Chawla, Lakhmir S. Kaufman, James S. Devarajan, Prasad Toto, Robert M. Hsu, Chi-yuan Greene, Tom Mehta, Ravindra L. Stokes, John B. Thompson, Aliza M. Thompson, B. Taylor Westenfelder, Christof S. Tumlin, James A. Warnock, David G. Shah, Sudhir V. Xie, Yining Duggan, Emily G. Kimmel, Paul L. Star, Robert A. TI Design of Clinical Trials in Acute Kidney Injury: Report from an NIDDK Workshop on Trial Methodology SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; ACUTE-RENAL-FAILURE; CARDIAC-SURGERY; CONSENSUS CONFERENCE; SEVERE SEPSIS; OUTCOMES; NETWORK; MORTALITY; VETERANS; SURVIVAL AB Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis. Clin J Am Soc Nephrol 7: 844-850, 2012. doi: 10.2215/CJN.12791211 C1 [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM KimmelP@extra.niddk.nih.gov OI Murray, Patrick/0000-0001-8516-1839 NR 41 TC 38 Z9 38 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2012 VL 7 IS 5 BP 844 EP 850 DI 10.2215/CJN.12791211 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 937AZ UT WOS:000303632700022 PM 22442182 ER PT J AU Okusa, MD Molitoris, BA Palevsky, PM Chinchilli, VM Liu, KD Cheung, AK Weisbord, SD Faubel, S Kellum, JA Wald, R Chertow, GM Levin, A Waikar, SS Murray, PT Parikh, CR Shaw, AD Go, AS Chavvla, LS Kaufman, JS Devarajan, P Toto, RM Hsu, CY Greene, TH Mehta, RL Stokes, JB Thompson, AM Thompson, BT Westenfelder, CS Tumlin, JA Warnock, DG Shah, SV Xie, YN Duggan, EG Kimmel, PL Star, RA AF Okusa, Mark D. Molitoris, Bruce A. Palevsky, Paul M. Chinchilli, Vernon M. Liu, Kathleen D. Cheung, Alfred K. Weisbord, Steven D. Faubel, Sarah Kellum, John A. Wald, Ron Chertow, Glenn M. Levin, Adeera Waikar, Sushrut S. Murray, Patrick T. Parikh, Chirag R. Shaw, Andrew D. Go, Alan S. Chavvla, Lakhmir S. Kaufman, James S. Devarajan, Prasad Toto, Robert M. Hsu, Chi-yuan Greene, Tom H. Mehta, Ravindra L. Stokes, John B. Thompson, Aliza M. Thompson, B. Taylor Westenfelder, Christof S. Tumlin, James A. Warnock, David G. Shah, Sudhir V. Xie, Yining Duggan, Emily G. Kimmel, Paul L. Star, Robert A. TI Design of Clinical Trials in Acute Kidney Injury: A Report from an NIDDK Workshop-Prevention Trials SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CONTRAST-INDUCED NEPHROPATHY; ACUTE-RENAL-FAILURE; CORONARY-ANGIOGRAPHY; SODIUM-BICARBONATE; RANDOMIZED-TRIAL; OUTCOMES; INTERVENTION; SALINE AB AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI. Clin J Ant Soc Nephrol 7: 851-855,2012. doi: 10.2215/CJN.12811211 C1 [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM KimmelP@extra.niddk.nih.gov OI Murray, Patrick/0000-0001-8516-1839 NR 20 TC 22 Z9 22 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2012 VL 7 IS 5 BP 851 EP 855 DI 10.2215/CJN.12811211 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 937AZ UT WOS:000303632700023 PM 22442188 ER PT J AU Molitoris, BA Okusa, MD Palevsky, PM Chawla, LS Kaufman, JS Devarajan, P Toto, RM Hsu, CY Greene, TH Faubel, SG Kellum, JA Wald, R Chertow, GM Levin, A Waikar, SS Murray, PT Parikh, CR Shaw, AD Go, AS Chinchilli, VM Liu, KD Cheung, AK Weisbord, SD Mehta, RL Stokes, JB Thompson, AM Thompson, BT Westenfelder, CS Turnin, JA Warnock, DG Shah, SV Xie, YN Duggan, EG Kimmel, PL Star, RA AF Molitoris, Bruce A. Okusa, Mark D. Palevsky, Paul M. Chawla, Lakhmir S. Kaufman, James S. Devarajan, Prasad Toto, Robert M. Hsu, Chi-yuan Greene, Tom H. Faubel, Sarah G. Kellum, John A. Wald, Ron Chertow, Glenn M. Levin, Adeera Waikar, Sushrut S. Murray, Patrick T. Parikh, Chirag R. Shaw, Andrew D. Go, Alan S. Chinchilli, Vernon M. Liu, Kathleen D. Cheung, Alfred K. Weisbord, Steven D. Mehta, Ravindra L. Stokes, John B. Thompson, Aliza M. Thompson, B. Taylor Westenfelder, Christof S. Turnin, James A. Warnock, David G. Shah, Sudhir V. Xie, Yining Duggan, Emily G. Kimmel, Paul L. Star, Robert A. TI Design of Clinical Trials in AKI: A Report from an NIDDK Workshop. Trials of Patients with Sepsis and in Selected Hospital Settings SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE KIDNEY INJURY; ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; CARDIAC-SURGERY; OUTCOMES; DISEASE; MULTICENTER; MORTALITY; DIAGNOSIS; SURVIVAL AB AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients. Clin J Am Soc Nephrol 7: 856-860, 2012. doi: 10.2215/CJN.12821211 C1 [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM KimmelP@extra.niddk.nih.gov OI Murray, Patrick/0000-0001-8516-1839 NR 27 TC 16 Z9 16 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2012 VL 7 IS 5 BP 856 EP 860 DI 10.2215/CJN.12821211 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 937AZ UT WOS:000303632700024 PM 22442184 ER PT J AU Dorman, JS Valdez, R Liu, TB Wang, C Rubinstein, WS O'Neill, SM Acheson, LS Ruffin, MT Khoury, MJ AF Dorman, Janice S. Valdez, Rodolfo Liu, Tiebin Wang, Catharine Rubinstein, Wendy S. O'Neill, Suzanne M. Acheson, Louise S. Ruffin, Mack T. Khoury, Muin J. TI Health beliefs among individuals at increased familial risk for type 2 diabetes: Implications for prevention SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Family history; Health beliefs; Diabetes; Coronary heart disease; Stroke ID LIFE-STYLE INTERVENTION; CORONARY-HEART-DISEASE; SCREENING TOOL; CAROTID-ARTERY; IMPACT TRIAL; HISTORY; MELLITUS; PERCEPTIONS; POPULATION; STROKE AB Aim: To evaluate perceived risk, control, worry, and severity about diabetes, coronary heart disease (CHD) and stroke among individuals at increased familial risk of diabetes. Methods: Data analyses were based on the Family Healthware (TM) Impact Trial. Baseline health beliefs were compared across three groups: (1) no family history of diabetes, CHD or stroke (n = 836), (2) family history of diabetes alone (n = 267), and (3) family history of diabetes and CHD and/or stroke (n = 978). Results: After adjusting for age, gender, race, education and BMI, scores for perceived risk for diabetes (p < 0.0001), CHD (p < 0.0001) and stroke (p < 0.0001) were lowest in Group 1 and highest in Group 3. Similar results were observed about worry for diabetes (p < 0.0001), CHD (p < 0.0001) and stroke (p < 0.0001). Perceptions of control or severity for diabetes, CHD or stroke did not vary across the three groups. Conclusions: Among individuals at increased familial risk for diabetes, having family members affected with CHD and/or stroke significantly influenced perceived risk and worry. Tailored lifestyle interventions for this group that assess health beliefs and emphasize approaches for preventing diabetes, as well as its vascular complications, may be an effective strategy for reducing the global burden of these serious but related chronic disorders. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Dorman, Janice S.] Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. [Valdez, Rodolfo; Liu, Tiebin; Khoury, Muin J.] Ctr Dis Control, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Wang, Catharine] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA USA. [Rubinstein, Wendy S.] NorthShore Univ HealthSyst, Dept Med, Div Genet, Evanston, IL USA. [Rubinstein, Wendy S.] Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [O'Neill, Suzanne M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Acheson, Louise S.] Case Western Reserve Univ, Dept Family Med, Div Res, Cleveland, OH 44106 USA. [Acheson, Louise S.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Acheson, Louise S.] Case Comprehens Canc Ctr, Cleveland, OH USA. [Ruffin, Mack T.] Univ Michigan, Dept Family Med, Ann Arbor, MI 48109 USA. RP Dorman, JS (reprint author), Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. EM jsd@pitt.edu OI Ruffin, Mack/0000-0001-8336-478X; Wang, Catharine/0000-0001-8584-2781 FU Centers for Disease Control; Association for Prevention Teaching and Research [ENH-U50/CCU300860 TS-1216]; American Association of Medical Colleges [UM-U36/CCU319276 MM-0789, CWR-U36/CCU319276 MM0630]; National Cancer Institute [K07 CA086958, NCT00164658] FX Sources of support: The Family Healthware (TM) Impact Trial (FHITr) was supported through cooperative agreements between the Centers for Disease Control and the Association for Prevention Teaching and Research (ENH-U50/CCU300860 TS-1216) and the American Association of Medical Colleges (Grants UM-U36/CCU319276 MM-0789 and CWR-U36/CCU319276 MM0630). Drs. Acheson (K07 CA086958) and Wang (K07 CA131103) also received salary support from the National Cancer Institute. Trial Registration: NCT00164658 'Evaluating Tools for Health Promotion and Disease Prevention'. NR 49 TC 10 Z9 11 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD MAY PY 2012 VL 96 IS 2 BP 156 EP 162 DI 10.1016/j.diabres.2011.12.017 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 937OO UT WOS:000303668000020 PM 22257420 ER PT J AU Dmitriev, AA Kashuba, VI Haraldson, K Senchenko, VN Pavlova, TV Kudryavtseva, AV Anedchenko, EA Krasnov, GS Pronina, IV Loginov, VI Kondratieva, TT Kazubskaya, TP Braga, EA Yenamandra, SP Ignatjev, I Ernberg, I Klein, G Lerman, MI Zabarovsky, ER AF Dmitriev, Alexey A. Kashuba, Vladimir I. Haraldson, Klas Senchenko, Vera N. Pavlova, Tatiana V. Kudryavtseva, Anna V. Anedchenko, Ekaterina A. Krasnov, George S. Pronina, Irina V. Loginov, Vitalij I. Kondratieva, Tatiana T. Kazubskaya, Tatiana P. Braga, Eleonora A. Yenamandra, Surya P. Ignatjev, Ilya Ernberg, Ingemar Klein, George Lerman, Michael I. Zabarovsky, Eugene R. TI Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays SO EPIGENETICS LA English DT Article DE epigenetics; lung cancer; biomarkers; tumor-suppressor gene; NotI-microarrays; methylation; RT-qPCR; methylation specific microarrays ID TUMOR-SUPPRESSOR GENE; HUMAN-CHROMOSOME 3; HOMOZYGOUS DELETION REGION; REAL-TIME PCR; HUMAN GENOME; PROMOTER HYPERMETHYLATION; EPITHELIAL MALIGNANCIES; DNA METHYLATION; SHORT ARM; 3P21.3 AB This study aimed to clarify genetic and epigenetic alterations that occur during lung carcinogenesis and to design perspective sets of newly identified biomarkers. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI clones associated with genes for hybridization with 40 paired normal/tumor DNA samples of primary lung tumors: 28 squamous cell carcinomas (SCC) and 12 adenocarcinomas (ADC). The NotI-microarray data were confirmed by qPCR and bisulfite sequencing analyses. Forty-four genes showed methylation and/or deletions in more than 15% of non-small cell lung cancer (NSCLC) samples. In general, SCC samples were more frequently methylated/deleted than ADC. Moreover, the SCC alterations were observed already at stage I of tumor development, whereas in ADC many genes showed tumor progression specific methylation/deletions. Among genes frequently methylated/deleted in NSCLC, only a few were already known tumor suppressor genes: RBSP3 (CTDSPL), VHL and THRB. The RPL32, LOC285205, FGD5 and other genes were previously not shown to be involved in lung carcinogenesis. Ten methylated genes, i.e., IQSEC1, RBSP3, ITGA9, FOXP1, LRRN1, GNAI2, VHL, FGD5, ALDH1L1 and BCL6 were tested for expression by qPCR and were found downregulated in the majority of cases. Three genes (RBSP3, FBLN2 and ITGA9) demonstrated strong cell growth inhibition activity. A comprehensive statistical analysis suggested the set of 19 gene markers, ANKRD28, BHLHE40, CGGBP1, RBSP3, EPHB1, FGD5, FOXP1, GORASP1/TTC21, IQSEC1, ITGA9, LOC285375, LRRC3B, LRRN1, MITF, NKIRAS1/RPL15, TRH, UBE2E2, VHL, WNT7A, to allow early detection, tumor progression, metastases and to discriminate between SCC and ADC with sensitivity and specificity of 80-100%. C1 [Dmitriev, Alexey A.; Kashuba, Vladimir I.; Haraldson, Klas; Pavlova, Tatiana V.; Yenamandra, Surya P.; Ignatjev, Ilya; Ernberg, Ingemar; Klein, George; Zabarovsky, Eugene R.] Karolinska Inst, Dept Microbiol, Stockholm, Sweden. [Dmitriev, Alexey A.; Senchenko, Vera N.; Pavlova, Tatiana V.; Kudryavtseva, Anna V.; Anedchenko, Ekaterina A.; Krasnov, George S.; Zabarovsky, Eugene R.] Engelhardt Inst Mol Biol, Moscow, Russia. [Kashuba, Vladimir I.] Ukrainian Acad Sci, Inst Mol Biol & Genet, UA-252627 Kiev, Ukraine. [Pronina, Irina V.; Loginov, Vitalij I.; Braga, Eleonora A.] Russian State Genet Ctr GosNIIgenetika, Moscow, Russia. [Kondratieva, Tatiana T.; Kazubskaya, Tatiana P.] RAMS, Blokhin Canc Res Ctr, Moscow, Russia. [Lerman, Michael I.] NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. [Zabarovsky, Eugene R.] Linkoping Univ, Inst Klin & Expt Med, Linkoping, Sweden. RP Zabarovsky, ER (reprint author), Karolinska Inst, Dept Microbiol, Stockholm, Sweden. EM eugzab@ki.se RI Dmitriev, Alexey/D-6109-2011; Senchenko, Vera/C-8992-2014; Kudryavtseva, Anna/C-9032-2014; Krasnov, George/E-6529-2014; Braga, Eleonora/P-5574-2016; OI Dmitriev, Alexey/0000-0002-6827-9584; Senchenko, Vera/0000-0002-3119-515X; Kudryavtseva, Anna/0000-0002-3722-8207; Krasnov, George/0000-0002-6493-8378 FU Swedish Cancer Society; Swedish Institute; Swedish Research Council; Karolinska Institute [02.740.11.5227, 16.552.11.7034]; Russian Ministry of Education and Science; Russian Foundation for Basic Research [10-04-01213-a, 11-04-00269]; UICC FX We would like to thank Dr. Nina Oparina for helpful discussion of our results. This work was supported by research grants from the Swedish Cancer Society, the Swedish Institute, the Swedish Research Council and Karolinska Institute, State Contracts 02.740.11.5227 and 16.552.11.7034 with the Russian Ministry of Education and Science, grants 10-04-01213-a and 11-04-00269 from the Russian Foundation for Basic Research and by a UICC International Cancer Technology Transfer Fellowship to DAA. NR 52 TC 31 Z9 36 U1 2 U2 12 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD MAY PY 2012 VL 7 IS 5 BP 502 EP 513 DI 10.4161/epi.19801 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 935NB UT WOS:000303524700011 PM 22491060 ER PT J AU Peltsverger, MY Butler, PW Alberobello, AT Smith, S Guevara, Y Dubaz, OM Luzon, JA Linderman, J Celi, FS AF Peltsverger, Maya Y. Butler, Peter W. Alberobello, Anna Teresa Smith, Sheila Guevara, Yanina Dubaz, Ornella M. Luzon, Javier A. Linderman, Joyce Celi, Francesco S. TI The-258A/G (SNP rs12885300) polymorphism of the human type 2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID IODOTHYRONINE DEIODINASE; THR92ALA POLYMORPHISM; INSULIN-RESISTANCE; THYROTROPIN; THYROXINE; DIO2; 3,5,3'-TRIIODOTHYRONINE; IDENTIFICATION; 5'-DEIODINASE; PARAMETERS AB Objective: Type 2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of -258A/G polymorphism on intrathyroidal thyroxine (T-4) to triiodothyronine (T-3) conversion and thyroid hormone (TH) secretion pattern, we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland. Design: Retrospective analysis. Methods: The TH secretion in response to 500 mu g i.v. TRH injection was studied in 45 healthy volunteers. Results: Twenty-six subjects (16 females and ten males, 32.8 +/- 10.4 years) were homozygous for the ancestral (-258A/A) allele and 19 (11 females and eight males, 31.1 +/- 10.9 years) were carriers of the (-258G/x) variant. While no differences in the peak TSH and T-3 levels were observed, carriers of the -258G/x allele showed a blunted rise in free T-4 (FT4; P < 0.01). The -258G/x92Thr/Thr haplotype, compared with the other groups, had lower TSH values at 60 min (P < 0.03). No differences were observed between genotypes in baseline TH levels. Conclusions: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated FT4 secretion with a normal T3 release from the thyroid gland consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism causes changes in the pattern of hormone secretion. These findings are a proof of concept that common polymorphisms in DIO2 can subtly affect the circulating levels of TH and might modulate the TH homeostasis. C1 [Peltsverger, Maya Y.; Butler, Peter W.; Alberobello, Anna Teresa; Smith, Sheila; Guevara, Yanina; Dubaz, Ornella M.; Luzon, Javier A.; Linderman, Joyce; Celi, Francesco S.] NIDDK, Diabet Endocrinol & Obes Branch, CRC, Bethesda, MD 20892 USA. [Peltsverger, Maya Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod & Adult Endocrinol Branch, NIH, CRC, Bethesda, MD USA. [Butler, Peter W.] Baystate Med Ctr, Endocrine & Diabet Div, Springfield, MA USA. RP Celi, FS (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, CRC, Bldg 10,RM 6-3940,10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM fc93a@nih.gov FU National Institute of Diabetes, Digestive, and Kidney Diseases [Z01-DK047057-01, Z01-DK047057-02] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases, programs Z01-DK047057-01 and Z01-DK047057-02. NR 26 TC 10 Z9 10 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD MAY PY 2012 VL 166 IS 5 BP 839 EP 845 DI 10.1530/EJE-11-1073 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 939ZS UT WOS:000303860400009 PM 22307573 ER PT J AU Chen, ZM Janes, K Chen, C Doyle, T Bryant, L Tosh, DK Jacobson, KA Salvemini, D AF Chen, Zhoumou Janes, Kali Chen, Collin Doyle, Tim Bryant, Leesa Tosh, Dilip K. Jacobson, Kenneth A. Salvemini, Daniela TI Controlling murine and rat chronic pain through A(3) adenosine receptor activation SO FASEB JOURNAL LA English DT Article DE IB-MECA; MRS1898; paclitaxel; oxaliplatin; bortezomib ID ISCHEMIC BRAIN-INJURY; PERIPHERAL NEUROPATHY; SYNAPTIC-TRANSMISSION; RHEUMATOID-ARTHRITIS; INTERNATIONAL UNION; INFLAMMATORY PAIN; CELL-LINES; CANCER; AGONISTS; TARGET AB Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A(3) adenosine receptor (A(3)AR) agonism as a new target-based therapeutic strategy. The development of mechanoallodynia in a well-characterized mouse model of neuropathic pain following chronic constriction injury of the sciatic nerve was rapidly and dose-dependently reversed by the A(3)AR agonists: IB-MECA, its 2-chlorinated analog (Cl-IB-MECA), and the structurally distinct MRS1898. These effects were naloxone insensitive and thus are not opioid receptor mediated. IB-MECA was >= 1.6-fold more efficacious than morphine and >5-fold more potent. In addition, IB-MECA was equally efficacious as gabapentin (Neurontin) or amitriptyline, but respectively >350- and >75-fold more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB-MECA significantly increased the antiallodynic effects of all 3 analgesics. Moreover, neuropathic pain development in rats caused by widely used chemotherapeutics in the taxane (paclitaxel), platinum-complex (oxaliplatin), and proteasome-inhibitor (bortezomib) classes was blocked by IB-MECA without antagonizing their antitumor effect. A(3)AR agonist effects were blocked with A(3)AR antagonist MRS1523, but not with A(1)AR (DPCPX) or A(2)AAR (SCH-442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A(3)AR agonists for chronic pain.-Chen, Z., Janes, K., Chen, C., Doyle, T., Bryant, L., Tosh, D. K., Jacobson, K. A., Salvemini, D. Controlling murine and rat chronic pain through A(3) adenosine receptor activation. FASEB J. 26, 1855-1865 (2012). www.fasebj.org C1 [Chen, Zhoumou; Janes, Kali; Chen, Collin; Doyle, Tim; Bryant, Leesa; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Tosh, Dilip K.; Jacobson, Kenneth A.] NIDDK, NIH, Bethesda, MD USA. RP Salvemini, D (reprint author), St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, 1402 S Grand Blvd, St Louis, MO 63104 USA. EM salvemd@slu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU U.S. National Institutes of Health (NIH) [R01 DA024074]; St. Louis University; NIH National Institute of Diabetes and Digestive and Kidney Diseases FX The authors are grateful to Dr. Gary Bennett, (McGill University, Montreal, QC, Canada) for critically reviewing our work. This work was supported by U.S. National Institutes of Health (NIH) grant R01 DA024074 (D. S.), St. Louis University President Research Funds (D. S.), and the NIH National Institute of Diabetes and Digestive and Kidney Diseases Intramural Program (K.A.J.). The authors report no conflicts of interest. NR 58 TC 39 Z9 39 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2012 VL 26 IS 5 BP 1855 EP 1865 DI 10.1096/fj.11-201541 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 937TD UT WOS:000303680800014 PM 22345405 ER PT J AU Gilchrist, DA Fromm, G dos Santos, G Pham, LN McDaniel, IE Burkholder, A Fargo, DC Adelman, K AF Gilchrist, Daniel A. Fromm, George dos Santos, Gilberto Pham, Linh N. McDaniel, Ivy E. Burkholder, Adam Fargo, David C. Adelman, Karen TI Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks SO GENES & DEVELOPMENT LA English DT Article DE gene expression; transcription elongation; polymerase pausing; gene networks ID RNA-POLYMERASE-II; EMBRYONIC STEM-CELLS; B FACTOR RELISH; TRANSCRIPTION ELONGATION; DROSOPHILA-MELANOGASTER; P-TEFB; PROMOTER; ACTIVATION; NELF; COMPLEX AB The expression of many metazoan genes is regulated through controlled release of RNA polymerase II (Pol II) that has paused during early transcription elongation. Pausing is highly enriched at genes in stimulus-responsive pathways, where it has been proposed to poise downstream targets for rapid gene activation. However, whether this represents the major function of pausing in these pathways remains to be determined. To address this question, we analyzed pausing within several stimulus-responsive networks in Drosophila and discovered that paused Pol II is much more prevalent at genes encoding components and regulators of signal transduction cascades than at inducible downstream targets. Within immune-responsive pathways, we found that pausing maintains basal expression of critical network hubs, including the key NF-kappa B transcription factor that triggers gene activation. Accordingly, loss of pausing through knockdown of the pause-inducing factor NELF leads to broadly attenuated immune gene activation. Investigation of murine embryonic stem cells revealed that pausing is similarly widespread at genes encoding signaling components that regulate self-renewal, particularly within the MAPK/ERK pathway. We conclude that the role of pausing goes well beyond poising-inducible genes for activation and propose that the primary function of paused Pol II is to establish basal activity of signal-responsive networks. C1 [Gilchrist, Daniel A.; Fromm, George; dos Santos, Gilberto; Pham, Linh N.; McDaniel, Ivy E.; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Adelman, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov OI Gilchrist, Daniel/0000-0003-1668-2790 FU NIH, National Institute of Environmental Health Sciences [Z01 ES101987] FX We thank the Adelman laboratory members for their helpful suggestions on this manuscript, and Neal Silverman and Svenja Stoven for generously providing expression constructs. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101987). NR 42 TC 52 Z9 54 U1 0 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 1 PY 2012 VL 26 IS 9 BP 933 EP 944 DI 10.1101/gad.187781.112 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 935RW UT WOS:000303538900007 PM 22549956 ER PT J AU Kim, YJ Bao, H Bonanno, L Zhang, B Serpe, M AF Kim, Young-Jun Bao, Hong Bonanno, Liana Zhang, Bing Serpe, Mihaela TI Drosophila Neto is essential for clustering glutamate receptors at the neuromuscular junction SO GENES & DEVELOPMENT LA English DT Article DE glutamatergic synapses; postsynaptic density; glutamate receptor; synapse assembly; auxiliary subunits; Drosophila; neuromuscular junction ID PRESYNAPTIC NEUROTRANSMITTER RELEASE; KAINATE RECEPTORS; AUXILIARY SUBUNITS; TRANSMEMBRANE PROTEIN; SYNAPTIC PLASTICITY; TERMINAL DOMAIN; AMPA RECEPTORS; ACTIVE ZONES; LOCALIZATION; MELANOGASTER AB Neurotransmitter receptor recruitment at postsynaptic specializations is key in synaptogenesis, since this step confers functionality to the nascent synapse. The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse, similar in composition and function to mammalian central synapses. Various mechanisms regulating the extent of postsynaptic ionotropic glutamate receptor (iGluR) clustering have been described, but none are known to be essential for the initial localization and clustering of iGluRs at postsynaptic densities (PSDs). We identified and characterized the Drosophila neto (neuropilin and tolloid-like) as an essential gene required for clustering of iGluRs at the NMJ. Neto colocalizes with the iGluRs at the PSDs in puncta juxtaposing the active zones. neto loss-of-function phenotypes parallel the loss-of-function defects described for iGluRs. The defects in neto mutants are effectively rescued by muscle-specific expression of neto transgenes. Neto clustering at the Drosophila NMJ coincides with and is dependent on iGluRs. Our studies reveal that Drosophila Neto is a novel, essential component of the iGluR complexes and is required for iGluR clustering, organization of PSDs, and synapse functionality. C1 [Kim, Young-Jun; Bonanno, Liana; Serpe, Mihaela] NICHHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Bao, Hong; Zhang, Bing] Univ Oklahoma, Dept Zool, Norman, OK 73019 USA. RP Serpe, M (reprint author), NICHHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM serpemih@mail.nih.gov FU NIH; NIH/NINDS [R01NS06878]; NSF [IOS-0822236, IOS-1025556] FX We thank Ed Giniger, Mark Mayer, Chi-Hon Lee, Alan Hinnebusch, Kevin Cook, and Mike O'Connor for helpful discussions and suggestions. We are grateful to Aaron DiAntonio, David Featherstone, and Nicholas Harden for antibodies. We thank Peter Nguyen for technical assistance. This work was supported in part by the Intramural Research Program at NIH. H.B. and B.Z. were supported by grants from NIH/NINDS (R01NS06878) and NSF (IOS-0822236 and IOS-1025556). NR 74 TC 16 Z9 16 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 1 PY 2012 VL 26 IS 9 BP 974 EP 987 DI 10.1101/gad.185165.111 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 935RW UT WOS:000303538900010 PM 22499592 ER PT J AU Cabral, WA Barnes, AM Adeyemo, A Cushing, K Chitayat, D Porter, FD Panny, SR Gulamali-Majid, F Tishkoff, SA Rebbeck, TR Gueye, SM Bailey-Wilson, JE Brody, LC Rotimi, CN Marini, JC AF Cabral, Wayne A. Barnes, Aileen M. Adeyemo, Adebowale Cushing, Kelly Chitayat, David Porter, Forbes D. Panny, Susan R. Gulamali-Majid, Fizza Tishkoff, Sarah A. Rebbeck, Timothy R. Gueye, Serigne M. Bailey-Wilson, Joan E. Brody, Lawrence C. Rotimi, Charles N. Marini, Joan C. TI A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta SO GENETICS IN MEDICINE LA English DT Article DE founder mutation; LEPRE1; osteogenesis imperfecta; West Africa ID DISEASE; COLLAGEN; FREQUENCY; DEFICIENCY; CRTAP AB Purpose: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (01). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. Methods: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. Results: Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive 01, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). Conclusion: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE). C1 [Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Cushing, Kelly; Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Chitayat, David] Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1X5, Canada. [Chitayat, David] Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Chitayat, David] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Porter, Forbes D.] NICHHD, Program Dev Genet & Endocrinol, NIH, Bethesda, MD 20892 USA. [Panny, Susan R.] Maryland Dept Hlth & Mental Hyg, Off Genet & Children Special Hlth Care Needs, Baltimore, MD USA. [Gulamali-Majid, Fizza] Maryland Dept Hlth & Mental Hyg, Labs Adm, Baltimore, MD USA. [Tishkoff, Sarah A.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Tishkoff, Sarah A.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Abramson Canc Ctr, Philadelphia, PA USA. [Gueye, Serigne M.] Hop Gen Grand Yoff, Dept Urol Androl, Dakar, Senegal. [Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Marini, JC (reprint author), NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920; Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institute of Child Health and Human Development; NHGRI; [R01-GM076637-05]; [DP1-OD-006445-01]; [R01-CA085074]; [P50-CA105641] FX The authors thank the members of the Ostrander Lab (National Human Genome Research Institute, NHGRI) and Peter Chines (NHGRI) for assistance with microsatellite genotyping and haplotype data analysis. For assistance with African sample preparation, we thank William Beggs, Amy Walker, Teo Tran, Charnita Zeigler-Johnson, and Elaine Spangler at the University of Pennsylvania. For providing access to the Maryland Department of Mental Health and Hygiene newborn metabolic screening cards, we thank John M. DeBoy. We also thank David Eltis, coeditor of the Transatlantic Slave Trade database, for critical reading of the manuscript. This work was supported by the intramural research programs of the National Institute of Child Health and Human Development (J.C.M, F.D.P) and the NHGRI (C.N.R, L.C.B, J.E.B.-W.), as well as grant support to S.A.T. (R01-GM076637-05 and DP1-OD-006445-01) and T.R.R (R01-CA085074 and P50-CA105641). NR 40 TC 22 Z9 22 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD MAY PY 2012 VL 14 IS 5 BP 543 EP 551 DI 10.1038/gim.2011.44 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 939BM UT WOS:000303781800007 PM 22281939 ER PT J AU Logan, RA AF Logan, Robert A. TI Health Literacy Through The National Library Of Medicine SO HEALTH AFFAIRS LA English DT Letter C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Logan, RA (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAY PY 2012 VL 31 IS 5 DI 10.1377/hlthaff.2012.0378 PG 1 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 940EP UT WOS:000303873100040 PM 22566460 ER PT J AU Eisenhofer, G Vocke, CD Elkahloun, A Huynh, TT Prodanov, T Lenders, JWM Timmers, HJ Benhammou, JN Linehan, WM Pacak, K AF Eisenhofer, G. Vocke, C. D. Elkahloun, A. Huynh, T. -T. Prodanov, T. Lenders, J. W. M. Timmers, H. J. Benhammou, J. N. Linehan, W. M. Pacak, K. TI Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE pheochromocytoma; paraganglioma; von Hippel-Lindau syndrome; mutation testing; germline mutations; loss of heterozygosity ID GERMLINE MUTATIONS; SPORADIC PHEOCHROMOCYTOMAS; PARAGANGLIOMA; HEREDITARY; DISTINCT; DELETIONS; HYPOXIA; DISEASE AB Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs. C1 [Eisenhofer, G.] Univ Dresden, Inst Clin Chem & Lab Med, Div Clin Neurochem, D-01307 Dresden, Germany. [Eisenhofer, G.] Univ Dresden, Dept Med 3, D-01307 Dresden, Germany. [Vocke, C. D.; Benhammou, J. N.; Linehan, W. M.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Elkahloun, A.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Huynh, T. -T.; Prodanov, T.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Lenders, J. W. M.] Dept Internal Med, Nijmegen, Netherlands. [Timmers, H. J.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. RP Eisenhofer, G (reprint author), Univ Dresden, Inst Clin Chem & Lab Med, Div Clin Neurochem, Fetscherstr 74, D-01307 Dresden, Germany. EM Graeme.Eisenhofer@uniklinikum-dresden.de RI Lenders, J.W.M./L-4487-2015 FU Deutsche Forschungsgesellschaft; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Center for Cancer Research, National Cancer Institute; National Human Genome Research Institute, NIH FX This work was supported by the Deutsche Forschungsgesellschaft and the intramural programmes of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Center for Cancer Research, National Cancer Institute, and the National Human Genome Research Institute, NIH. NR 25 TC 6 Z9 6 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2012 VL 44 IS 5 BP 343 EP 348 DI 10.1055/s-0032-1304662 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 939AC UT WOS:000303774500005 PM 22438210 ER PT J AU Timmers, HJLM Taieb, D Pacak, K AF Timmers, H. J. L. M. Taieb, D. Pacak, K. TI Current and Future Anatomical and Functional Imaging Approaches to Pheochromocytoma and Paraganglioma SO HORMONE AND METABOLIC RESEARCH LA English DT Review DE FDG PET; MIBG scintigraphy; FDOPA PET; FDA PET ID POSITRON-EMISSION-TOMOGRAPHY; IN-111-PENTETREOTIDE SCINTIGRAPHY; NECK PARAGANGLIOMAS; I-123 METAIODOBENZYLGUANIDINE; METASTATIC PHEOCHROMOCYTOMA; OCTREOTIDE SCINTIGRAPHY; MIBG SCINTIGRAPHY; PET; HEAD; LOCALIZATION AB After establishing a biochemical diagnosis, pheochromocytomas and extra-adrenal paragangliomas (PPGLs) can be localized using different anatomical and functional imaging modalities. These include computed tomography, magnetic resonance imaging, single-photon emission computed tomography (SPECT) using I-123-metaiodobenzylguanidine or In-111-DTPA-pentetreotide, and positron emission tomography (PET) using 6-[F-18]-fluorodopamine (F-18-FDA), 6-[F-18]-fluoro-L-3,4-dihydroxyphenylalanine (F-18-DOPA), and 2-[F-18]-fluoro-2-deoxy-D-glucose. We review the currently available data on the performance of anatomical imaging, SPECT, and PET for the detection of (metastatic) PPGL as well as parasympathetic head and neck paragangliomas. We show that there appears to be no 'gold-standard' imaging technique for all patients with (suspected) PPGL. A tailor-made approach is warranted, guided by clinical, biochemical, and genetic characteristics. In the current era of a growing number of PET tracers, PPGL imaging has moved beyond tumor localization towards functional characterization of tumors. C1 [Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Timmers, H. J. L. M.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Taieb, D.] Aix Marseille Univ, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bldg 10,CRC 1E-3140,MSC 1109,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural NIH HHS [Z01 HD008735-08] NR 45 TC 27 Z9 29 U1 0 U2 6 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2012 VL 44 IS 5 BP 367 EP 372 DI 10.1055/s-0031-1299712 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 939AC UT WOS:000303774500009 PM 22399235 ER PT J AU Cowley, AW Nadeau, JH Baccarelli, A Berecek, K Fornage, M Gibbons, GH Harrison, DG Liang, MY Nathanielsz, PW O'Connor, DT Ordovas, J Peng, WQ Soares, MB Szyf, M Tolunay, HE Wood, KC Zhao, K Galis, ZS AF Cowley, Allen W., Jr. Nadeau, Joseph H. Baccarelli, Andrea Berecek, Kathleen Fornage, Myriam Gibbons, Gary H. Harrison, David G. Liang, Mingyu Nathanielsz, Peter W. O'Connor, Daniel T. Ordovas, Jose Peng, Weiqun Soares, Marcelo Bento Szyf, Moshe Tolunay, H. Eser Wood, Katherine C. Zhao, Keji Galis, Zorina S. TI Report of the National Heart, Lung, and Blood Institute Working Group on Epigenetics and Hypertension SO HYPERTENSION LA English DT Review ID GENOME-WIDE ASSOCIATION; COMPLEX TRAITS; DISEASE RISK; DEVELOPMENTAL PLASTICITY; MISSING HERITABILITY; PRESSURE; SUSCEPTIBILITY; INHERITANCE; GENE; MECHANISMS C1 [Cowley, Allen W., Jr.] Med Coll Wisconsin, Dept Physiol, Ctr Cardiovasc, Milwaukee, WI 53226 USA. [Nadeau, Joseph H.] Inst Syst Biol, Seattle, WA USA. [Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Lab Environm Epigenet, Dept Environm Hlth,Exposure Epidemiol & Risk Prog, Boston, MA 02115 USA. [Berecek, Kathleen] Univ Alabama Birmingham, Dept Physiol & Biophys, Birmingham Comprehens Diabet Ctr, Birmingham, AL USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Gibbons, Gary H.] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Harrison, David G.] Vanderbilt Univ Sch Med, Nashville, TN USA. [Nathanielsz, Peter W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet Gynecol, Ctr Pregnancy & Newborn Res, San Antonio, TX 78229 USA. [O'Connor, Daniel T.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ordovas, Jose] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Ordovas, Jose] Ctr Nacl Invest Cardiovasc, Dept Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose] IMDEA Alimentac, Madrid, Spain. [Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Soares, Marcelo Bento] Northwestern Univ, Childrens Mem Res Ctr, Falk Brain Tumor Ctr, Chicago, IL 60611 USA. [Szyf, Moshe] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. [Tolunay, H. Eser; Galis, Zorina S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Wood, Katherine C.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Keji] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. RP Cowley, AW (reprint author), Med Coll Wisconsin, Dept Physiol, Ctr Cardiovasc, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM cowley@mcw.edu; jnadeau@systemsbiology.org OI Baccarelli, Andrea/0000-0002-3436-0640; Nathanielsz, Peter/0000-0001-8410-6280 FU National heart, Lung, and Blood Institute FX The proceedings of the Epigenetics and Hypertension Working Group were supported through funds provided by the National heart, Lung, and Blood Institute. NR 54 TC 47 Z9 48 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2012 VL 59 IS 5 BP 899 EP 905 DI 10.1161/HYPERTENSIONAHA.111.190116 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 938VH UT WOS:000303760900014 PM 22431584 ER PT J AU Alderman, MH Piller, LB Ford, CE Probstfield, JL Oparil, S Cushman, WC Einhorn, PT Franklin, SS Papademetriou, V Ong, ST Eckfeldt, JH Furberg, CD Calhoun, DA Davis, BR AF Alderman, Michael H. Piller, Linda B. Ford, Charles E. Probstfield, Jeffrey L. Oparil, Suzanne Cushman, William C. Einhorn, Paula T. Franklin, Stanley S. Papademetriou, Vasilios Ong, Stephen T. Eckfeldt, John H. Furberg, Curt D. Calhoun, David A. Davis, Barry R. CA Antihypertensive & Lipid-Lowering TI Clinical Significance of Incident Hypokalemia and Hyperkalemia in Treated Hypertensive Patients in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial SO HYPERTENSION LA English DT Article DE hypertension; hypokalemia; hyperkalemia; diuretic; calcium-channel blocker; angiotensin-converting enzyme inhibitor ID SERUM POTASSIUM; CARDIOVASCULAR EVENTS; BLOOD-PRESSURE; RISK; ALLHAT; DIURETICS; INHIBITOR; DISEASE; BLOCKER; STROKE AB Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a large practice-based clinical trial, made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone (C) versus amlodipine or lisinopril as a first-step drug were stratified by year-1 potassium. Postyear-1 outcomes among hypokalemics (potassium, <3.5 mmol/L) and hyperkalemics (potassium, >5.4 mmol/L) were compared with normokalemics (potassium, 3.5-5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in C (12.9%) differed from amlodipine (2.1%; P<0.001) and lisinopril (1.0%; P<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than in C (1.2%; P<0.01) or amlodipine (1.9%; P<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than in normokalemics (Cox hazard ratio, 1.21 [95% CI, 1.02-1.44]) with statistically significant (interaction, P<0.01) disparity in hazard ratios for the 3 treatment arms (hazard ratios, C=1.21, amlodipine = 1.60, lisinopril = 3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio, 1.58 [95% CI, 1.15-2.18]) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of C. Thus, for most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5-25.0 mg of C). (Hypertension. 2012;59:926-933.) . Online Data Supplement C1 [Piller, Linda B.; Ford, Charles E.; Davis, Barry R.] Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX 77030 USA. [Alderman, Michael H.] Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. [Probstfield, Jeffrey L.] Univ Washington, Clin Trials Serv Unit, Seattle, WA 98195 USA. [Oparil, Suzanne; Calhoun, David A.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Einhorn, Paula T.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Franklin, Stanley S.] Univ Calif Irvine, Dept Med, Irvine, CA USA. [Papademetriou, Vasilios] Vet Affairs Med Ctr Washington, Washington, DC USA. [Ong, Stephen T.] Ong Med Ctr, Oxon Hill, MD USA. [Eckfeldt, John H.] Univ Minnesota Hosp & Clin, Minneapolis, MN 55455 USA. [Furberg, Curt D.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. RP Ford, CE (reprint author), Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, 1200 Herman Pressler Dr,W-940, Houston, TX 77030 USA. EM Charles.E.Ford@uth.tmc.edu OI Papademetriou, Vasilios/0000-0002-2882-2757 FU National Heart, Lung, and Blood Institute [N01-HC-35130]; Pfizer, Inc.; Sankyo; GlaxoSmithKline; Novartis; Amarin Pharmaceutical; Amylin Pharmaceutical; Daiichi Sankyo Pharmaceutical; Forest-Pharmaceutical; Johnson and Johnson; Luitpold; Pfizer; Roche; Sanofi Aventis; Takeda; XOMA; Amgen; Daiichi Sankyo; Gilead; Merck; Abbott Laboratories; Boehringer Ingelheim FX This research was supported by contract number N01-HC-35130 from the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc (amlodipine); AstraZeneca (atenolol and lisinopril); and Bristol-Myers Squibb (pravastatin), as well as financial support by Pfizer, Inc.; M.H.A. has received research grants from Sankyo. D.A.C. has consulted for Eli Lilly and Novartis. W.C.C. has consulted for Daiichi Sankyo, Novartis, Noven, Sanofi Aventis, Takeda, and Theravance, has received honoraria from Bristol-Meyer Squibb, Daiichi Sankyo, Novartis, and Sanofi-Aventis, and has received research grants from GlaxoSmithKline and Novartis. B.R.D. has consulted for Amgen and Takeda. S.T.O. has received honoraria from Novartis and has received research grants from Amarin, Amylin, Daiichi Sankyo, Forest-Pharmaceuticals, GlaxoSmithKline, Johnson and Johnson, Luitpold, Novartis, Pfizer, Roche, Sanofi Aventis, Takeda, and XOMA. S.O. has consulted for Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Forest Laboratories, Forest Pharmaceuticals, NicOx, Novartis, Omron Healthcare, Pfizer, and Schering Plough and has received research grants from Amgen, Daiichi Sankyo, Gilead, Merck, and Takeda. V.P. has received honoraria from Astra-Zeneca and Forest Pharmaceuticals. J.L.P. has received research grants from Abbott Laboratories, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi Aventis. NR 20 TC 31 Z9 32 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2012 VL 59 IS 5 BP 926 EP + DI 10.1161/HYPERTENSIONAHA.111.180554 PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 938VH UT WOS:000303760900020 PM 22431578 ER PT J AU Shibao, C Buchowski, MS Chen, KY Yu, C Biaggioni, H AF Shibao, Cyndya Buchowski, Maciej S. Chen, Kong Y. Yu, Chang Biaggioni, Halo TI Chronic Sympathetic Attenuation and Energy Metabolism in Autonomic Failure SO HYPERTENSION LA English DT Article DE autonomic failure; energy metabolism; energy expenditure ID SPINAL-CORD-INJURY; NERVOUS-SYSTEM; ORTHOSTATIC HYPOTENSION; THERMOGENIC RESPONSE; BLOOD-PRESSURE; VAGAL NERVE; HUMANS; EXPENDITURE; RADIOIMMUNOASSAY; STIMULATION AB The sympathetic nervous system regulates thermogenesis and energy homeostasis in humans. When activated it increases energy expenditure, particularly resting energy expenditure. Most human studies used acute infusion of beta-blockers as a model to eliminate sympathetic stimulation and to examine the contribution of the sympathetic nervous system to energy metabolism and balance. Clinically, however, it is also important to assess the effect of chronic sympathetic attenuation on energy metabolism. In this context, we hypothesized that resting energy expenditure is decreased in patients with autonomic failure who, by definition, have low sympathetic tone. We measured 24-hour energy expenditure using whole-room indirect calorimeter in 10 adults with chronic autonomic failure (6 women; age, 64.9 +/- 9.1 years; body mass index, 25.2 +/- 4.4 kg/m(2)) and 15 sedentary healthy controls of similar age and body composition (8 women; age, 63.1 +/- 4.0 years; body mass index, 24.4 +/- 3.9 kg/m(2)). In 4 patients, we eliminated residual sympathetic activity with the ganglionic bocker trimethaphan. We found that, after adjusting for body composition, resting energy expenditure did not differ between patients with autonomic failure and healthy controls. However, resting energy expenditure significantly decreased when residual sympathetic activity was eliminated. Our findings suggest that sympathetic tonic support of resting energy expenditure is preserved, at least in part, in pathophysiological models of chronic sympathetic attenuation. (Hypertension. 2012;59:985-990.) C1 [Shibao, Cyndya; Biaggioni, Halo] Vanderbilt Univ, Sch Med, Div Clin Pharmacol & Auton Dysfunct Ctr, Nashville, TN 37240 USA. [Buchowski, Maciej S.] Vanderbilt Univ, Sch Med, Div Gasteroenterol Energy Balance Lab, Nashville, TN USA. [Yu, Chang] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA. [Yu, Chang] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN USA. [Chen, Kong Y.] NIDDK, Div Intramural Res, Natl Inst Hlth, Diabet Endocrinol & Obes Branch, Bethesda, MD USA. RP Shibao, C (reprint author), 556 Robinson Res Bldg, Nashville, TN 37232 USA. EM cyndya.shibao@vandebilt.edu RI Buchowski, Maciej/A-2683-2008; OI Buchowski, Maciej/0000-0002-0566-1743; Chen, Kong/0000-0002-0306-1904 FU American Heart Association; National Center for Research Resources, National Institutes of Health [1UL1 RR024975]; National Institute of Neurological Disorders and Stroke [U54 NS065736]; Office of Rare Diseases Research; Rare Diseases Clinical Research Network [PO1 HL56693]; Vanderbilt Diabetes Research and Training Center [DK069465]; National Institutes of Health [K23 HL103976-01]; [DK020593] FX C.S. is supported by National Institutes of Health grant K23 HL103976-01 and American Heart Association Clinical Research Program. M.S.B. was supported in part by grant DK020593. Funding and/or programmatic support for this project has been provided by Vanderbilt Clinical and Translational Science Award grant 1UL1 RR024975 from the National Center for Research Resources, National Institutes of Health, U54 NS065736 from National Institute of Neurological Disorders and Stroke, the Office of Rare Diseases Research, the Rare Diseases Clinical Research Network, PO1 HL56693, and Vanderbilt Diabetes Research and Training Center grant DK069465. NR 34 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD MAY PY 2012 VL 59 IS 5 BP 985 EP 990 DI 10.1161/HYPERTENSIONAHA.111.190157 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 938VH UT WOS:000303760900028 PM 22469621 ER PT J AU Battesti, A Tsegaye, YM Packer, DG Majdalani, N Gottesman, S AF Battesti, A. Tsegaye, Y. M. Packer, D. G. Majdalani, N. Gottesman, S. TI H-NS Regulation of IraD and IraM Antiadaptors for Control of RpoS Degradation SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; OSMOTIC REGULATION; MOLECULAR ADAPTER; RNA-POLYMERASE; SIGMA-FACTOR; PROTEIN; STPA; DNA; STABILITY; RSSB AB RpoS, the master sigma factor during stationary phase and under a variety of stress conditions, is regulated at multiple levels, including regulated degradation. Degradation is dependent upon ClpXP and the RssB adaptor protein. H-NS, a nucleoid-associated protein, affects the regulated degradation of RpoS; in the absence of H-NS, RpoS is stable. The mechanisms involved in this regulation were not known. We have found that H-NS inhibits the expression of iraD and iraM, the genes coding for two anti-adaptor proteins that stabilize RpoS when overexpressed. The regulation by H-NS of iraM is independent from the previously demonstrated regulation by the PhoP/PhoQ two-component system. Moreover, differences in the behavior of several hats alleles are explained by a role for StpA, an H-NS-like protein, in the regulation of RpoS stability. This finding parallels recent observations for a role of StpA in regulation of RpoS stability in Salmonella. C1 [Battesti, A.; Tsegaye, Y. M.; Packer, D. G.; Majdalani, N.; Gottesman, S.] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU 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 37 TC 17 Z9 17 U1 0 U2 7 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 MAY PY 2012 VL 194 IS 10 BP 2470 EP 2478 DI 10.1128/JB.00132-12 PG 9 WC Microbiology SC Microbiology GA 937WH UT WOS:000303693400007 PM 22408168 ER PT J AU Gomes, MS Hugo, FN Hilgert, JB Padilha, DMP Simonsick, EM Ferrucci, L Reynolds, MA AF Gomes, Maximiliano Schuenke Hugo, Fernando Neves Hilgert, Juliana Balbinot Pereira Padilha, Dalva Maria Simonsick, Eleanor Marie Ferrucci, Luigi Reynolds, Mark Allan TI Validity of Self-reported History of Endodontic Treatment in the Baltimore Longitudinal Study of Aging SO JOURNAL OF ENDODONTICS LA English DT Article DE Apical periodontitis; endodontic treatment; self-report; validity ID CORONARY-HEART-DISEASE; ORAL-HEALTH; PERIODONTAL-DISEASE; APICAL PERIODONTITIS; PERIAPICAL RADIOGRAPHY; CLINICAL EXAMINATION; POPULATION; VALIDATION; QUESTIONNAIRE; RISK AB Introduction: Self-reported history of endodontic treatment (SRHET) has been used as a simplified method to estimate the history of endodontic disease and treatment. This study aimed to quantify the validity of SRHET, as reported in the Baltimore Longitudinal Study of Aging (BLSA), as a method to identify individuals who experienced endodontic treatment (ET) and to identify individuals who present with apical periodontitis (AP). Methods: SRHET was collected through the BLSA questionnaire in 247 participants. Data on ET and AP were determined from panoramic radiographs. The total number of ET, AP, and missing teeth were recorded for each individual. The validity of SRHET was determined based on ET and AP separately. Accuracy, efficiency, sensitivity, specificity, positive and negative predictive values (+PV and -PV), and positive and negative likelihood ratios (+LR and -LR) were calculated according to standard methods. Results: After exclusions, 229 participants were available for ET analysis and 129 for AP analysis. The SRHET validity values were sensitivity (ET = 0.915, AP = 0.782), specificity (ET = 0.891, AP = 0.689), +PV (ET = 0.824, AP = 0.353), -PV (ET = 0.949, AP = 0.936), +LR (ET = 8.394, AP = 2.514), and -LR (ET = 0.095, AP = 0.316). Conclusions: SRHET was found to be a highly accurate method to predict ET but a weak predictor of the presence of AP among participants in the BLSA. (J Endod 2012;38:589-593) C1 [Hugo, Fernando Neves; Hilgert, Juliana Balbinot; Pereira Padilha, Dalva Maria] Univ Fed Rio Grande do Sul, Sch Dent, Dept Community Dent, Porto Alegre, RS, Brazil. [Gomes, Maximiliano Schuenke] Mil Police Rio Grande Sul, Med & Dent Ctr, Porto Alegre, RS, Brazil. [Simonsick, Eleanor Marie; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Reynolds, Mark Allan] Univ Maryland, Sch Dent, Dept Periodont, Baltimore, MD 21201 USA. RP Gomes, MS (reprint author), Fed Univ Rio Grande Sul R Ramiro Barcelos, Sch Dent, BR-90035003 Porto Alegre, RS, Brazil. EM endomax@gmail.com RI Gomes, Maximiliano/O-1193-2015; OI Gomes, Maximiliano/0000-0002-0394-5400; Hugo, Fernando/0000-0003-2222-7719 FU NIH/NIA, National Institute on Aging; CAPES Foundation, Ministry of Education of Brazil [1433/11-3]; Military Police, State Government of Rio Grande do Sul, Brazil FX Supported in part by the Intramural Research Program of the NIH/NIA, National Institute on Aging; the CAPES Foundation, Ministry of Education of Brazil (doctorate scholarship number 1433/11-3); and the Military Police, State Government of Rio Grande do Sul, Brazil. NR 35 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0099-2399 J9 J ENDODONT JI J. Endod. PD MAY PY 2012 VL 38 IS 5 BP 589 EP 593 DI 10.1016/j.joen.2012.02.006 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 940OY UT WOS:000303904100005 PM 22515884 ER PT J AU Valencia, CA Rhodenizer, D Bhide, S Chin, E Littlejohn, MR Keong, LM Rutkowski, A Bonnemann, C Hegde, M AF Valencia, C. Alexander Rhodenizer, Devin Bhide, Shruti Chin, Ephrem Littlejohn, Martin Robert Keong, Lisa Mari Rutkowski, Anne Bonnemann, Carsten Hegde, Madhuri TI Assessment of Target Enrichment Platforms Using Massively Parallel Sequencing for the Mutation Detection for Congenital Muscular Dystrophy SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID HYBRID SELECTION; GENERATION; CAPTURE; GENOME; DIAGNOSTICS; GENE AB Sequencing individual genes by Sanger sequencing is a time-consuming and costly approach to resolve clinically heterogeneous genetic disorders. Panel testing offers the ability to efficiently and cost-effectively screen all of the genes for a particular genetic disorder. We assessed the analytical sensitivity and specificity of two different enrichment technologies, solution-based hybridization and microdroplet-based PCR target enrichment, in conjunction with next-generation sequencing (NGS), to identify mutations in 321 exons representing 12 different genes involved with congenital muscular dystrophies. Congenital muscular dystrophies present diagnostic challenges due to phenotypic variability, lack of standard access to and inherent difficulties with muscle immunohistochemical stains, and a general lack of clinician awareness. NGS results were analyzed across several parameters, including sequencing metrics and genotype concordance with Sanger sequencing. Genotyping data showed that both enrichment technologies produced suitable calls for use in clinical laboratories. However, microdroplet-based PCR target enrichment is more appropriate for a clinical laboratory, due to excellent sequence specificity and uniformity, reproducibility, high coverage of the target exons, and the ability to distinguish the active gene versus known pseudogenes. Regardless of the method, exons with highly repetitive and high GC regions are not well enriched and require Sanger sequencing for completeness. Our study demonstrates the successful application of targeted sequencing in conjunction with NGS to screen for mutations in hundreds of exons in a genetically heterogeneous human disorder. (J Mol Diagn 2012, 14: 233-246; DOI: 10.1016/j.jmoldx.2012.01.009) C1 [Valencia, C. Alexander; Rhodenizer, Devin; Bhide, Shruti; Chin, Ephrem; Littlejohn, Martin Robert; Keong, Lisa Mari; Hegde, Madhuri] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Rutkowski, Anne] Cure CMD, Los Angeles, CA USA. [Rutkowski, Anne] Kaiser So Calif Permanente Med Grp, Los Angeles, CA USA. [Bonnemann, Carsten] NINDS, NIH, Bethesda, MD 20892 USA. RP Hegde, M (reprint author), Whitehead Biomed Res Bldg,615 Michael St,Ste 301, Atlanta, GA 30322 USA. EM mhegde@emory.edu FU NIHRC [1NS 069541-01]; MDA [G6396330]; Public Health Service, NIH, National Center for Research Resources [UL1 RR025008, KL2 R0025009, TL1 RR025010] FX Supported by grants from NIHRC 1NS 069541-01 and MDA G6396330. In addition, this research was supported in part by a Public Health Service grant (UL1 RR025008, KL2 R0025009, or TL1 RR025010) from the Clinical and Translational Science Award Program, NIH, National Center for Research Resources. NR 29 TC 28 Z9 28 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAY PY 2012 VL 14 IS 3 BP 233 EP 246 DI 10.1016/j.jmoldx.2012.01.009 PG 14 WC Pathology SC Pathology GA 936UX UT WOS:000303616600007 PM 22426012 ER PT J AU de Langen, AJ Vincent, A Velasquez, LM van Tinteren, H Boellaard, R Shankar, LK Boers, M Smit, EF Stroobants, S Weber, WA Hoekstra, OS AF de Langen, Adrianus J. Vincent, Andrew Velasquez, Linda M. van Tinteren, Harm Boellaard, Ronald Shankar, Lalitha K. Boers, Maarten Smit, Egbert F. Stroobants, Sigrid Weber, Wolfgang A. Hoekstra, Otto S. TI Repeatability of F-18-FDG Uptake Measurements in Tumors: A Metaanalysis SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE F-18-FDG; PET; repeatability; cancer ID POSITRON-EMISSION-TOMOGRAPHY; CELL LUNG-CANCER; ROI DEFINITION; FDG-PET; RESPONSE ASSESSMENT; MALIGNANT-TUMORS; THERAPY RESPONSE; BREAST-CANCER; UPTAKE VALUES; SOLID TUMORS AB PET with the glucose analog F-18-FDG is increasingly used to monitor tumor response to therapy. To use quantitative measurements of tumor F-18-FDG uptake for assessment of tumor response, the repeatability of this quantitative metabolic imaging method needs to be established. Therefore, we determined the repeatability of different standardized uptake value (SUV) measurements using the available data. Methods: A systematic literature search was performed to identify studies addressing F-18-FDG repeatability in malignant tumors. The level of agreement between test and retest values of 2 PET uptake measures, maximum SUV (SUVmax) and mean SUV (SUVmean), was assessed with the coefficient of repeatability using generalized linear mixed-effects models. In addition, the influence of tumor volume on repeatability was assessed. Principal component transformation was used to compare the reproducibility of the 2 different uptake measures. Results: Five cohorts were identified for this metaanalysis. For SUVmax and SUVmean, datasets of 86 and 102 patients, respectively, were available. Percentage repeatability is a function of the level of uptake. SUVmean had the best repeatability characteristics; for serial PET scans, a threshold of a combination of 20% as well as 1.2 SUVmean units was most appropriate. After adjusting for uptake rate, tumor volume had minimal influence on repeatability. Conclusion: SUVmean had better repeatability performance than SUVmax. Both measures showed poor repeatability for lesions with low F-18-FDG uptake. We recommend the evaluation of biologic effects in PET by reporting a combination of minimal relative and absolute changes to account for test retest variability. C1 [de Langen, Adrianus J.; Smit, Egbert F.] Vrije Univ Amsterdam Med Ctr, Dept Pulm Dis, NL-1007 MB Amsterdam, Netherlands. [Vincent, Andrew; van Tinteren, Harm] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Biostat, Amsterdam, Netherlands. [Velasquez, Linda M.] Bristol Myers Squibb Co, Princeton, NJ USA. [Boellaard, Ronald; Hoekstra, Otto S.] Vrije Univ Amsterdam Med Ctr, Dept Nucl Med, NL-1007 MB Amsterdam, Netherlands. [Boellaard, Ronald; Hoekstra, Otto S.] Vrije Univ Amsterdam Med Ctr, PET Res, NL-1007 MB Amsterdam, Netherlands. [Shankar, Lalitha K.] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. [Boers, Maarten] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. [Stroobants, Sigrid] Univ Hosp Antwerpen, Dept Nucl Med, Antwerp, Belgium. [Weber, Wolfgang A.] Univ Freiburg Klinikum, Nukl Med Klin, Freiburg, Germany. RP de Langen, AJ (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Pulm Dis, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM j.delangen@vumc.nl OI Boellaard, Ronald/0000-0002-0313-5686 NR 29 TC 67 Z9 67 U1 1 U2 10 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 MAY PY 2012 VL 53 IS 5 BP 701 EP 708 DI 10.2967/jnumed.111.095299 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 939BU UT WOS:000303782700011 PM 22496583 ER PT J AU Pavletic, AJ Hnatiuk, O AF Pavletic, Adriana J. Hnatiuk, Oleh TI Puzzling Dyspnea Caused by Respiratory Muscle Weakness SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article DE ALS (Amyotrophic Lateral Sclerosis); Dyspnea; Neuromuscular Disorders; Respiratory Muscles AB Dyspnea is common in advanced stages of neuromuscular disorders, but it is infrequently the presenting symptom. However, dyspnea is a frequent complaint in a primary care setting but is rarely caused by a respiratory muscle weakness. Consequently, the diagnosis of respiratory muscle weakness often is delayed. First symptoms may occur when respiratory muscles are under increased load, such as when standing in the water higher than the chest, swimming, or in the supine position. We describe a patient in whom dyspnea was the first symptom of amyotrophic lateral sclerosis to remind clinicians of clinical features of respiratory muscle weakness and to help avoid the delay in diagnosis. (J Am Board Fam Med 2012;25:396-397.) C1 [Pavletic, Adriana J.] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Hnatiuk, Oleh] Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Pavletic, AJ (reprint author), NIMH, Off Clin Director, 10 Ctr Dr, Bethesda, MD 20892 USA. EM pavletia@mail.nih.gov FU National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. NR 5 TC 2 Z9 2 U1 0 U2 1 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD MAY-JUN PY 2012 VL 25 IS 3 BP 396 EP 397 DI 10.3122/jabfm.2012.03.110220 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 939KY UT WOS:000303810600020 PM 22570404 ER PT J AU Figueroa, JD Brinton, LA AF Figueroa, Jonine D. Brinton, Louise A. TI Unraveling Genes, Hormones, and Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PREMENOPAUSAL WOMEN; SUSCEPTIBILITY LOCI; ASSOCIATION CONSORTIUM; SEX STEROIDS; RISK; ESTROGENS; PROLACTIN; ANCESTRY C1 [Figueroa, Jonine D.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Figueroa, JD (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Ste 550,Rm 5104,MSC 7234, Rockville, MD 20852 USA. EM figueroaj@mail.nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU Intramural NIH HHS NR 21 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 9 BP 641 EP 642 DI 10.1093/jnci/djs193 PG 2 WC Oncology SC Oncology GA 936PM UT WOS:000303602500001 PM 22472542 ER PT J AU Umar, A AF Umar, Asad TI Is 15-LOX-1 a Tumor Suppressor? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CANCER CELLS; EXPRESSION; INFLAMMATION; GAMMA C1 NCI, Gastrointestinal & Other Cancers Res Grp, Canc Prevent Div, Rockville, MD 20852 USA. RP Umar, A (reprint author), NCI, Gastrointestinal & Other Cancers Res Grp, Canc Prevent Div, Execut Plaza N 2142,6130 Execut Blvd, Rockville, MD 20852 USA. EM umara@mail.nih.gov NR 11 TC 7 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 9 BP 645 EP 647 DI 10.1093/jnci/djs192 PG 3 WC Oncology SC Oncology GA 936PM UT WOS:000303602500003 PM 22472307 ER PT J AU Timmers, HJLM Chen, CC Carrasquillo, JA Whatley, M Ling, A Eisenhofer, G King, KS Rao, JU Wesley, RA Adams, KT Pacak, K AF Timmers, Henri J. L. M. Chen, Clara C. Carrasquillo, Jorge A. Whatley, Millie Ling, Alexander Eisenhofer, Graeme King, Kathryn S. Rao, Jyotsna U. Wesley, Robert A. Adams, Karen T. Pacak, Karel TI Staging and Functional Characterization of Pheochromocytoma and Paraganglioma by F-18-Fluorodeoxyglucose (F-18-FDG) Positron Emission Tomography SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PET; MUTATIONS; LOCALIZATION; SDHB; DIAGNOSIS AB Background Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of F-18-fluorodeoxyglucose positron emission tomography with computed tomography (F-18-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [I-123]-metaiodobenzylguanidine single photon emission CT (I-123-MIBG SPECT), CT, and magnetic resonance imaging (MRI). Methods A total of 216 patients (106 men, 110 women, aged 45.2 +/- 14.9 years) with suspected PPGL underwent CT or MRI, F-18-FDG PET/CT, and I-123-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. Results Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of F-18-FDG was similar to that of I-123-MIBG but less than that of CT/MRI (sensitivity of F-18-FDG = 76.8%; of I-123-MIBG = 75.0%; of CT/MRI = 95.7%; F-18-FDG vs I-123-MIBG: difference = 1.8%, 95% confidence interval [CI] = 214.8% to 14.8%, P = .210; F-18-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for F-18-FDG, 91.8% for I-123-MIBG, and 90.2% for CT/MRI. F-18-FDG uptake was higher in succinate dehydrogenase complex-and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for F-18-FDG and CT/MRI than for I-123-MIBG (sensitivity of F-18-FDG = 82.5%; of I-123-MIBG = 50.0%; of CT/MRI = 74.4%; F-18-FDG vs I-123-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs I-123-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, F-18-FDG was more sensitive than CT/MRI (sensitivity of F-18-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). Conclusions Compared with I-123-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by F-18-FDG PET. F-18-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL. C1 [Timmers, Henri J. L. M.; Rao, Jyotsna U.] Radboud Univ Nijmegen, Dept Endocrinol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Timmers, Henri J. L. M.; Rao, Jyotsna U.] Radboud Univ Nijmegen, Dept Lab Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.; Carrasquillo, Jorge A.; Whatley, Millie] Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD USA. [Chen, Clara C.; Carrasquillo, Jorge A.; Whatley, Millie; Ling, Alexander] Warren G Magnuson Clin Ctr, Dept Radiol & Imaging Sci, Bethesda, MD USA. [Wesley, Robert A.] NIH, Biostat Serv, Bethesda, MD 20892 USA. [Carrasquillo, Jorge A.] Mem Sloan Kettering Canc Ctr, Nucl Med Sect, Dept Radiol, New York, NY 10021 USA. [Eisenhofer, Graeme] Univ Dresden, Inst Clin Chem & Lab Med, Dept Med, Dept Clin Chem, Dresden, Germany. [Eisenhofer, Graeme] Univ Dresden, Div Clin Neurochem, Dresden, Germany. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bldg 10,CRC 1E-3140,MSC 1109,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov OI Carrasquillo, Jorge/0000-0002-8513-5734 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (NICHD/NIH); Pheo Para Alliance; European Union [259735] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (NICHD/NIH) and Pheo Para Alliance. The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259735. NR 31 TC 70 Z9 73 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 9 BP 700 EP 708 DI 10.1093/jnci/djs188 PG 9 WC Oncology SC Oncology GA 936PM UT WOS:000303602500011 PM 22517990 ER PT J AU Fojo, T Amiri-Kordestani, L Bates, SE AF Fojo, Tito Amiri-Kordestani, Laleh Bates, Susan E. TI Re: Potential Pitfalls of Crossover and Thoughts on Iniparib in Triple-Negative Breast Cancer Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Fojo, Tito; Amiri-Kordestani, Laleh; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 2 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 9 BP 718 EP 718 DI 10.1093/jnci/djs166 PG 1 WC Oncology SC Oncology GA 936PM UT WOS:000303602500016 ER PT J AU Engstrom, PF AF Engstrom, Paul F. TI Ten Years of Progress in Colon Cancer Therapy SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Engstrom, Paul F.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Engstrom, Paul F.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Engstrom, Paul F.] NCI, Bethesda, MD 20892 USA. [Engstrom, Paul F.] Armed Forces Inst Pathol, Sci Advisory Board, Washington, DC 20306 USA. RP Engstrom, PF (reprint author), Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NR 1 TC 0 Z9 2 U1 0 U2 2 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD MAY PY 2012 VL 10 IS 5 BP 574 EP 576 PG 3 WC Oncology SC Oncology GA 935YI UT WOS:000303557700002 PM 22570287 ER PT J AU Bolduc, B Shaughnessy, DP Wolf, YI Koonin, EV Roberto, FF Young, M AF Bolduc, Benjamin Shaughnessy, Daniel P. Wolf, Yuri I. Koonin, Eugene V. Roberto, Francisco F. Young, Mark TI Identification of Novel Positive-Strand RNA Viruses by Metagenomic Analysis of Archaea-Dominated Yellowstone Hot Springs SO JOURNAL OF VIROLOGY LA English DT Article ID PROVIDES ACQUIRED-RESISTANCE; PROTEIN HOMOLOGY DETECTION; SHORT PALINDROMIC REPEATS; STRUCTURE PREDICTION; VIRAL COMMUNITY; IMMUNE-SYSTEMS; NATIONAL-PARK; CRISPR; EVOLUTION; DIVERSITY AB There are no known RNA viruses that infect Archaea. Filling this gap in our knowledge of viruses will enhance our understanding of the relationships between RNA viruses from the three domains of cellular life and, in particular, could shed light on the origin of the enormous diversity of RNA viruses infecting eukaryotes. We describe here the identification of novel RNA viral genome segments from high-temperature acidic hot springs in Yellowstone National Park in the United States. These hot springs harbor low-complexity cellular communities dominated by several species of hyperthermophilic Archaea. A viral metagenomics approach was taken to assemble segments of these RNA virus genomes from viral populations isolated directly from hot spring samples. Analysis of these RNA metagenomes demonstrated unique gene content that is not generally related to known RNA viruses of Bacteria and Eukarya. However, genes for RNA-dependent RNA polymerase (RdRp), a hallmark of positive-strand RNA viruses, were identified in two contigs. One of these contigs is approximately 5,600 nucleotides in length and encodes a polyprotein that also contains a region homologous to the capsid protein of nodaviruses, tetraviruses, and birnaviruses. Phylogenetic analyses of the RdRps encoded in these contigs indicate that the putative archaeal viruses form a unique group that is distinct from the RdRps of RNA viruses of Eukarya and Bacteria. Collectively, our findings suggest the existence of novel positive-strand RNA viruses that probably replicate in hyperthermophilic archaeal hosts and are highly divergent from RNA viruses that infect eukaryotes and even more distant from known bacterial RNA viruses. These positive-strand RNA viruses might be direct ancestors of RNA viruses of eukaryotes. C1 [Bolduc, Benjamin; Shaughnessy, Daniel P.; Young, Mark] Montana State Univ, Thermal Biol Inst, Bozeman, MT 59717 USA. [Young, Mark] Montana State Univ, Dept Microbiol, Bozeman, MT 59717 USA. [Shaughnessy, Daniel P.; Young, Mark] Montana State Univ, Dept Plant Sci & Plant Pathol, Bozeman, MT 59717 USA. [Bolduc, Benjamin] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. [Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Roberto, Francisco F.] Idaho Natl Lab, Idaho Falls, ID USA. RP Young, M (reprint author), Montana State Univ, Thermal Biol Inst, Bozeman, MT 59717 USA. EM myoung@montana.edu FU National Science Foundation [DEB-0936178, EF-080220]; National Aeronautics and Space Administration [NNA-08CN85A]; Department of Health and Human Services (NIH, National Library of Medicine) FX This work was supported by National Science Foundation grant numbers DEB-0936178 and EF-080220 and National Aeronautics and Space Administration grant number NNA-08CN85A. Y.I.W. and E.V.K. are supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). NR 75 TC 44 Z9 46 U1 1 U2 21 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 MAY PY 2012 VL 86 IS 10 BP 5562 EP 5573 DI 10.1128/JVI.07196-11 PG 12 WC Virology SC Virology GA 939DJ UT WOS:000303787100014 PM 22379100 ER PT J AU Heiss, BL Maximova, OA Thach, DC Speicher, JM Pletnev, AG AF Heiss, Brian L. Maximova, Olga A. Thach, Dzung C. Speicher, James M. Pletnev, Alexander G. TI MicroRNA Targeting of Neurotropic Flavivirus: Effective Control of Virus Escape and Reversion to Neurovirulent Phenotype SO JOURNAL OF VIROLOGY LA English DT Article ID RNA RECOMBINATION; DENGUE TYPE-4; ENCEPHALITIS; REGION; PATHOGENICITY; INTERFERENCE; RECOGNITION; ATTENUATION; MECHANISMS; EXPRESSION AB Neurotropic flaviviruses can efficiently replicate in the developing and mature central nervous systems (CNS) of mice causing lethal encephalitis. Insertion of a single copy of a target for brain-expressed microRNAs (miRNAs) in the 3' noncoding region (3'NCR) of the flavivirus genome (chimeric tick-borne encephalitis virus/dengue virus) abolished virus neurovirulence in the mature mouse CNS. However, in the developing CNS of highly permissive suckling mice, the miRNA-targeted viruses can revert to a neurovirulent phenotype by accumulating deletions or mutations within the miRNA target sequence. Virus escape from miRNA-mediated suppression in the developing CNS was markedly diminished by increasing the number of miRNA target sites and by extending the distance between these sites in the virus genome. Insertion of multiple miRNA targets into the 3'NCR altered virus neuroinvasiveness, decreased neurovirulence and neuroinflammatory responses, and prevented neurodegeneration without loss of immunogenicity. Although the onset of encephalitis was delayed, a small number of suckling mice still succumbed to lethal intracerebral infection with the miRNA-targeted viruses. Sequence analysis of brain isolates from moribund mice revealed that the viruses escaped from miRNA-mediated suppression exclusively through the deletion of miRNA targets and viral genome sequence located between the two miRNA targets separated by the greatest distance. These findings offer a general strategy to control the reversion of virus to a virulent phenotype: a simultaneous miRNA targeting of the viral genome at many different functionally important regions could prevent virus escape from miRNA-based attenuation, since a deletion of the targeted genomic sequences located between the inserted miRNA binding sites would be lethal for the virus. C1 [Heiss, Brian L.; Maximova, Olga A.; Thach, Dzung C.; Speicher, James M.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. We do not have a conflict of financial or other interest. NR 37 TC 26 Z9 27 U1 0 U2 6 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 MAY PY 2012 VL 86 IS 10 BP 5647 EP 5659 DI 10.1128/JVI.07125-11 PG 13 WC Virology SC Virology GA 939DJ UT WOS:000303787100022 PM 22419812 ER PT J AU Shukla, P Nguyen, HT Faulk, K Mather, K Torian, U Engle, RE Emerson, SU AF Shukla, P. Nguyen, H. T. Faulk, K. Mather, K. Torian, U. Engle, R. E. Emerson, S. U. TI Adaptation of a Genotype 3 Hepatitis E Virus to Efficient Growth in Cell Culture Depends on an Inserted Human Gene Segment Acquired by Recombination SO JOURNAL OF VIROLOGY LA English DT Article ID CIS-REACTIVE ELEMENT; HYPERVARIABLE REGION; ANIMAL RESERVOIRS; RNA SEQUENCE; PATIENT; PROTEIN; REPLICATION; INFECTION; REVEALS; RELEASE AB An infectious cDNA clone of a genotype 3 strain of hepatitis E virus adapted to growth in HepG2/C3A human hepatoma cells was constructed. This virus was unusual in that the hypervariable region of the adapted virus contained a 171-nucleotide insertion that encoded 58 amino acids of human S17 ribosomal protein. Analyses of virus from six serial passages indicated that genomes with this insert, although initially rare, were selected during the first passage, suggesting it conferred a significant growth advantage. RNA transcripts from this cDNA and the viruses encoded by them were infectious for cells of both human and swine origin, the major host species for this zoonotic virus. Mutagenesis studies demonstrated that the S17 insert was a major factor in cell culture adaptation. Introduction of 54 synonymous mutations into the insert had no detectable effect, thus implicating protein, rather than RNA, as the important component. Truncation of the insert by 50% decreased the levels of successful transfection by similar to 3-fold. Substitution of the S17 sequence by a different ribosomal protein sequence or by GTPase-activating protein sequence resulted in a partial enhancement of transfection levels, whereas substitution with 58 amino acids of green fluorescent protein had no effect. Therefore, both the sequence length and the amino acid composition of the insert were important. The S17 sequence did not affect transfection of human hepatoma cells when inserted into the hypervariable region of a genotype 1 strain, but this chimeric genome acquired a dramatic ability to replicate in hamster cells. C1 [Emerson, S. U.] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 34 TC 58 Z9 59 U1 0 U2 6 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 MAY PY 2012 VL 86 IS 10 BP 5697 EP 5707 DI 10.1128/JVI.00146-12 PG 11 WC Virology SC Virology GA 939DJ UT WOS:000303787100026 PM 22398290 ER PT J AU Brock, LG Karron, RA Krempl, CD Collins, PL Buchholz, UJ AF Brock, Linda G. Karron, Ruth A. Krempl, Christine D. Collins, Peter L. Buchholz, Ursula J. TI Evaluation of Pneumonia Virus of Mice as a Possible Human Pathogen SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; HOUSE MICE; SEROLOGICAL SURVEY; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; HEPARAN-SULFATE; GENOME SEQUENCE; DENDRITIC CELLS; MUS-DOMESTICUS; MESSENGER-RNA AB Pneumonia virus of mice (PVM), a relative of human respiratory syncytial virus (RSV), causes respiratory disease in mice. There is serologic evidence suggesting widespread exposure of humans to PVM. To investigate replication in primates, African green monkeys (AGM) and rhesus macaques (n = 4) were inoculated with PVM by the respiratory route. Virus was shed intermittently at low levels by a subset of animals, suggesting poor permissiveness. PVM efficiently replicated in cultured human cells and inhibited the type I interferon (IFN) response in these cells. This suggests that poor replication in nonhuman primates was not due to a general nonpermissiveness of primate cells or poor control of the IFN response. Seroprevalence in humans was examined by screening sera from 30 adults and 17 young children for PVM-neutralizing activity. Sera from a single child (6%) and 40% of adults had low neutralizing activity against PVM, which could be consistent with increasing incidence of exposure following early childhood. There was no cross-reaction of human or AGM sera between RSV and PVM and no cross-protection in the mouse model. In native Western blots, human sera reacted with RSV but not PVM proteins under conditions in which AGM immune sera reacted strongly. Serum reactivity was further evaluated by flow cytometry using unfixed Vero cells infected with PVM or RSV expressing green fluorescent protein (GFP) as a measure of viral gene expression. The reactivity of human sera against RSV-infected cells correlated with GFP expression, whereas reactivity against PVM-infected cells was low and uncorrelated with GFP expression. Thus, PVM specificity was not evident. Our results indicate that the PVM-neutralizing activity of human sera is not due to RSV- or PVM-specific antibodies but may be due to low-affinity, polyreactive natural antibodies of the IgG subclass. The absence of PVM-specific antibodies and restriction in nonhuman primates makes PVM unlikely to be a human pathogen. C1 [Brock, Linda G.; Collins, Peter L.; Buchholz, Ursula J.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Karron, Ruth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Krempl, Christine D.] Univ Wurzburg, Inst Virol & Immunbiol, D-8700 Wurzburg, Germany. RP Buchholz, UJ (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Krempl, Christine/O-2081-2015 FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 73 TC 7 Z9 7 U1 0 U2 4 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 MAY PY 2012 VL 86 IS 10 BP 5829 EP 5843 DI 10.1128/JVI.00163-12 PG 15 WC Virology SC Virology GA 939DJ UT WOS:000303787100039 PM 22438539 ER PT J AU Wu, XL Wang, C O'Dell, S Li, YX Keele, BF Yang, ZJ Imamichi, H Doria-Rose, N Hoxie, JA Connors, M Shaw, GM Wyatt, RT Mascola, JR AF Wu, Xueling Wang, Charlene O'Dell, Sijy Li, Yuxing Keele, Brandon F. Yang, Zhongjia Imamichi, Hiromi Doria-Rose, Nicole Hoxie, James A. Connors, Mark Shaw, George M. Wyatt, Richard T. Mascola, John R. TI Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBTYPE-C INFECTION; RECOMBINANT GLYCOPROTEIN-120 VACCINE; MULTIPLE SEQUENCE ALIGNMENT; HUMAN MONOCLONAL-ANTIBODY; TYPE-1 INFECTION; HIGH-THROUGHPUT; EVOLUTION; GP120; RESPONSES AB The monoclonal antibody (MAb) VRC01 was isolated from a slowly progressing HIV-1-infected donor and was shown to neutralize diverse HIV-1 strains by binding to the conserved CD4 binding site (CD4bs) of gp120. To better understand the virologic factors associated with such antibody development, we characterized HIV-1 envelope (Env) variants from this donor and five other donors who developed broadly neutralizing antibodies. A total of 473 env sequences were obtained by single-genome amplification, and 100 representative env clones were expressed and tested for entry and neutralization sensitivity. While VRC01 neutralizes about 90% of the genetically diverse heterologous HIV-1 strains tested, only selective archival Env variants from the VRC01 donor were sensitive to VRC01 and all of the Env variants derived from the donor plasma were resistant, indicating strong antibody-based selection pressure. Despite their resistance to this broadly reactive MAb that partially mimics CD4, all Env variants required CD4 for entry. Three other CD4bs MAbs from the same donor were able to neutralize some VRC01 escape variants, suggesting that CD4bs antibodies continued to evolve in response to viral escape. We also observed a relatively high percentage of VRC01-resistant Env clones in the plasma of four of five additional broadly neutralizing donors, suggesting the presence of CD4bs-directed neutralizing antibodies in these donors. In total, these data indicate that the CD4bs-directed neutralizing antibodies exert ongoing selection pressure on the conserved CD4bs epitope of HIV-1 Env. C1 [Wu, Xueling; Wang, Charlene; O'Dell, Sijy; Yang, Zhongjia; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Imamichi, Hiromi; Doria-Rose, Nicole; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Li, Yuxing; Wyatt, Richard T.] Scripps Res Inst, Dept Med & Microbial Sci, IAVI Ctr Neutralizing Antibodies TSRI, La Jolla, CA 92037 USA. [Keele, Brandon F.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. [Hoxie, James A.; Shaw, George M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU Vaccine Research Center, NIAID, NIH; NIH [AI067854]; Bill & Melinda Gates Foundation [37874] FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. G.M.S. was supported by grants from the NIH (AI067854) and the Bill & Melinda Gates Foundation Grand Challenges Program (37874). NR 82 TC 45 Z9 46 U1 1 U2 13 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 MAY PY 2012 VL 86 IS 10 BP 5844 EP 5856 DI 10.1128/JVI.07139-11 PG 13 WC Virology SC Virology GA 939DJ UT WOS:000303787100040 PM 22419808 ER PT J AU Yamamoto, T Johnson, MJ Price, DA Wolinsky, DI Almeida, JR Petrovas, C Nason, M Yeh, WW Shen, L Roederer, M Rao, SS McDermott, AB Lefebvre, F Nabel, GJ Haddad, EK Letvin, NL Douek, DC Koup, RA AF Yamamoto, Takuya Johnson, Matthew J. Price, David A. Wolinsky, David I. Almeida, Jorge R. Petrovas, Constantinos Nason, Martha Yeh, Wendy W. Shen, Ling Roederer, Mario Rao, Srinivas S. McDermott, Adrian B. Lefebvre, Francois Nabel, Gary J. Haddad, Elias K. Letvin, Norman L. Douek, Daniel C. Koup, Richard A. TI Virus Inhibition Activity of Effector Memory CD8(+) T Cells Determines Simian Immunodeficiency Virus Load in Vaccinated Monkeys after Vaccine Breakthrough Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CONVERGENT RECOMBINATION; IMMUNE-RESPONSES; HIV-1 INFECTION; SIV INFECTION; RECEPTOR; VIREMIA; ESCAPE; DISEASE; USAGE AB The goal of an effective AIDS vaccine is to generate immunity that will prevent human immunodeficiency virus 1 (HIV-1) acquisition. Despite limited progress toward this goal, renewed optimism has followed the recent success of the RV144 vaccine trial in Thailand. However, the lack of complete protection in this trial suggests that breakthroughs, where infection occurs despite adequate vaccination, will be a reality for many vaccine candidates. We previously reported that neutralizing antibodies elicited by DNA prime-recombinant adenovirus serotype 5 (rAd5) boost vaccination with simian immunodeficiency virus strain mac239 (SIVmac239) Gag-Pol and Env provided protection against pathogenic SIVsmE660 acquisition after repeated mucosal challenge. Here, we report that SIV-specific CD8(+) T cells elicited by that vaccine lowered both peak and set-point viral loads in macaques that became infected despite vaccination. These SIV-specific CD8(+) T cells showed strong virus-inhibitory activity (VIA) and displayed an effector memory (EM) phenotype. VIA correlated with high levels of CD107a mobilization and perforin expression in SIV-specific CD8(+) T cells. Remarkably, both the frequency and the number of Gag CM9-specific public clonotypes were strongly correlated with VIA mediated by EM CD8(+) T cells. The ability to elicit such virus-specific EM CD8(+) T cells might contribute substantially to an efficacious HIV/AIDS vaccine, even after breakthrough infection. C1 [Yamamoto, Takuya; Johnson, Matthew J.; Price, David A.; Wolinsky, David I.; Almeida, Jorge R.; Petrovas, Constantinos; Roederer, Mario; Rao, Srinivas S.; McDermott, Adrian B.; Nabel, Gary J.; Douek, Daniel C.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Yeh, Wendy W.; Shen, Ling; Letvin, Norman L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Lefebvre, Francois; Haddad, Elias K.] VGTI FL, Port St Lucie, FL USA. RP Koup, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov RI Yamamoto, Takuya/L-2642-2013; Price, David/C-7876-2013; OI Yamamoto, Takuya/0000-0003-3753-1211; Price, David/0000-0001-9416-2737; Ramos de Almeida, Jorge/0000-0002-5009-8478 FU Vaccine Research Center, NIAID, National Institutes of Health; Harvard Medical School Center for AIDS Research [AI060354]; Bill & Melinda Gates Foundation [OPP1032325] FX This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health, Harvard Medical School Center for AIDS Research grant AI060354, and Collaboration for AIDS Vaccine Discovery (CAVD) grant number OPP1032325 from the Bill & Melinda Gates Foundation. NR 33 TC 26 Z9 28 U1 0 U2 6 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 MAY PY 2012 VL 86 IS 10 BP 5877 EP 5884 DI 10.1128/JVI.00315-12 PG 8 WC Virology SC Virology GA 939DJ UT WOS:000303787100043 PM 22419810 ER PT J AU Boyer, PL Clark, PK Hughes, SH AF Boyer, Paul L. Clark, Patrick K. Hughes, Stephen H. TI HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL DRUG-RESISTANCE; T-LYMPHOCYTES; DE-NOVO; MUTATIONS; EXCISION; EMERGENCE; SUBDOMAIN; INFECTION; COMPLEX AB As anti-HIV therapy becomes more widely available in developing nations, it is clear that drug resistance will continue to be a major problem. The related viruses HIV-1 and HIV-2 share many of the same resistance pathways to nucleoside reverse transcriptase inhibitors (NRTIs). However, clinical data suggest that while HIV-1 reverse transcriptase (RT) usually uses an ATP-dependent excision pathway to develop resistance to the nucleoside analog zidovudine (AZT), HIV-2 RT does not appear to use this pathway. We previously described data that suggested that wild-type (WT) HIV-2 RT has a much lower ability to excise AZT monophosphate (AZTMP) than does WT HIV-1 RT and suggested that this is the reason that HIV-2 RT more readily adopts an exclusion pathway against AZT triphosphate (AZTTP), while HIV-1 RT is better able to exploit the ATP-dependent pyrophosphorolysis mechanism. However, we have now done additional experiments, which show that while HIV-1 RT can adopt either an exclusion- or excision-based resistance mechanism against AZT, HIV-2 RT can use only the exclusion mechanism. All of our attempts to make HIV-2 RT excision competent did not produce an AZT-resistant RI but instead yielded RTs that were less able to polymerize than the WT. This suggests that the exclusion pathway is the only pathway available to HIV-2. C1 [Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Clark, Patrick K.] SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. EM hughesst@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN26120080001E] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. NR 40 TC 19 Z9 19 U1 0 U2 6 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 MAY PY 2012 VL 86 IS 10 BP 5885 EP 5894 DI 10.1128/JVI.06597-11 PG 10 WC Virology SC Virology GA 939DJ UT WOS:000303787100044 PM 22438533 ER PT J AU Howard, AR Moss, B AF Howard, Amanda R. Moss, Bernard TI Formation of Orthopoxvirus Cytoplasmic A-Type Inclusion Bodies and Embedding of Virions Are Dynamic Processes Requiring Microtubules SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIN-BASED MOTILITY; VACCINIA VIRUS A26; COWPOX VIRUS; INTRACELLULAR MOVEMENT; MATURE VIRIONS; MAJOR PROTEIN; MATRIX; GENE; TRANSLATION; PARTICLES AB In cells infected with some orthopoxviruses, numerous mature virions (MVs) become embedded within large, cytoplasmic A-type inclusions (ATIs) that can protect infectivity after cell lysis. ATIs are composed of an abundant viral protein called ATIp, which is truncated in orthopoxviruses such as vaccinia virus (VACV) that do not form ATIs. To study ATI formation and occlusion of MVs within ATIs, we used recombinant VACVs that express the cowpox full-length ATIp or we transfected plasmids encoding ATIp into cells infected with VACV, enabling ATI formation. ATI enlargement and MV embedment required continued protein synthesis and an intact microtubular network. For live imaging of ATIs and MVs, plasmids expressing mCherry fluorescent protein fused to ATIp were transfected into cells infected with VACV expressing the viral core protein A4 fused to yellow fluorescent protein. ATIs appeared as dynamic, mobile bodies that enlarged by multiple coalescence events, which could be prevented by disrupting microtubules. Coalescence of ATIs was confirmed in cells infected with cowpox virus. MVs were predominantly at the periphery of Ails early in infection. We determined that coalescence contributed to the distribution of MVs within Ails and that microtubule-disrupting drugs abrogated coalescence-mediated MV embedment. In addition, MVs were shown to move from viral factories at speeds consistent with microtubular transport to the peripheries of ATIs, whereas disruption of microtubules prevented such trafficking. The data indicate an important role for microtubules in the coalescence of ATIs into larger structures, transport of MVs to Ails, and embedment of MVs within the ATI matrix. C1 [Howard, Amanda R.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX The work was supported by the Division of Intramural Research, NIAID, NIH. NR 33 TC 6 Z9 6 U1 0 U2 1 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 MAY PY 2012 VL 86 IS 10 BP 5905 EP 5914 DI 10.1128/JVI.06997-11 PG 10 WC Virology SC Virology GA 939DJ UT WOS:000303787100046 PM 22438543 ER PT J AU Xiao, S Paldurai, A Nayak, B Samuel, A Bharoto, EE Prajitno, TY Collins, PL Samal, SK AF Xiao, Sa Paldurai, Anandan Nayak, Baibaswata Samuel, Arthur Bharoto, Eny E. Prajitno, Teguh Y. Collins, Peter L. Samal, Siba K. TI Complete Genome Sequences of Newcastle Disease Virus Strains Circulating in Chicken Populations of Indonesia SO JOURNAL OF VIROLOGY LA English DT Article ID FUSION PROTEIN; VIRULENCE AB Eight highly virulent Newcastle disease virus (NDV) strains were isolated from vaccinated commercial chickens in Indonesia during outbreaks in 2009 and 2010. The complete genome sequences of two NDV strains and the sequences of the surface protein genes (F and HN) of six other strains were determined. Phylogenetic analysis classified them into two new subgroups of genotype VII in the class II cluster that were genetically distinct from vaccine strains. This is the first report of complete genome sequences of NDV strains isolated from chickens in Indonesia. C1 [Xiao, Sa; Paldurai, Anandan; Nayak, Baibaswata; Samuel, Arthur; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Bharoto, Eny E.] Vaksindo Satwa Nusantara, Jakarta, Indonesia. [Prajitno, Teguh Y.] Japfa Comfeed Indonesia, Jakarta, Indonesia. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID, NIH FX This work was supported by NIAID contract N01A060009 (85% support) and the NIAID, NIH, Intramural Research Program (15% support). NR 8 TC 21 Z9 24 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2012 VL 86 IS 10 BP 5969 EP 5970 DI 10.1128/JVI.00546-12 PG 2 WC Virology SC Virology GA 939DJ UT WOS:000303787100061 PM 22532534 ER PT J AU Wentzensen, N AF Wentzensen, Nicolas TI Screening for anal cancer: endpoints needed SO LANCET ONCOLOGY LA English DT Editorial Material ID CERVICAL-CANCER; INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; PREVENTION C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov NR 8 TC 10 Z9 11 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2012 VL 13 IS 5 BP 438 EP 440 DI 10.1016/S1470-2045(12)70101-8 PG 4 WC Oncology SC Oncology GA 935HC UT WOS:000303508700024 PM 22445258 ER PT J AU Madan, RA Mohebtash, M Arlen, PM Vergati, M Rauckhorst, M Steinberg, SM Tsang, KY Poole, DJ Parnes, HL Wright, JJ Dahut, WL Schlom, J Gulley, JL AF Madan, Ravi A. Mohebtash, Mahsa Arlen, Philip M. Vergati, Matteo Rauckhorst, Myrna Steinberg, Seth M. Tsang, Kwong Y. Poole, Diane J. Parnes, Howard L. Wright, John J. Dahut, William L. Schlom, Jeffrey Gulley, James L. TI Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial SO LANCET ONCOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; IMMUNOTHERAPY; MELANOMA; SURVIVAL; CTLA-4; AUTOIMMUNITY; PROGRESSION; CARCINOMA; BLOCKADE; SAFETY AB Background Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. Methods We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2x10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1x10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. Findings We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. Interpretation The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. C1 [Madan, Ravi A.; Mohebtash, Mahsa; Arlen, Philip M.; Vergati, Matteo; Rauckhorst, Myrna; Tsang, Kwong Y.; Poole, Diane J.; Schlom, Jeffrey; Gulley, James L.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Arlen, Philip M.; Parnes, Howard L.; Wright, John J.; Dahut, William L.; Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU US National Institutes of Health; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX US National Institutes of Health.; We acknowledge the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, for its support of this study. We also express appreciation to the professionals at the NIH Clinical Center Blood Bank for their part in apheresis procedures for study patients, and to the medical oncology fellows at the National Cancer Institute for their attention to patient care. We thank Bonnie L Casey and Debra Weingarten for their editorial assistance in the preparation of this report. NR 31 TC 148 Z9 149 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2012 VL 13 IS 5 BP 501 EP 508 DI 10.1016/S1470-2045(12)70006-2 PG 8 WC Oncology SC Oncology GA 935HC UT WOS:000303508700041 PM 22326924 ER PT J AU Galanis, E Wu, WT Cloughesy, T Lamborn, K Mann, B Wen, PY Reardon, DA Wick, W Macdonald, D Armstrong, TS Weller, M Vogelbaum, M Colman, H Sargent, DJ van den Bent, MJ Gilbert, M Chang, S AF Galanis, Evanthia Wu, Wenting Cloughesy, Timothy Lamborn, Kathleen Mann, Bhupinder Wen, Patrick Y. Reardon, David A. Wick, Wolfgang Macdonald, David Armstrong, Terri S. Weller, Michael Vogelbaum, Michael Colman, Howard Sargent, Daniel J. van den Bent, Martin J. Gilbert, Mark Chang, Susan TI Phase 2 trial design in neuro-oncology revisited: a report from the RANO group SO LANCET ONCOLOGY LA English DT Review ID II CLINICAL-TRIALS; NEWLY-DIAGNOSED GLIOBLASTOMA; RANDOMIZED DISCONTINUATION DESIGN; GLIOMAS RESPONSE ASSESSMENT; RECURRENT GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; PROGNOSTIC-FACTORS; PLUS TEMOZOLOMIDE; RADIATION-THERAPY; MALIGNANT GLIOMA AB Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents-which are competing for a small patient population, in view of the low incidence of primary brain tumours-draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs-such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs-can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology. C1 [Galanis, Evanthia] Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. [Wu, Wenting; Sargent, Daniel J.] Mayo Clin, Dept Stat, Rochester, MN 55905 USA. [Cloughesy, Timothy] Ronald Reagan UCLA Med Ctr, Neurooncol Program, Los Angeles, CA USA. [Lamborn, Kathleen; Chang, Susan] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Mann, Bhupinder] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Wen, Patrick Y.; Reardon, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wick, Wolfgang] Univ Heidelberg, Dept Neurooncol, Heidelberg, Germany. [Wick, Wolfgang] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Macdonald, David] London Reg Canc Ctr, Dept Med Oncol, London, ON N6A 4L6, Canada. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Sch Nursing, Dept Integrated Care, Houston, TX USA. [Armstrong, Terri S.; Gilbert, Mark] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Weller, Michael] Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland. [Vogelbaum, Michael] Cleveland Clin, Dept Neurol Surg, Cleveland, OH 44106 USA. [Colman, Howard] Univ Utah, Dept Neurosurg, Salt Lake City, UT USA. [van den Bent, Martin J.] Erasmus Univ, Med Ctr, Dept Neurooncol, Daniel den Hoed Canc Ctr, Rotterdam, Netherlands. RP Galanis, E (reprint author), Mayo Clin, Dept Oncol, Rochester, MN 55905 USA. EM galanis.evanthia@mayo.edu FU Roche; Novartis; Amgen; AstraZeneca; Sanofi-Aventis; Genentech; Vascular Biogenics; Esai; Exelixis; MSD; Boehinger-Ingelheim; Merck; Merck Serono; Bayer Onyx; Myrexis; Schering FX MJvdB has a consultant role with Roche, MSD, Siena Biotech, Antisense Pharma, and Merck Ag; and has received honoraria from MSD and research funding from Roche. MV has a consultant role with Merck, Bristol-Myers Squibb, and Pharmaco-kinesis. TC has a consultant role with Genentech/Roche, Lilly, Novartis, and Agio; and has received honoraria from Merck. PYW has a consultant role with Novartis, Merck, and Stemline Therapeutics; and has received honoraria from Merck and research support from Novartis, Amgen, AstraZeneca, Sanofi-Aventis, Genentech, Vascular Biogenics, Esai, and Exelixis. DAR has a consultant role with Genentech/Roche, EMD Serono, and Merck/Schering; and has received honoraria from Genentech/Roche, EMD Serono, and Merck/Schering. WWi has a consultant role with Roche, Magforce, and MSD; and has received honoraria from MSD and research funding from MSD and Boehinger-Ingelheim. TSA has received honoraria from Merck and research funding from Merck and Genentech. MW has a consultant role with Roche, Merck, and SMD; and has received research funding from Roche and Merck Serono. HC has a consultant role with Castle Biosciences and has received research funding from Bayer Onyx and Myrexis. MG has a consultant role with Genentech, Merck, and Abbott; and has received honoraria and research funding from Merck and Genentech. SC has received research funding from Novartis and Schering. DM has received honoraria from Merck and Roche. EG, WWu, DJS, KL, and BM declare that they have no conflicts of interest in relation to this manuscript. NR 47 TC 23 Z9 23 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2012 VL 13 IS 5 BP E196 EP E204 PG 9 WC Oncology SC Oncology GA 935HC UT WOS:000303508700016 PM 22554547 ER PT J AU Baskar, S Wiestner, A Wilson, WH Pastan, I Rader, C AF Baskar, Sivasubramanian Wiestner, Adrian Wilson, Wyndham H. Pastan, Ira Rader, Christoph TI Targeting malignant B cells with an immunotoxin against ROR1 SO MABS LA English DT Article DE ROR1; immunotoxin; monoclonal antibody; chronic lymphocytic leukemia; mantle cell lymphoma ID CHRONIC LYMPHOCYTIC-LEUKEMIA; RECEPTOR TYROSINE KINASE; STABILIZED FV FRAGMENTS; PSEUDOMONAS EXOTOXIN-A; RECOMBINANT IMMUNOTOXIN; RFB4(DSFV)-PE38 BL22; HEMATOLOGIC MALIGNANCIES; MONOCLONAL-ANTIBODY; CYTOTOXIC ACTIVITY; CLL CELLS AB The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has made ROR1 a novel and promising target for therapeutic monoclonal antibodies (mAbs). Four mouse mAbs generated by hybridoma technology exhibited specific binding to human ROR1 (hROR1). Epitope mapping studies showed that two mAbs (2A2 and 2D11) recognized N-terminal epitopes in the extracellular region of ROR1 and the other two (1A1 and 1A7) recognized C-terminal epitopes. A ROR1-immunotoxin (BT-1) consisting of truncated Pseudomonas exotoxin A ( PE 38) and the V H and V L fragments of 2A2-IgG was made recombinantly. Both 2A2-IgG and BT-1 showed dose-dependent and selective binding to primary CLL and MCL cells and MCL cell lines. Kinetic analyses revealed 0.12-nM (2A2-IgG) to 65-nM (BT-1) avidity/affinity to hROR1, depicting bivalent and monovalent interactions, respectively. After binding to cell surface ROR1, 2A2-IgG and BT-1 were partially internalized by primary CLL cells and MCL cell lines, and BT-1 induced profound apoptosis of ROR1-expressing MCL cell lines in vitro (EC50 = 16 pM-16 nM), but did not affect ROR1-negative cell lines. Our data suggest that ROR1-immunotoxins such as BT-1 could serve as targeted therapeutic agents for ROR1-expressing B cell malignancies and other cancers. C1 [Baskar, Sivasubramanian; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wiestner, Adrian] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Baskar, S (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM baskars@mail.nih.gov FU National Institutes of Health [National Cancer Institute and National Heart, Lung and Blood Institute] FX This work was funded by the Intramural Research Program of the National Institutes of Health [National Cancer Institute and National Heart, Lung and Blood Institute]. We thank Mr. Michael G. Kennedy and Dr. Jiahui Yang for the generation of recombinant ROR1 proteins, Dr. Anders Rosen for providing the 232-B4 cell line and Dr. William G. Telford and Ms. Veena Kapoor for maintaining the flow cytometry core facility. NR 51 TC 27 Z9 28 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 J9 MABS-AUSTIN JI mAbs PD MAY-JUN PY 2012 VL 4 IS 3 BP 349 EP 361 DI 10.4161/mabs.19870 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 938LT UT WOS:000303735700007 PM 22531447 ER PT J AU Koay, CG Ozarslan, E Johnson, KM Meyerand, ME AF Koay, Cheng Guan Oezarslan, Evren Johnson, Kevin M. Meyerand, M. Elizabeth TI Sparse and optimal acquisition design for diffusion MRI and beyond SO MEDICAL PHYSICS LA English DT Article DE sparse design; optimal acquisition; diffusion MRI; multiple-shell acquisition; 3D radial MRI; moderately greedy combinatorial search; combinatorial optimization ID FAST SPIN-ECHO; HUMAN BRAIN; WEIGHTED MRI; RESOLUTION; RECONSTRUCTION; CONTRAST; OPTIMIZATION; ANGIOGRAPHY; FRAMEWORK; SCHEMES AB Purpose: Diffusion magnetic resonance imaging (MRI) in combination with functional MRI promises a whole new vista for scientists to investigate noninvasively the structural and functional connectivity of the human brain-the human connectome, which had heretofore been out of reach. As with other imaging modalities, diffusion MRI data are inherently noisy and its acquisition time-consuming. Further, a faithful representation of the human connectome that can serve as a predictive model requires a robust and accurate data-analytic pipeline. The focus of this paper is on one of the key segments of this pipeline-in particular, the development of a sparse and optimal acquisition (SOA) design for diffusion MRI multiple-shell acquisition and beyond. Methods: The authors propose a novel optimality criterion for sparse multiple-shell acquisition and quasimultiple-shell designs in diffusion MRI and a novel and effective semistochastic and moderately greedy combinatorial search strategy with simulated annealing to locate the optimum design or configuration. The goal of the optimality criteria is threefold: first, to maximize uniformity of the diffusion measurements in each shell, which is equivalent to maximal incoherence in angular measurements; second, to maximize coverage of the diffusion measurements around each radial line to achieve maximal incoherence in radial measurements for multiple-shell acquisition; and finally, to ensure maximum uniformity of diffusion measurement directions in the limiting case when all the shells are coincidental as in the case of a single-shell acquisition. The approach taken in evaluating the stability of various acquisition designs is based on the condition number and the A-optimal measure of the design matrix. Results: Even though the number of distinct configurations for a given set of diffusion gradient directions is very large in general-e.g., in the order of 10(232) for a set of 144 diffusion gradient directions, the proposed search strategy was found to be effective in finding the optimum configuration. It was found that the square design is the most robust (i.e., with stable condition numbers and A-optimal measures under varying experimental conditions) among many other possible designs of the same sample size. Under the same performance evaluation, the square design was found to be more robust than the widely used sampling schemes similar to that of 3D radial MRI and of diffusion spectrum imaging (DSI). Conclusions: A novel optimality criterion for sparse multiple-shell acquisition and quasimultiple-shell designs in diffusion MRI and an effective search strategy for finding the best configuration have been developed. The results are very promising, interesting, and practical for diffusion MRI acquisitions. (C) 2012 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.3700166] C1 [Koay, Cheng Guan; Johnson, Kevin M.; Meyerand, M. Elizabeth] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Oezarslan, Evren] NICHHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Oezarslan, Evren] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Meyerand, M. Elizabeth] Univ Wisconsin, Dept Biomed Engn, Madison, WI 53705 USA. RP Koay, CG (reprint author), Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53705 USA. EM cgkoay@wisc.edu RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU National Institutes of Health [IRCMH090912-01]; Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM); Henry M. Jackson Foundation (HJF) FX C.G.K. dedicates this work to Pauline Toh and Eng Khoon Leong. Software related to this work will be made available through the following URL: http://sites.google.com/site/hispeedpackets. This work was supported in part by the National Institutes of Health Grant No. IRCMH090912-01. E.O. was supported by the Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) and the Henry M. Jackson Foundation (HJF). NR 66 TC 11 Z9 11 U1 0 U2 7 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2012 VL 39 IS 5 BP 2499 EP 2511 DI 10.1118/1.3700166 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 936QE UT WOS:000303604300020 PM 22559620 ER PT J AU Hewitt, SC Li, LP Grimm, SA Chen, Y Liu, LW Li, Y Bushel, PR Fargo, D Korach, KS AF Hewitt, Sylvia C. Li, Leping Grimm, Sara A. Chen, Yu Liu, Liwen Li, Yin Bushel, Pierre R. Fargo, David Korach, Kenneth S. TI Research Resource: Whole-Genome Estrogen Receptor alpha Binding in Mouse Uterine Tissue Revealed by ChIP-Seq SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID RNA-POLYMERASE-II; GENE-EXPRESSION; PROGESTERONE-RECEPTOR; NULL MUTATION; TARGET GENES; IN-VIVO; CELLS; EXPOSURE; UTERUS; HOXA10 AB To advance understanding of mechanisms leading to biological and transcriptional endpoints related to estrogen action in the mouse uterus, we have mapped ER alpha and RNA polymerase II (PolII) binding sites using chromatin immunoprecipitation followed by sequencing of enriched chromatin fragments. In the absence of hormone, 5184 ER alpha-binding sites were apparent in the vehicle-treated ovariectomized uterine chromatin, whereas 17,240 were seen 1 h after estradiol (E-2) treatment, indicating that some sites are occupied by unliganded ER alpha, and that ER alpha binding is increased by E-2. Approximately 15% of the uterine ER alpha-binding sites were adjacent to (<10 kb) annotated transcription start sites, and many sites are found within genes or are found more than 100 kb distal from mapped genes; however, the density (sites per base pair) of ER alpha-binding sites is significantly greater adjacent to promoters. An increase in quantity of sites but no significant positional differences were seen between vehicle and E-2-treated samples in the overall locations of ER alpha-binding sites either distal from, adjacent to, or within genes. Analysis of the PolII data revealed the presence of poised promoter-proximal PolII on some highly up-regulated genes. Additionally, corecruitment of PolII and ER alpha to some distal enhancer regions was observed. A de novo motif analysis of sequences in the ER alpha-bound chromatin confirmed that estrogen response elements were significantly enriched. Interestingly, in areas of ER alpha binding without predicted estrogen response element motifs, homeodomain transcription factor-binding motifs were significantly enriched. The integration of the ER alpha- and PolII-binding sites from our uterine sequencing of enriched chromatin fragments data with transcriptional responses revealed in our uterine microarrays has the potential to greatly enhance our understanding of mechanisms governing estrogen response in uterine and other estrogen target tissues. (Molecular Endocrinology 26: 887-898, 2012) C1 [Hewitt, Sylvia C.; Li, Yin; Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Li, Leping; Bushel, Pierre R.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Liu, Liwen] NIEHS, Biostat Branch, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), NIEHS, Lab Reprod & Dev Toxicol, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM curtiss@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health [Z01ES70065, Z01ES101765] FX This work was supported by National Institutes of Health Intramural Research project numbers Z01ES70065 (to S.C.H., Y.L., and K.S.K.) and Z01ES101765 (to L. Li). NR 48 TC 36 Z9 37 U1 0 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2012 VL 26 IS 5 BP 887 EP 898 DI 10.1210/me.2011-1311 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 940BL UT WOS:000303864900016 PM 22446102 ER PT J AU Li, M Du, X Villaruz, AE Diep, BA Wang, DC Song, Y Tian, YR Hu, JH Yu, FY Lu, Y Otto, M AF Li, Min Du, Xin Villaruz, Amer E. Diep, Binh An Wang, Decheng Song, Yan Tian, Yueru Hu, Jinhui Yu, Fangyou Lu, Yuan Otto, Michael TI MRSA epidemic linked to a quickly spreading colonization and virulence determinant SO NATURE MEDICINE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; NASAL COLONIZATION; GENOME SEQUENCE; 2 HOSPITALS; INFECTIONS; EVOLUTION; ADHERENCE; CARRIAGE; STRAINS; EVASION AB The molecular processes underlying epidemic waves of methicillin-resistant Staphylococcus aureus (MRSA) infection are poorly understood(1). Although a major role has been attributed to the acquisition of virulence determinants by horizontal gene transfer(2), there are insufficient epidemiological and functional data supporting that concept. We here report the spread of clones containing a previously extremely rare(3,4) mobile genetic element-encoded gene, sasX. We demonstrate that sasX has a key role in MRSA colonization and pathogenesis, substantially enhancing nasal colonization, lung disease and abscess formation and promoting mechanisms of immune evasion. Moreover, we observed the recent spread of sasX from sequence type 239 (ST239) to invasive clones belonging to other sequence types. Our study identifies sasX as a quickly spreading crucial determinant of MRSA pathogenic success and a promising target for therapeutic interference. Our results provide proof of principle that horizontal gene transfer of key virulence determinants drives MRSA epidemic waves. C1 [Villaruz, Amer E.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Li, Min; Du, Xin; Song, Yan; Tian, Yueru; Hu, Jinhui; Lu, Yuan] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Lab Med, Shanghai 200433, Peoples R China. [Diep, Binh An] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA USA. [Wang, Decheng] Fudan Univ, Shanghai Med Coll, Inst Med Microbiol, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. [Wang, Decheng] Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. [Yu, Fangyou] Wenzhou Med Coll, Affiliated Hosp 1, Dept Lab Med, Wenzhou, Peoples R China. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM yuanlu@hsh.stn.sh.cn; motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU China National Clinical Key Subject; National Natural Science Foundation of China [30900026, 81171623]; Shanghai Pujiang Program [09PJ1402300]; National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This study was supported by a grant from the China National Clinical Key Subject to Y.L., the National Natural Science Foundation of China (grants 30900026 and 81171623) and the Shanghai Pujiang Program (grant 09PJ1402300) to M.L., and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (to M.O.). NR 30 TC 98 Z9 120 U1 3 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2012 VL 18 IS 5 BP 816 EP U217 DI 10.1038/nm.2692 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 938WE UT WOS:000303763500050 PM 22522561 ER PT J AU Federoff, M Jimenez-Rolando, B Nalls, MA Singleton, AB AF Federoff, Monica Jimenez-Rolando, Belen Nalls, Michael A. Singleton, Andrew B. TI A large study reveals no association between APOE and Parkinson's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Parkinson's disease; Genetics; APOE ID APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; DEMENTIA; ALLELE; METAANALYSIS; POPULATION; PREVALENCE; ONSET; RISK AB Background: Research focusing on the role of APOE in Parkinson's disease (PD) has been largely inconclusive. creating a broad discrepancy in association studies. Objective: To elucidate the role of APOE alleles in PD risk by studying a large sample size and controlling for population substructure. Patients and methods: In total, 3465 case and control samples were genotyped, obtained from the NINDS Neurogenetics repository. Results: No significant differences in epsilon 4 dosages exist between PD cases and controls. The frequency of epsilon 4 carriers differed slightly between cases and controls at 24% (580/2412) and 26% (270/1053), respectively. Likewise, mean dosages of APOE 62 were not significantly different between cases and controls. APOE epsilon 2 carriers were observed at a frequency of 13.6% (329/2412) among cases and 15% (158/1053) among controls. Logistic regression models evaluating PD as possibly associated with epsilon 4 or epsilon 2 carrier status and allele dosages yielded no significant results. The mean MMSE score among all PD cases was 28.35 (SD = 2.58) and memory loss was reported in only 11.9% (105/879) of cases. Linear regression models comparing MMSE scores as predicted by epsilon 4 or epsilon 2 carrier status and allele dosages were not significant. Conclusions: There is no association between APOE epsilon alleles and Parkinson's disease. Published by Elsevier Inc. C1 [Federoff, Monica; Jimenez-Rolando, Belen; Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000950-09] FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000950-09. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), as well as clinical data. NR 17 TC 26 Z9 27 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAY PY 2012 VL 46 IS 2 BP 389 EP 392 DI 10.1016/j.nbd.2012.02.002 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 937BC UT WOS:000303633000015 PM 22349451 ER PT J AU Matthews, E Plotz, PH Portaro, S Parton, M Elliott, P Humbel, RL Holton, JL Keegan, BM Hanna, MG AF Matthews, E. Plotz, P. H. Portaro, S. Parton, M. Elliott, P. Humbel, R. L. Holton, J. L. Keegan, B. M. Hanna, M. G. TI A case of necrotizing myopathy with proximal weakness and cardiomyopathy SO NEUROLOGY LA English DT Editorial Material ID SIGNAL RECOGNITION PARTICLE; IDIOPATHIC INFLAMMATORY MYOPATHY; DIFFERENTIAL-DIAGNOSIS; BORRELIA-BURGDORFERI; CLINICAL-FEATURES; LYME MYOSITIS; DERMATOMYOSITIS; POLYMYOSITIS; AUTOANTIBODIES; PATHOGENESIS C1 [Matthews, E.; Portaro, S.; Parton, M.; Holton, J. L.; Hanna, M. G.] UCL, Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. [Plotz, P. H.] NIH, Bethesda, MD 20892 USA. [Elliott, P.] Univ Coll London Hosp, Dept Cardiol, Heart Hosp, London, England. [Humbel, R. L.] Immunopathol Lab, Esch Sur Alzette, Luxembourg. [Portaro, S.] Univ Messina, AOU Policlin G Martino, Dept Neurosci Psychiat & Anesthesiol, Messina, Italy. [Keegan, B. M.] Mayo Clin, Dept Neurol, Rochester, MN USA. RP Hanna, MG (reprint author), UCL, Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. EM m.hanna@ucl.ac.uk RI Hanna, Michael/B-1995-2009; Holton, Janice/F-6831-2011 OI Holton, Janice/0000-0002-3882-5249 FU Medical Research Council [G0601943] NR 31 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY PY 2012 VL 78 IS 19 BP 1527 EP 1532 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 939AW UT WOS:000303776900016 PM 22565568 ER PT J AU Tang, BS Lee, SM Kim, HS Shin, IS Razjouyan, F Wang, ST Yao, ZS Pastan, I Dreher, MR Paik, CH AF Tang, Beom-Su Lee, Sang-Myung Kim, Hyung Sub Shin, In Soo Razjouyan, Faezeh Wang, Shutao Yao, Zhengsheng Pastan, Ira Dreher, Matthew R. Paik, Chang H. TI Combined-modality radioimmunotherapy: synergistic effect of paclitaxel and additive effect of bevacizumab SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article ID METASTATIC BREAST-CANCER; INTERSTITIAL FLUID PRESSURE; B3 MONOCLONAL-ANTIBODY; BINDING-SITE BARRIER; REFRACTORY LOW-GRADE; SOLID TUMORS; PHASE-I; COMPARATIVE BIODISTRIBUTION; CARCINOEMBRYONIC ANTIGEN; BIOLOGICAL IMPEDIMENTS AB Introduction: This study was undertaken to investigate the effect of paclitaxel and bevacizumab on the therapeutic efficacy of Y-90-labeled B3 monoclonal antibody, directed against Le(y) antigen, for the treatment of Le(y)-positive A431 tumors implanted subcutaneously in the right hind flank of nude mice. Methods: When the tumor size reached similar to 200 mm(3), the mice received a single dose of intravenous (iv) Y-90-labeled B3 (60 mu Ci/150 mu g or 100 mu Ci/150 mu g B3), intraperitoneal paclitaxel (40 mg/kg) or iv bevacizumab (5 mg/kg) for monotherapy. To investigate the effect of combined therapies on survival, the mice were treated with two or three agents in the following combinations: Y-90-B3 on day 0 and paclitaxel on day 1; bevacizumab on -1 day and Y-90-B3 on day -1; bevacizumab on 1 day and paclitaxel on day 1; bevacizumab, Y-90-B3 and paclitaxel each at I-day intervals. The mice with no treatment were used as a control. The tumor volume at 1000 mm3 was used as a surrogate end point of survival. Results: Compared to control animals, paclitaxel delayed tumor growth with a significantly longer median survival time (P<.001), whereas bevacizumab alone showed a less pronounced effect on a median survival time (P=.18). Y-90-B3 increased the median survival time in a dose-dependent manner (P<.05). The combined therapy of bevacizumab with paclitaxel produced a trend toward an increase of the median survival time compared to paclitaxel alone (P=.06), whereas bevacizumab combined with Y-90-B3 showed a statistically insignificant increase in the median survival time compared to Y-90-B3 alone (P=.25). The tumor sizes of all animals in these groups reached the surrogate end point of survival by day 35. In contrast, the combined therapy involving Y-90-B3 with paclitaxel showed a striking synergistic effect in shrinking tumors and prolonging the survival time (P<.001); on day 120, three of nine mice (33%) and six of six mice (100%) were alive without tumor when treated with 60 mu Ci Y-90-B3 and 100 mu Ci Y-90-B3, respectively. The addition of bevacizumab treatment 1 day before the combined therapy of 60 mu Ci Y-90-B3 with paclitaxel did not produce a statistically significant increase in survival when compared to the Y-90-B3 with paclitaxel (P>.10). Fluorescence microscopy analysis indicated that paclitaxel increased, whereas bevacizumab decreased, the accumulation and penetration of Alexa Fluor 647-B3 into tumor microenvironment compared to the control (P<.05). Conclusion: Our findings on the paclitaxel effect support a hypothesis that the increased tumor accumulation and penetration of Y-90-B3 as well as the high radiosensitization of tumor cells by paclitaxel may be the major factors responsible for the synergistic effect of the combined therapy involving Y-90-B3 with paclitaxel. Published by Elsevier Inc. C1 [Tang, Beom-Su; Lee, Sang-Myung; Kim, Hyung Sub; Shin, In Soo; Yao, Zhengsheng; Paik, Chang H.] NCI, Radiopharmaceut Lab, NIH, Bethesda, MD 20892 USA. [Razjouyan, Faezeh; Wang, Shutao; Dreher, Matthew R.] NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Clin Ctr, NIH, Bethesda, MD 20892 USA. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), NCI, Radiopharmaceut Lab, NIH, Bethesda, MD 20892 USA. EM cpaik@mail.nih.gov FU Clinical Center, NIH; Center for Interventional Oncology, NIH FX This research was supported by the intramural research program of Clinical Center, NIH, and the Center for Interventional Oncology, NIH. We thank Dr. Bradford Wood for his useful discussion and support of this study. We also thank Dr. Insook Kim for her critical review and editorial assistance of this manuscript. NR 67 TC 0 Z9 0 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAY PY 2012 VL 39 IS 4 BP 472 EP 483 DI 10.1016/j.nucmedbio.2011.10.020 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 939EP UT WOS:000303790600004 ER PT J AU Haspel, RL Atkinson, JB Barr, FG Kaul, KL Leonard, DGB O'Daniel, J Rinder, HM Scott, J Sobel, ME Speights, VO AF Haspel, Richard L. Atkinson, James B. Barr, Frederic G. Kaul, Karen L. Leonard, Debra G. B. O'Daniel, Julianne Rinder, Henry M. Scott, Joan Sobel, Mark E. Speights, V. O. CA Training Residents Genomics Workin TI TRIG on TRACK: educating pathology residents in genomic medicine SO PERSONALIZED MEDICINE LA English DT Review DE genomics; next-generation sequencing; pathology; post-graduate medical education; residency training ID HEALTH-CARE PROFESSIONALS; PERSONALIZED MEDICINE; INACTIVATING MUTATIONS; AGENDA; ASSOCIATION; SIGNATURES; CARCINOMA; GENETICS; FUTURE AB Genomic technologies are dramatically changing the practice of medicine. Next-generation sequencing has allowed prognostic stratification of cancer patients, personalized drug therapy and the identification of genetic risk factors for a multitude of diseases. As the physicians who oversee tissue- and laboratory-based diagnostic testing, pathologists must understand and utilize this new technology for the benefit of patients; however, only a minority of pathology residency programs currently provide training in genomics. In response to this urgent need, the Training Residents in Genomics (TRIG) Working Group has made significant progress towards creating, implementing, evaluating and disseminating a national curriculum in genomic pathology. Although presented in the context of pathology training, the approach described in this review can serve as model for education in genomic medicine of students, trainees or professionals in other areas of healthcare. C1 [Atkinson, James B.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Barr, Frederic G.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kaul, Karen L.] N Shore Univ Hlth Syst, Dept Pathol & Lab Med, Evanston, IL USA. [Leonard, Debra G. B.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [O'Daniel, Julianne] Illumina Inc, San Diego, CA USA. [Rinder, Henry M.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Scott, Joan] Natl Coalit Hlth Profess Educ Genet, Lutherville Timonium, MD USA. [Sobel, Mark E.] Amer Soc Invest Pathol, Bethesda, MD USA. [Speights, V. O.] Texas A&M Univ, Scott & White Mem Hosp, Dept Pathol, Hlth Sci Ctr, Temple, TX USA. RP Haspel, RL (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM rhaspel@bidmc.harvard.edu NR 37 TC 6 Z9 6 U1 0 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD MAY PY 2012 VL 9 IS 3 BP 287 EP 293 DI 10.2217/PME.12.6 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 937ZJ UT WOS:000303702400008 ER PT J AU Boninger, ML Brienza, D Charlifue, S Chen, YY Curley, KC Graves, DE Groah, S Heinemann, AW Hudson, LM Jackson, AB Johnson, KL Kalpakjian, CZ Kusiak, A Larson, KE Agustin, TS Sherwood, AM Shinowara, N Stripling, T Tate, D AF Boninger, M. L. Brienza, D. Charlifue, S. Chen, Y-Y Curley, K. C. Graves, D. E. Groah, S. Heinemann, A. W. Hudson, L. M. Jackson, A. B. Johnson, K. L. Kalpakjian, C. Z. Kusiak, A. Larson, K. E. Agustin, T. S. Sherwood, A. M. Shinowara, N. Stripling, T. Tate, D. TI State of the Science Conference in Spinal Cord Injury Rehabilitation 2011: introduction SO SPINAL CORD LA English DT Editorial Material DE spinal cord injury; rehabilitation; research funding ID MODEL SYSTEMS C1 [Heinemann, A. W.] Northwestern Univ, Dept Phys Med & Rehabil, Ctr Rehabil Outcomes Res, Feinberg Sch Med,Rehabil Inst Chicago, Chicago, IL 60611 USA. [Boninger, M. L.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Boninger, M. L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [Brienza, D.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Rehabil Engn Res Ctr Spinal Cord Injury, Pittsburgh, PA USA. [Charlifue, S.] Craig Hosp, SCI Model Syst, Englewood, CO USA. [Chen, Y-Y] Univ Alabama Birmingham, Dept Phys Med & Rehabil, Birmingham, AL USA. [Curley, K. C.] USA, Telemed & Adv Technol Res Ctr, Med Res & Mat Command, ATTN MCMR RTC, Ft Detrick, MD USA. [Curley, K. C.] Ctr Disaster & Humanitarian Assistance Med, Dept Sci & Med, Bethesda, MD USA. [Curley, K. C.] Uniformed Serv Univ Hlth Sci, Dept Biomed Informat, Bethesda, MD 20814 USA. [Curley, K. C.] Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD 20814 USA. [Graves, D. E.] Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [Groah, S.] Natl Rehabil Hosp, Washington, DC USA. [Hudson, L. M.] Shepherd Ctr, SE Reg SCI Model Syst, Atlanta, GA USA. [Jackson, A. B.] Univ Alabama Birmingham, Sch Med, Dept PM&R, Birmingham, AL USA. [Johnson, K. L.] Univ Washington, Sch Med, Dept Rehabil Med, Div Rehabil Counseling, Seattle, WA 98195 USA. [Kalpakjian, C. Z.] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Kusiak, A.] US EPA, Off Res & Dev, Dept Vet Affairs, Washington, DC 20460 USA. [Larson, K. E.] NSCIA, Elmhurst, NY USA. [Agustin, T. S.] Natl Inst Disabil & Rehabil Res, OSERS US Dept Educ, Washington, DC USA. [Sherwood, A. M.] Baylor Coll Med, Washington, DC USA. [Shinowara, N.] NICHD, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD USA. [Stripling, T.] Larkview Court, Fairfax Stn, VA USA. [Tate, D.] Univ Michigan, Michigan Burlington Off Ctr, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. RP Heinemann, AW (reprint author), Northwestern Univ, Dept Phys Med & Rehabil, Ctr Rehabil Outcomes Res, Feinberg Sch Med,Rehabil Inst Chicago, 345 E Super St, Chicago, IL 60611 USA. EM a-heinemann@northwestern.edu RI Heinemann, Allen /K-6283-2012; OI Heinemann, Allen /0000-0003-2782-7326; Sherwood, Arthur/0000-0002-0110-4317; Boninger, Michael/0000-0001-6966-919X FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [UL1 RR024153] NR 2 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD MAY PY 2012 VL 50 IS 5 SI SI BP 342 EP 343 DI 10.1038/sc.2012.13 PG 2 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 938ZF UT WOS:000303771700002 PM 22450887 ER PT J AU Boninger, M French, J Abbas, J Nagy, L Ferguson-Pell, M Taylor, SJ Rodgers, M Saunders, N Peckham, H Marshall, R Sherwood, A AF Boninger, M. French, J. Abbas, J. Nagy, L. Ferguson-Pell, M. Taylor, S. J. Rodgers, M. Saunders, N. Peckham, H. Marshall, R. Sherwood, A. TI Technology for mobility in SCI 10 years from now SO SPINAL CORD LA English DT Article DE spinal cord injury; mobility; assistive technology; International Classification of Function ID SPINAL-CORD-INJURY; VIRTUAL-REALITY; REHABILITATION; WALKING; DESIGN; EXOSKELETONS; MULTICENTER; INTERFACE; MEDICINE; THERAPY AB Objectives: To identify technological advances and that are likely to have a great impact on the quality of life and participation in individuals with spinal cord injury (SCI). Methods: In this paper we use the International Classification of Function to frame a discussion on how technology is likely to impact SCI in 10 years. In addition, we discuss the implication of technological advances on future research. Results/Conclusion: Although technology advances are exciting, a large challenge for the research community will be how to effectively apply and deploy this technology. Advances occurring in the next 10 years that reduce cost of technology may be more important to the population with SCI than brand new technologies. Social context is everything. As a research community we must advocate for better systems of care. Advocating now for better care will lead to a world in 2020 that is ready to adopt new technologies that are truly transformative. Spinal Cord (2012) 50, 358-363; doi:10.1038/sc.2011.165; published online 17 January 2012 C1 [Boninger, M.] UPMC Rehabil Inst, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Boninger, M.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [French, J.] Neurotech Network, Tampa, FL USA. [Abbas, J.] Arizona State Univ, Sch Biol & Hlth Syst Engn, Ctr Adapt Neural Syst, Tempe, AZ USA. [Nagy, L.] MetroHlth Rehabil Inst Ohio, Community Advisory Board, Cleveland, OH USA. [Ferguson-Pell, M.] Univ Alberta, Fac Rehabil Med, Edmonton, AB, Canada. [Taylor, S. J.] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Rodgers, M.] Univ Maryland, Sch Med, Dept Phys Therapy & Rehabil Sci, Baltimore, MD 21201 USA. [Rodgers, M.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Saunders, N.] Univ Melbourne, Dept Pharmacol, Parkville, Vic 3052, Australia. [Peckham, H.] Case Western Reserve Univ, Dept Biomed Engn, Sch Med, Cleveland, OH 44106 USA. [Peckham, H.] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. [Marshall, R.] Univ Adelaide, Fac Hlth Sci, Sch Med, Adelaide, SA, Australia. [Sherwood, A.] Natl Inst Disabil & Rehabil Res, US Dept Educ, Washington, DC USA. RP Boninger, M (reprint author), UPMC Rehabil Inst, Dept Phys Med & Rehabil, 3471 5th Ave,Suite 201, Pittsburgh, PA 15213 USA. EM boninger@pitt.edu OI Sherwood, Arthur/0000-0002-0110-4317; Saunders, Norman/0000-0001-6660-7639; Boninger, Michael/0000-0001-6966-919X; Abbas, James/0000-0002-3647-7041 NR 36 TC 3 Z9 3 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD MAY PY 2012 VL 50 IS 5 SI SI BP 358 EP 363 DI 10.1038/sc.2011.165 PG 6 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 938ZF UT WOS:000303771700005 PM 22249329 ER PT J AU Bokkers, RPH Hernandez, DA Merino, JG Mirasol, RV van Osch, MJ Hendrikse, J Warach, S Latour, LL AF Bokkers, Reinoud P. H. Hernandez, Daymara A. Merino, Jose G. Mirasol, Raymond V. van Osch, Matthias J. Hendrikse, Jeroen Warach, Steven Latour, Lawrence L. CA Natl Inst Hlth Stroke Nat Hist Inv TI Whole-Brain Arterial Spin Labeling Perfusion MRI in Patients With Acute Stroke SO STROKE LA English DT Article DE acute stroke; cerebral hemodynamics; imaging; MRI; stroke management ID NEPHROGENIC SYSTEMIC FIBROSIS; ACUTE ISCHEMIC-STROKE; CEREBRAL-BLOOD-FLOW; TRANSIT-TIME; GADOLINIUM; INVERSION; SIGNAL; 3T AB Background and Purpose-Perfusion MRI can be used to identify patients with acute ischemic stroke who may benefit from reperfusion therapies. The risk of nephrogenic systemic fibrosis, however, limits the use of contrast agents. Our objective was to evaluate the ability of arterial spin labeling (ASL), an alternative noninvasive perfusion technique, to detect perfusion deficits compared with dynamic susceptibility contrast (DSC) perfusion imaging. Methods-Consecutive patients referred for emergency assessment of suspected acute stroke within a 7-month period were imaged with both ASL and DSC perfusion MRI. Images were interpreted in a random order by 2 experts blinded to clinical information for image quality, presence of perfusion deficits, and diffusion-perfusion mismatches. Results-One hundred fifty-six patients were scanned with a median time of 5.6 hours (range, 3.0-17.7 hours) from last seen normal. Stroke diagnosis was clinically confirmed in 78 patients. ASL and DSC imaging were available in 64 of these patients. A perfusion deficit was detected with DSC in 39 of these patients; ASL detected 32 of these index perfusion deficits, missing 7 lesions. The median volume of the perfusion deficits as determined with DSC was smaller in patients who were evaluated as normal with ASL than in those with a deficit (median [interquartile range], 56 [10-116] versus 114 [41-225] mL; P=0.01). Conclusions-ASL can depict large perfusion deficits and perfusion-diffusion mismatches in correspondence with DSC. Our findings show that a fast 21/2-minute ASL perfusion scan may be adequate for screening patients with acute stroke with contraindications to gadolinium-based contrast agents. (Stroke. 2012;43:1290-1294.) C1 [Bokkers, Reinoud P. H.; Hendrikse, Jeroen] Univ Med Ctr Utrecht, Dept Radiol, NL-3584 CX Utrecht, Netherlands. [Hernandez, Daymara A.; Merino, Jose G.; Mirasol, Raymond V.; Warach, Steven; Latour, Lawrence L.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD USA. [van Osch, Matthias J.] Leiden Univ, CJ Gorter Ctr High Field MRI, Dept Radiol, Med Ctr, Leiden, Netherlands. [Merino, Jose G.] Johns Hopkins Community Phys, Bethesda, MD USA. RP Bokkers, RPH (reprint author), Univ Med Ctr Utrecht, Dept Radiol, Heidelberglaan 100,HP E-01-132, NL-3584 CX Utrecht, Netherlands. EM r.p.h.bokkers@umcutrecht.nl OI Merino, Jose/0000-0002-6676-0008 FU Intramural Division of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; Technology Foundation STW, applied science division of The Netherlands Organisation for Scientific Research; Dutch Ministry of Economic Affairs; Netherlands Organization for Scientific Research [916-76-035] FX This work was supported by the Intramural Division of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Dr van Osch receives support from the Technology Foundation STW, applied science division of The Netherlands Organisation for Scientific Research, and the technology program of the Dutch Ministry of Economic Affairs.; Dr Hendrikse receives support from the Netherlands Organization for Scientific Research (grant 916-76-035). NR 26 TC 43 Z9 47 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2012 VL 43 IS 5 BP 1290 EP 1294 DI 10.1161/STROKEAHA.110.589234 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 936PO UT WOS:000303602700028 PM 22426319 ER PT J AU Sanchez, R Lee, TH Wen, L Montalvo, L Schechterly, C Colvin, C Alter, HJ Luban, NLC Busch, MP AF Sanchez, Rosa Lee, Tzong-Hae Wen, Li Montalvo, Leilani Schechterly, Cathy Colvin, Camilla Alter, Harvey J. Luban, Naomi L. C. Busch, Michael P. TI Absence of transfusion-associated microchimerism in pediatric and adult recipients of leukoreduced and gamma-irradiated blood components SO TRANSFUSION LA English DT Article ID VERSUS-HOST-DISEASE; POLYMERASE-CHAIN-REACTION; TRAUMA PATIENTS; POSTOPERATIVE INFECTION; LYMPHOCYTE-RESPONSE; DONOR CELLS; SURVIVAL; LONG; UPDATE; FETAL AB BACKGROUND: Transfusion-associated microchimerism (TA-MC), the persistence of significant levels of donor white blood cells (WBCs) in blood recipients for prolonged periods, has been demonstrated after nonleukoreduced and leukoreduced transfusion to patients with severe traumatic injury. Development of TA-MC has not been rigorously studied in settings that do not involve massive trauma where the blood is leukoreduced and irradiated. STUDY DESIGN AND METHODS: A cohort of 409 prospectively followed medical and surgical adult and pediatric female recipients of leukoreduced and mostly irradiated allogeneic red blood cell and platelet transfusions were evaluated to determine development of TA-MC. Four- and 8-weeks-posttransfusion samples were analyzed using quantitative real-time polymerase chain reaction for Y-chromosome sequences in WBC DNA, the marker for microchimeric cells in female blood recipients. Repeat testing was performed on Y-chromosomepositive samples to confirm microchimerism (MC), and subsequent posttransfusion samples were tested to investigate persistence of MC. RESULTS: On initial testing, 40 of 207 (19%) adult and 44 of 202 (22%) pediatric female blood recipients demonstrated low-level MC. On repeat testing of these and additional specimens, 12 (3%) recipients demonstrated low-level transient MC, but none had persistent TA-MC similar to that seen in transfused trauma patients. CONCLUSION: Persistence of MC was not demonstrated in adult and pediatric recipients of leukoreduced and mostly irradiated blood components. The risk of TA-MC appears to be dependent on the clinical setting and is rare other than in patients sustaining severe traumatic injury. C1 [Sanchez, Rosa] Blood Syst Res Inst, San Francisco, CA 94118 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Div Lab Med, Washington, DC 20052 USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. RP Sanchez, R (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM rsanchezrosen@bloodsystems.org FU National Heart, Lung, and Blood Institute, National Institutes of Health [R01HL083388, R01HL67229] FX This work was supported by Award Numbers R01HL083388 and R01HL67229 from the National Heart, Lung, and Blood Institute, National Institutes of Health. [Correction added after online publication 07-Oct-2011: Award Numbers were updated.] NR 45 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAY PY 2012 VL 52 IS 5 BP 936 EP 945 DI 10.1111/j.1537-2995.2011.03366.x PG 10 WC Hematology SC Hematology GA 940GB UT WOS:000303876900005 PM 21981710 ER PT J AU Zeng, PB Wang, JX Huang, Y Guo, XM Li, JL Wen, GX Yang, TH Yun, ZQ He, M Liu, Y Yuan, YZ Schulmann, J Glynn, S Ness, P Jackson, JB Shan, H AF Zeng, Peibin Wang, Jingxing Huang, Yi Guo, Xiaoming Li, Julin Wen, Guoxin Yang, Tonghan Yun, Zhongqiao He, Miao Liu, Yu Yuan, Yuzhe Schulmann, Jane Glynn, Simone Ness, Paul Jackson, J. Brooks Shan, Hua CA NHLBI Retrovirus Epidemiology TI The human immunodeficiency virus-1 genotype diversity and drug resistance mutations profile of volunteer blood donors from Chinese blood centers SO TRANSFUSION LA English DT Article ID REVERSE-TRANSCRIPTASE; SUBTYPE-B; ANTIRETROVIRAL THERAPY; 1-INFECTED PATIENTS; EAST-ASIA; TYPE-1; HIV-1; PREVALENCE; PATTERNS; STRAINS AB BACKGROUND: The global human immunodeficiency virus (HIV)-1 epidemic is becoming increasingly diverse and complex. Molecular epidemiologic characteristics were studied for HIV-1infected blood donors from five Chinese regions to determine genotype diversity and drug resistance mutations (DRMs) profile. STUDY DESIGN AND METHODS: HIV-1 confirmed-reactive serum samples were collected from 172 blood donors from five blood centers during 2007 to 2010. HIV-1 Pol including whole protease and partial reverse transcriptase genes was amplified, sequenced, and analyzed for the subtype determination and drug resistance profile description. RESULT: A total of 113 amplified sequences including 82 from Kunming blood center and 31 from four other blood centers had the following genotype characteristics: G (0.9%), B (2.7%), circulating recombinant form (CRF) 01_AE (32.7%), CRF07_BC (22.1%), and CRF08_BC (41.6%). Female donors represent 45.1% of all cases and 63.9% cases with DRMs. The prevalence of samples with potential low or higher resistance among Chinese blood donors is 4.4%. CONCLUSION: HIV-1 infection in Chinese blood donors is genetically diverse and the subtype distribution reflects that from the high-risk populations. Our results support continuous molecular epidemiologic surveillance for HIV-1 in blood donors as a part of a comprehensive HIV control program. C1 [Wang, Jingxing] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu 610052, Sichuan Provinc, Peoples R China. Guangxi Blood Ctr, Liuzhou, Guangxi, Peoples R China. Mianyang Blood Ctr, Mianyang, Sichuan, Peoples R China. Urumqi City Blood Ctr, Urumqi, Xinjiang, Peoples R China. Yunnan Kunming Blood Ctr, Kunming, Yunnan, Peoples R China. Luoyang Blood Ctr, Luoyang, Henan, Peoples R China. WESTAT Corp, Rockville, MD 20850 USA. NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Wang, JX (reprint author), Chinese Acad Med Sci, Inst Blood Transfus, 26 Hua Cai Rd, Chengdu 610052, Sichuan Provinc, Peoples R China. EM jingxing_wang@vip.163.com FU NHLBI Retroviral Epidemiology Donor Study-II [RFP-05-8067] FX This work was supported by NHLBI Retroviral Epidemiology Donor Study-II [RFP-05-8067]. NR 50 TC 13 Z9 15 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAY PY 2012 VL 52 IS 5 BP 1041 EP 1049 DI 10.1111/j.1537-2995.2011.03415.x PG 9 WC Hematology SC Hematology GA 940GB UT WOS:000303876900016 PM 22044422 ER PT J AU Huvard, MJ Schmid, P Stroncek, DF Flegel, WA AF Huvard, Michael J. Schmid, Pirmin Stroncek, David F. Flegel, Willy A. TI Frequencies of SLC44A2 alleles encoding human neutrophil antigen-3 variants in the African American population SO TRANSFUSION LA English DT Article ID ACUTE LUNG INJURY; TRANSPORTER-LIKE PROTEIN-2; DONOR ANTIBODIES; TRALI; 5B AB BACKGROUND: The human neutrophil antigen-3 (HNA-3) epitopes reside on the choline transporter-like protein-2 (CTL2). A single-nucleotide substitution (461G>A; Arg154Gln) on the CTL2 gene (SLC44A2) defines the allele SLC44A2*1, which expresses HNA-3a, and SLC44A2*2, which expresses HNA-3b; an additional substitution (457C>T; Leu153Phe) in SLC44A2*1:2 may impact genotyping systems. People who only express HNA-3b may develop anti-HNA-3a. These alloantibodies have been linked to severe transfusion-related acute lung injury, which may be a reason to screen blood donors for SLC44A2*2 homozygosity. For Caucasian and Asian populations, SLC44A2 allele frequencies are known. Our primary objective was to determine the SLC44A2 allele frequencies in the African American population. STUDY DESIGN AND METHODS: Purified DNA from 334 individuals (202 male, 132 female; 241 African American, 93 Caucasian) was collected. Two real-time polymerase chain reaction assays were developed to genotype all samples; results were confirmed by nucleotide sequencing. RESULTS: In 241 African American donors, the allele frequency of SLC44A2*1 was 93% (85%-<100%; 95% confidence intervals, Poisson distribution) while SLC44A2*2 was 7% (5%-10%). In 93 Caucasian donors, the allele frequency of SLC44A2*1 was 83% (71%-98%) and SLC44A2*2 was 17% (11%-24%), matching previously reported data for Caucasians but differing from African Americans (p < 0.001, Fisher's exact test). CONCLUSIONS: This study describes the allele frequencies of the three known HNA-3 variants in an African American population. We found that African Americans have a significantly lower probability of possessing the SLC44A2*2 allele and may thus be less likely to form the clinically relevant anti-HNA-3a. C1 [Flegel, Willy A.] NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 23 TC 10 Z9 12 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAY PY 2012 VL 52 IS 5 BP 1106 EP 1111 DI 10.1111/j.1537-2995.2011.03396.x PG 6 WC Hematology SC Hematology GA 940GB UT WOS:000303876900024 PM 22040064 ER PT J AU Chalancon, G Ravarani, CNJ Balaji, S Martinez-Arias, A Aravind, L Jothi, R Babu, MM AF Chalancon, Guilhem Ravarani, Charles N. J. Balaji, S. Martinez-Arias, Alfonso Aravind, L. Jothi, Raja Babu, M. Madan TI Interplay between gene expression noise and regulatory network architecture SO TRENDS IN GENETICS LA English DT Review DE expression noise; gene regulatory network; persistence; phenotypic variation; single-cell analysis; differentiation; development ID DETERMINES CELL FATE; ESCHERICHIA-COLI; SINGLE-CELL; GENOMIC ANALYSIS; DYNAMICS; VARIABILITY; TRANSCRIPTION; EVOLUTION; SELECTION; YEAST AB Complex regulatory networks orchestrate most cellular processes in biological systems. Genes in such networks are subject to expression noise, resulting in isogenic cell populations exhibiting cell-to-cell variation in protein levels. Increasing evidence suggests that cells have evolved regulatory strategies to limit, tolerate or amplify expression noise. In this context, fundamental questions arise: how can the architecture of gene regulatory networks generate, make use of or be constrained by expression noise? Here, we discuss the interplay between expression noise and gene regulatory network at different levels of organization, ranging from a single regulatory interaction to entire regulatory networks. We then consider how this interplay impacts a variety of phenomena, such as pathogenicity, disease, adaptation to changing environments, differential cell-fate outcome and incomplete or partial penetrance effects. Finally, we highlight recent technological developments that permit measurements at the single-cell level, and discuss directions for future research. C1 [Chalancon, Guilhem; Ravarani, Charles N. J.; Babu, M. Madan] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Balaji, S.] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Balaji, S.] Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Balaji, S.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Martinez-Arias, Alfonso] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Jothi, Raja] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Chalancon, G (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 0QH, England. EM guilhem@mrc-lmb.cam.ac.uk; madanm@mrc-lmb.cam.ac.uk RI Martinez Arias, Alfonso/F-1966-2010; Jothi, Raja/G-3780-2015 FU Gates Cambridge Scholarship; Knox Trinity studentship; AFR; Medical Research Council; EMBO; HFSP [RGY0073/2010]; European Research Council; NIH, National Institute of Environmental Health Sciences [1ZIAES102625-03]; NLM, NCBI FX We thank Mania Buljan, Kai Kruse, Elizabeth Ing-Simmons and Andrew Deonarine for helpful remarks. This work was supported by the Gates Cambridge Scholarship and the Knox Trinity studentship (G.C.), the AFR Grant Scheme (C.N.J.R.), the Medical Research Council (G.C., C.N.J.R. and M.M.B.), EMBO young investigator program, HFSP (RGY0073/2010; M.M.B.), European Research Council (AM.-A.) and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (RJ: 1ZIAES102625-03) and NLM, NCBI (L.A.). NR 125 TC 74 Z9 75 U1 5 U2 70 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD MAY PY 2012 VL 28 IS 5 BP 221 EP 232 DI 10.1016/j.tig.2012.01.006 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 937BU UT WOS:000303634800004 PM 22365642 ER PT J AU Shuch, B Singer, EA Bratslavsky, G AF Shuch, Brian Singer, Eric A. Bratslavsky, Gennady TI The Surgical Approach to Multifocal Renal Cancers: Hereditary Syndromes, Ipsilateral Multifocality, and Bilateral Tumors SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Renal cell carcinoma; Bilateral kidney cancer; Multifocal kidney cancer; Hereditary kidney cancer ID HOGG-DUBE-SYNDROME; NEPHRON-SPARING SURGERY; HIPPEL-LINDAU-DISEASE; TUBEROUS SCLEROSIS COMPLEX; GENOME-WIDE ASSOCIATION; CELL-CARCINOMA; PARTIAL NEPHRECTOMY; RADICAL NEPHRECTOMY; SIMPLE ENUCLEATION; UTERINE FIBROIDS AB Although the management of sporadic renal tumors is challenging enough, dealing with those with bilateral, multifocal, and hereditary kidney cancer adds an additional level of complexity. A clinician managing this patient population must understand the hereditary syndromes and the genetic testing available. Treating physicians must be familiar with enucleative surgery, complex or multiple tumor partial nephrectomy, complex renal reconstruction, re-operative renal surgery, and active surveillance strategies. With proper management, most patients affected with bilateral, multifocal, or hereditary RCC can have a long life expectancy while maintaining adequate renal function. C1 [Bratslavsky, Gennady] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Shuch, Brian; Singer, Eric A.; Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), SUNY Upstate Med Univ, Dept Urol, 750 E Adams St, Syracuse, NY 13210 USA. EM bratslag@upstate.edu NR 120 TC 14 Z9 16 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD MAY PY 2012 VL 39 IS 2 BP 133 EP + DI 10.1016/j.ucl.2012.01.006 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA 941EO UT WOS:000303946700004 PM 22487757 ER PT J AU Siggeirsdottir, K Aspelund, T Jonsson, BY Mogensen, B Launer, LJ Harris, TB Sigurdsson, G Gudnason, V AF Siggeirsdottir, Kristin Aspelund, Thor Jonsson, Brynjolfur Y. Mogensen, Brynjolfur Launer, Lenore J. Harris, Tamara B. Sigurdsson, Gunnar Gudnason, Vilmundur TI Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study SO AGE AND AGEING LA English DT Article DE vertebral fracture; health burden; osteoporotic fracture; strength; ADL; quality of life; mobility; elderly ID OSTEOPOROTIC FRACTURES; WOMEN; HEALTH; RISK; MEN; DISABILITY; EPIDEMIOLOGY; PREVALENCE; MORTALITY; OUTCOMES AB Objective: assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. Design: individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. Subjects: a total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. Method: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. Results: worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group. Conclusion: individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals. C1 [Siggeirsdottir, Kristin; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Jonsson, Brynjolfur Y.] Malmo Univ Hosp, Dept Orthopead, Malmo, Sweden. [Mogensen, Brynjolfur; Sigurdsson, Gunnar] Landspitalinn Univ Hosp, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MA USA. [Aspelund, Thor; Mogensen, Brynjolfur; Sigurdsson, Gunnar; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. RP Siggeirsdottir, K (reprint author), Iceland Heart Assoc Res Inst, Kopavogur, Iceland. EM kristin@hjarta.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health, USA [N01-AG-12100]; National Institute on Aging; Hjartavernd (The Icelandic Heart Association); Althingi (The Icelandic Parliament) FX This study was funded by the National Institutes of Health, USA contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (The Icelandic Heart Association) and the Althingi (The Icelandic Parliament). NR 30 TC 6 Z9 6 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAY PY 2012 VL 41 IS 3 BP 351 EP 357 DI 10.1093/ageing/afs003 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 933BU UT WOS:000303335000013 PM 22367357 ER PT J AU Chen, WZ Dimitrov, DS AF Chen, Weizao Dimitrov, Dimiter S. TI Monoclonal Antibody-Based Candidate Therapeutics Against HIV Type 1 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; SINGLE-CHAIN ANTIBODY; N-TRIMER REGION; ENVELOPE GLYCOPROTEINS; PASSIVE-IMMUNIZATION; IN-VITRO; SYNERGISTIC NEUTRALIZATION; CD4-BINDING SITE; RHESUS-MONKEYS AB Treatment of HIV-1 infection has been highly successful with small molecule drugs. However, resistance still develops. In addition, long-term use can lead to toxicity with unpredictable effects on health. Finally, current drugs do not lead to HIV-1 eradication. The presence of the virus leads to chronic inflammation, which can result in increased morbidity and mortality after prolonged periods of infection. Monoclonal antibodies (mAbs) have been highly successful during the past two decades for therapy of many diseases, primarily cancers and immune disorders. They are relatively safe, especially human mAbs that have evolved in humans at high concentrations to fight diseases and long-term use may not lead to toxicities. Several broadly neutralizing mAbs (bnmAbs) against HIV-1 can protect animals but are not effective when used for therapy of an established infection. We have hypothesized that HIV-1 has evolved strategies to effectively escape neutralization by full-size antibodies in natural infections but not by smaller antibody fragments. Therefore, a promising direction of research is to discover and exploit antibody fragments as potential candidate therapeutics against HIV-1. Here we review several bnmAbs and engineered antibody domains (eAds), their in vitro and in vivo antiviral efficacy, mechanisms used by HIV-1 to escape them, and strategies that could be effective to develop more powerful mAb-based HIV-1 therapeutics. C1 [Chen, Weizao] NCI Frederick, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21702 USA. RP Chen, WZ (reprint author), NCI Frederick, Prot Interact Grp, CCRNP, CCR,NIH, Miller Dr Bldg 469,Room 144, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov FU National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; Gates Foundation FX We thank John Owens and Emily Streaker from our group for technical assistance and helpful comments. This project was supported by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health (NIH), by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Gates Foundation (D.S.D.). NR 87 TC 5 Z9 5 U1 0 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY PY 2012 VL 28 IS 5 BP 425 EP 434 DI 10.1089/aid.2011.0226 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 933XY UT WOS:000303401500001 PM 21827278 ER PT J AU Plaeger, SF Collins, BS Musib, R Deeks, SG Read, S Embry, A AF Plaeger, Susan F. Collins, Brenda S. Musib, Runa Deeks, Steven G. Read, Sarah Embry, Alan TI Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; PLASMACYTOID DENDRITIC CELLS; SIV INFECTION; ANTIRETROVIRAL THERAPY; SYSTEM ACTIVATION; TYPE-1 INFECTION; PROGNOSTIC VALUE; MEMORY; AIDS AB With the advent of highly effective antiretroviral therapy (ART), infection with human immunodeficiency virus (HIV) has become a chronic disease rather than a death sentence. Nevertheless, effectively treated individuals have a higher than normal risk for developing noninfectious comorbidities, including cardiovascular and renal disease. Although traditional risk factors of aging as well as treatment toxicity contribute to this risk, many investigators consider chronic HIV-associated inflammation a significant factor in such end-organ disease. Despite effective viral suppression, chronic inflammation persists at levels higher than in uninfected people, yet the stimuli for the inflammation and the mechanism by which inflammation persists and promotes disease pathology remain incompletely understood. This critical gap in scientific understanding complicates and hampers effective decision making about appropriate medical intervention. To better understand the mechanism(s) of chronic immune activation in treated HIV disease, three questions need answers: (1) what is the cause of persistent immune activation during treated HIV infection, (2) what are the best surrogate markers of chronic immune activation in this setting, and (3) what therapeutic intervention(s) could prevent or reverse this process? The NIH sponsored and convened a meeting to discuss the state of knowledge concerning these questions and the best course for developing effective therapeutic strategies. This report summarizes the findings of that NIH meeting. C1 [Plaeger, Susan F.; Read, Sarah; Embry, Alan] NIAID, Basic Sci Program, Div Aids, NIH,HHS, Bethesda, MD 20892 USA. [Collins, Brenda S.] NIAID, Henry M Jackson Fdn Advancement Mil Med, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Musib, Runa] Henry M Jackson Fdn Advancement Mil Med, US Mil HIV Res Program, Rockville, MD USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Plaeger, SF (reprint author), NIAID, Basic Sci Program, Div Aids, NIH,HHS, 6700-B Rockledge Dr,Room 4101, Bethesda, MD 20892 USA. EM splaeger@niaid.nih.gov FU National Institute of Allergies and Infectious Diseases; National Institutes of Health; Department of Health and Human Services [HHSN272200800012C] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800012C. NR 63 TC 26 Z9 28 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY PY 2012 VL 28 IS 5 BP 469 EP 477 DI 10.1089/aid.2011.0213 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 933XY UT WOS:000303401500008 PM 21854232 ER PT J AU Ng, OT Eyzaguirre, LM Carr, JK Chew, KK Lin, L Chua, A Leo, YS Redd, AD Quinn, TC Laeyendecker, O AF Ng, Oon Tek Eyzaguirre, Lindsay M. Carr, Jean K. Chew, Kuan Kiat Lin, Li Chua, Arlene Leo, Yee Sin Redd, Andrew D. Quinn, Thomas C. Laeyendecker, Oliver TI Identification of New CRF51_01B in Singapore Using Full Genome Analysis of Three HIV Type 1 Isolates SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CIRCULATING RECOMBINANT FORM; THAILAND; CRF15-01B; CRF33-01B; SEQUENCE; MALAYSIA AB A recent HIV-1 molecular epidemiology survey in Singapore identified a novel CRF01_AE/B recombinant form, which accounted for 13 (11.9%) of 109 patient samples. Peripheral blood mononuclear cell DNA from three of these 13 patients was used to generate near full-length sequences to characterize the novel CRF01_AE/B recombinant form. The three isolates had a recombinant structure composed of CRF01_AE and subtype B, and shared identical breakpoints. As the three patients were not epidemiologically linked, this recombinant form has been designated CRF51_01B. Identification of the novel recombinant forms indicates ongoing active HIV-1 transmission in Singapore. C1 [Ng, Oon Tek; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Med Inst, Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Ng, Oon Tek; Chew, Kuan Kiat; Lin, Li; Chua, Arlene; Leo, Yee Sin] Tan Tock Seng Hosp, Dept Infect Dis, Singapore, Singapore. [Eyzaguirre, Lindsay M.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Redd, Andrew D.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. RP Ng, OT (reprint author), Johns Hopkins Univ, Sch Med, Rangos Bldg,Room 527,855 N Wolfe St, Baltimore, MD 21205 USA. EM oong@jhsph.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Chua, Arlene/0000-0001-6428-9083 FU Division of Intramural Research; NIAID; NIH; Singapore National Medical Research Training Fellowship FX A Singapore National Medical Research Training Fellowship grant provided salary support for O.T. Ng. We acknowledge the physicians, staff, and patients of the outpatient service at the Communicable Disease Centre, Singapore, who made this study possible. Additional support was provided by the Division of Intramural Research, NIAID, NIH. We thank Dr. Mark I. C. Chen, Mr. Ridzwan Abdullah, and Ms. Tan Pei Ling for help with patient recruitment and sample collection. O.T.N. and L.M.E. contributed equally to this work. The sequences analyzed in this study have been deposited in GenBank under accession numbers JN029801, JN029802, and JN029803. NR 12 TC 25 Z9 25 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY PY 2012 VL 28 IS 5 BP 527 EP 530 DI 10.1089/aid.2011.0177 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 933XY UT WOS:000303401500015 PM 21902588 ER PT J AU Delis, F Benveniste, H Xenos, M Grandy, D Wang, GJ Volkow, ND Thanos, PK AF Delis, Foteini Benveniste, Helene Xenos, Michalis Grandy, David Wang, Gene-Jack Volkow, Nora D. Thanos, Panayotis K. TI Loss of Dopamine D2 Receptors Induces Atrophy in the Temporal and Parietal Cortices and the Caudal Thalamus of Ethanol-Consuming Mice SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE D2 Receptors; Ethanol; Brain; MRI; Mouse ID PRENATAL ALCOHOL EXPOSURE; MATTER VOLUME LOSS; GRAY-MATTER; HIPPOCAMPAL VOLUME; AGONISTS PROTECT; HEAVY DRINKING; DEFICIENT MICE; BRAIN VOLUMES; DEPENDENCE; INDIVIDUALS AB Background: The need of an animal model of alcoholism becomes apparent when we consider the genetic diversity of the human populations, an example being dopamine D2 receptor (DRD2) expression levels. Research suggests that low DRD2 availability is associated with alcohol abuse, while higher DRD2 levels may be protective against alcoholism. This study aims to establish whether (i) the ethanol-consuming mouse is a suitable model of alcohol-induced brain atrophy and (ii) DRD2 protect the brain against alcohol toxicity. Methods: Adult Drd2+/+ and Drd2-/- mice drank either water or 20% ethanol solution for 6 months. At the end of the treatment period, the mice underwent magnetic resonance (MR) imaging under anesthesia. MR images were registered to a common space, and regions of interest were manually segmented. Results: We found that chronic ethanol intake induced a decrease in the volume of the temporal and parietal cortices as well as the caudal thalamus in Drd2-/- mice. Conclusions: The result suggests that (i) normal DRD2 expression has a protective role against alcohol-induced brain atrophy and (ii) in the absence of Drd2 expression, prolonged ethanol intake reproduces a distinct feature of human brain pathology in alcoholism, the atrophy of the temporal and parietal cortices. C1 [Delis, Foteini; Wang, Gene-Jack; Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Delis, Foteini; Volkow, Nora D.; Thanos, Panayotis K.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. [Benveniste, Helene] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. [Xenos, Michalis] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Grandy, David] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM thanos@bnl.gov OI Xenos, Michalis/0000-0001-8441-1306 FU NIAAA [AA 11034, AA07574, AA07611] FX This work was supported by the NIAAA (AA 11034 & AA07574, AA07611). We thank Vanessa Gopez for care of the animals, Michael Michaelides for MRI scheduling, and Yu Ma for suggestions on MRI analysis. NR 67 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2012 VL 36 IS 5 BP 815 EP 825 DI 10.1111/j.1530-0277.2011.01667.x PG 11 WC Substance Abuse SC Substance Abuse GA 933UJ UT WOS:000303388500009 PM 22017419 ER PT J AU Bongard, RD Myers, CR Lindemer, BJ Baumgardt, S Gonzalez, FJ Merker, MP AF Bongard, Robert D. Myers, Charles R. Lindemer, Brian J. Baumgardt, Shelley Gonzalez, Frank J. Merker, Marilyn P. TI Coenzyme Q(1) as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE pulmonary circulation; quinone; knockout mice; isolated perfused mouse lung; NAD(P)H:quinone oxidoreductase 1; mass spectrometry ID ARTERIAL ENDOTHELIAL-CELLS; PULMONARY-CIRCULATION; SUBMITOCHONDRIAL PARTICLES; OXIDATIVE-PHOSPHORYLATION; DUROQUINONE REDUCTION; ELECTRON-TRANSPORT; OXIDOREDUCTASE 1; INJURY SURVIVAL; MICE; NAD(P)H AB Bongard RD, Myers CR, Lindemer BJ, Baumgardt S, Gonzalez FJ, Merker MP. Coenzyme Q1 as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung. Am J Physiol Lung Cell Mol Physiol 302: L949-L958, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00251.2011.-Previous studies showed that coenzyme Q(1) (CoQ(1)) reduction on passage through the rat pulmonary circulation was catalyzed by NAD(P) H: quinone oxidoreductase 1 (NQO1) and mitochondrial complex I, but that NQO1 genotype was not a factor in CoQ(1) reduction on passage through the mouse lung. The aim of the present study was to evaluate the complex I contribution to CoQ(1) reduction in the isolated perfused wild-type (NQO1(+/+)) and Nqo1-null (NQO1(-/-))mouse lung. CoQ(1) reduction was measured as the steady-state pulmonary venous CoQ(1) hydroquinone (CoQ(1)H(2)) efflux rate during infusion of CoQ(1) into the pulmonary arterial inflow. CoQ(1)H(2) efflux rates during infusion of 50 mu M CoQ(1) were not significantly different for NQO1(+/+) and NQO1(-)/(-) lungs (0.80 +/- 0.03 and 0.68 +/- 0.07 mu mol.min(-1).g lung dry wt(-1), respectively, P > 0.05). The mitochondrial complex I inhibitor rotenone depressed CoQ(1)H(2) efflux rates for both genotypes (0.19 +/- 0.08 and 0.08 +/- 0.04 mu mol.min(-1).g lung dry wt(-1) for NQO1(+/+) and NQO1(-/-), respectively, P < 0.05). Exposure of mice to 100% O-2 for 48 h also depressed CoQ(1)H(2) efflux rates in NQO1(+/+) and NQO1 (-/-) lungs (0.43 +/- 0.03 and 0.11 +/- 0.04 mu mol.min(-1).g lung dry wt(-1), respectively, P < 0.05 by ANOVA). The impact of rotenone or hyperoxia on CoQ(1) redox metabolism could not be attributed to effects on lung wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total venous effluent CoQ(1) recoveries, the latter measured by spectrophotometry or mass spectrometry. Complex I activity in mitochondria-enriched lung fractions was depressed in hyperoxia-exposed lungs for both genotypes. This study provides new evidence for the potential utility of CoQ(1) as a nondestructive indicator of the impact of pharmacological or pathological exposures on complex I activity in the intact perfused mouse lung. C1 [Merker, Marilyn P.] Zablocki Vet Affairs Med Ctr, Milwaukee, WI 53295 USA. [Bongard, Robert D.] Med Coll Wisconsin, Dept Pulm Med, Milwaukee, WI 53295 USA. [Myers, Charles R.; Merker, Marilyn P.] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53295 USA. [Lindemer, Brian J.; Baumgardt, Shelley; Merker, Marilyn P.] Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53295 USA. [Gonzalez, Frank J.] Natl Canc Inst, Milwaukee, WI 53295 USA. RP Merker, MP (reprint author), Zablocki VAMC, Med Coll Wisconsin, Res Serv 151, Milwaukee, WI 53295 USA. EM mmerker@mcw.edu OI Myers, Charles/0000-0001-7956-3217 FU Department of Veterans Affairs (VA); National Cancer Institute FX This work was supported by the Department of Veterans Affairs (VA Medical Research Funds) and the National Cancer Institute Intramural Research Program. NR 53 TC 3 Z9 3 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAY PY 2012 VL 302 IS 9 BP L949 EP L958 DI 10.1152/ajplung.00251.2011 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 936TW UT WOS:000303613900015 PM 22268123 ER PT J AU Phillips, D Covian, R Aponte, AM Glancy, B Taylor, JF Chess, D Balaban, RS AF Phillips, Darci Covian, Raul Aponte, Angel M. Glancy, Brian Taylor, Joni F. Chess, David Balaban, Robert S. TI Regulation of oxidative phosphorylation complex activity: effects of tissue-specific metabolic stress within an allometric series and acute changes in workload SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE mitochondria; cytochrome oxidase; Complex V; F1-F0ATPase; oxygen consumption; energy metabolism; heart; liver; murine; porcine; rabbit; native gel electrophoresis; mass spectrometry; posttranslational modifications; phosphorylation ID CYTOCHROME-C-OXIDASE; PYRUVATE-DEHYDROGENASE ACTIVITY; MITOCHONDRIAL ATP SYNTHASE; OXYGEN-CONSUMPTION; PROTEIN-PHOSPHORYLATION; ENERGY-METABOLISM; CALCIUM-IONS; ELECTRON-TRANSFER; SKELETAL-MUSCLE; RABBIT HEART AB Phillips D, Covian R, Aponte AM, Glancy B, Taylor JF, Chess D, Balaban RS. Regulation of oxidative phosphorylation complex activity: effects of tissue-specific metabolic stress within an allometric series and acute changes in workload. Am J Physiol Regul Integr Comp Physiol 302: R1034-R1048, 2012. First published February 29, 2012; doi: 10.1152/ajpregu.00596.2011.-The concentration of mitochondrial oxidative phosphorylation complexes (MOPCs) is tuned to the maximum energy conversion requirements of a given tissue; however, whether the activity of MOPCs is altered in response to acute changes in energy conversion demand is unclear. We hypothesized that MOPCs activity is modulated by tissue metabolic stress to maintain the energy-metabolism homeostasis. Metabolic stress was defined as the observed energy conversion rate/maximum energy conversion rate. The maximum energy conversion rate was assumed to be proportional to the concentration of MOPCs, as determined with optical spectroscopy, gel electrophoresis, and mass spectrometry. The resting metabolic stress of the heart and liver across the range of resting metabolic rates within an allometric series (mouse, rabbit, and pig) was determined from MPOCs content and literature respiratory values. The metabolic stress of the liver was high and nearly constant across the allometric series due to the proportional increase in MOPCs content with resting metabolic rate. In contrast, the MOPCs content of the heart was essentially constant in the allometric series, resulting in an increasing metabolic stress with decreasing animal size. The MOPCs activity was determined in native gels, with an emphasis on Complex V. Extracted MOPCs enzyme activity was proportional to resting metabolic stress across tissues and species. Complex V activity was also shown to be acutely modulated by changes in metabolic stress in the heart, in vivo and in vitro. The modulation of extracted MOPCs activity suggests that persistent posttranslational modifications (PTMs) alter MOPCs activity both chronically and acutely, specifically in the heart. Protein phosphorylation of Complex V was correlated with activity inhibition under several conditions, suggesting that protein phosphorylation may contribute to activity modulation with energy metabolic stress. These data are consistent with the notion that metabolic stress modulates MOPCs activity in the heart. C1 [Phillips, Darci; Covian, Raul; Glancy, Brian; Taylor, Joni F.; Chess, David; Balaban, Robert S.] NHLBI, Lab Cardiac Energet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Lab Cardiac Energet, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Room B1D-416,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsb@nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU National Institutes of Health Division of Intramural Research FX This work was supported by the National Institutes of Health Division of Intramural Research. NR 92 TC 27 Z9 29 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAY PY 2012 VL 302 IS 9 BP R1034 EP R1048 DI 10.1152/ajpregu.00596.2011 PG 15 WC Physiology SC Physiology GA 935UQ UT WOS:000303547500002 PM 22378775 ER PT J AU Aravindhan, V Mohan, V Surendar, J Rao, MM Anuradha, R Deepa, M Babu, S AF Aravindhan, Vivekanandhan Mohan, Viswanathan Surendar, Jayagopi Rao, Maradana Muralidhara Anuradha, Rajamanickam Deepa, Mohan Babu, Subash TI Effect of Filarial Infection on Serum Inflammatory and Atherogenic Biomarkers in Coronary Artery Disease (CURES-121) SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID URBAN-RURAL-EPIDEMIOLOGY; INTIMAL MEDIAL THICKNESS; LYMPHATIC FILARIASIS; DECREASED PREVALENCE; HYGIENE HYPOTHESIS; ATHEROSCLEROSIS; ADIPOCYTOKINES; ASSOCIATION; MORTALITY; HELMINTHS AB Helminth infections can potentially confer protection against metabolic disorders, possibly through immunomodulation. In this study, the baseline prevalence of lymphatic filariasis (LF) among subjects without (AT = 236) and with (N = 217) coronary artery disease (CAD) was examined as part of the Chennai Urban Rural Epidemiological Study (CURES). The prevalence of LF was not significantly different between CAD(-) and CAD(+) subjects. The LF antigen load and antibody levels indicated comparable levels of infection and exposure between the groups. Within the CAD group, LF+ and LF- subjects had no significant difference in the intimal medial thickness and high-sensitivity C-reactive protein values. However, LF infection was associated with augmented levels of tumor necrosis factor-a and interleukin-6 among CAD(+) subjects. The LF infection had no effect on serum adipocytokine profile. In conclusion, unlike type-2 diabetes, there is no association between the prevalence of LF and CAD and also no evidence of protective immunomodulation of LF infection on CAD in the Asian Indian population. C1 [Aravindhan, Vivekanandhan] Anna Univ, Lab Mol Immunol, AU KBC Res Ctr, Madras 600044, Tamil Nadu, India. [Mohan, Viswanathan; Surendar, Jayagopi; Rao, Maradana Muralidhara; Deepa, Mohan] Madras Diabet Res Fdn, Madras, Tamil Nadu, India. Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India. [Anuradha, Rajamanickam; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, TB Res Ctr, Madras, Tamil Nadu, India. [Babu, Subash] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Aravindhan, V (reprint author), Anna Univ, Lab Mol Immunol, AU KBC Res Ctr, MIT Campus, Madras 600044, Tamil Nadu, India. EM cvaravindhan@yahoo.co.uk; drmohans@vsnl.net; surendarj85@gmail.com; raoinfoster@gmail.com; anuvenil@gmail.com; deepa.mohan1@gmail.com; sbabu@mail.nih.gov OI Aravindhan, Vivekanandhan/0000-0002-5639-4948 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, through the NIAID/TRC ICER; KB Chandrasekhar Research Foundation, India FX This work received partial support from the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, through the NIAID/TRC ICER program and KB Chandrasekhar Research Foundation, India. NR 29 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAY PY 2012 VL 86 IS 5 BP 828 EP 833 DI 10.4269/ajtmh.2012.11-0773 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 935WY UT WOS:000303554100017 PM 22556082 ER PT J AU Hartley, DM Barker, CM Le Menach, A Niu, TC Gaff, HD Reisen, WK AF Hartley, David M. Barker, Christopher M. Le Menach, Arnaud Niu, Tianchan Gaff, Holly D. Reisen, William K. TI Effects of Temperature on Emergence and Seasonality of West Nile Virus in California SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID CULEX-TARSALIS DIPTERA; LOUIS-ENCEPHALITIS-VIRUS; KERN COUNTY; SOUTHEASTERN CALIFORNIA; HOST-SEEKING; TRANSMISSION; CULICIDAE; BIRDS; MODEL; INFECTION AB Temperature has played a critical role in the spatiotemporal dynamics of West Nile virus transmission throughout California from its introduction in 2003 through establishment by 2009. We compared two novel mechanistic measures of transmission risk, the temperature-dependent ratio of virus extrinsic incubation period to the mosquito gonotrophic period (BT), and the fundamental reproductive ratio (R-0) based on a mathematical model, to analyze spatiotemporal patterns of receptivity to viral amplification. Maps of BT and R-0 were created at 20-km scale and compared throughout California to seroconversions in sentinel chicken flocks at half-month intervals. Overall, estimates of BT and R-0 agreed with intensity of transmission measured by the frequency of sentinel chicken seroconversions. Mechanistic measures such as these are important for understanding how temperature affects the spatiotemporal dynamics of West Nile virus transmission and for delineating risk estimates useful to inform vector control agency intervention decisions and communicate outbreak potential. C1 [Hartley, David M.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA. Georgetown Univ, Med Ctr, Dept Radiol, Washington, DC 20057 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Imaging Sci & Informat Syst Ctr, Washington, DC 20057 USA. Univ Calif Davis, Ctr Vectorborne Dis, Davis, CA 95616 USA. Resources Future Inc, Ctr Dis Dynam Econ & Policy, Washington, DC USA. Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. RP Hartley, DM (reprint author), Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, 2115 Wisconsin Ave NW,Suite 603, Washington, DC 20057 USA. EM Hartley@isis.georgetown.edu RI Niu, Tianchan/E-9771-2011; OI Hartley, David/0000-0001-5202-6278; , David/0000-0003-2589-2538 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Centers for Disease Control and Prevention [U01EH000418]; National Institutes of Allergy and Infectious Diseases, National Institues of Health [R01 AI55607] FX This study was supported by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. Christopher M. Barker and William K. Reisen are supported, in part, by Centers for Disease Control and Prevention grant U01EH000418 to study the impacts of climate change on mosquitoborne virus transmission, and National Institutes of Allergy and Infectious Diseases, National Institues of Health grant R01 AI55607 to model amplification of WNV. NR 72 TC 33 Z9 33 U1 4 U2 30 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAY PY 2012 VL 86 IS 5 BP 884 EP 894 DI 10.4269/ajtmh.2012.11-0342 PG 11 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 935WY UT WOS:000303554100027 PM 22556092 ER PT J AU Skare, O Jugessur, A Lie, RT Wilcox, AJ Murray, JC Lunde, A Nguyen, TT Gjessing, HK AF Skare, Oivind Jugessur, Astanand Lie, Rolv Terje Wilcox, Allen James Murray, Jeffrey Clark Lunde, Astrid Truc Trung Nguyen Gjessing, Hakon Kristian TI Application of a Novel Hybrid Study Design to Explore Gene-Environment Interactions in Orofacial Clefts SO ANNALS OF HUMAN GENETICS LA English DT Article DE Birth defects; orofacial cleft; cleft lip; cleft palate; genetic epidemiology ID GENOME-WIDE ASSOCIATION; CASE-PARENT TRIADS; ORAL CLEFTS; EXPOSURE INFORMATION; MATERNAL SMOKING; BIRTH-DEFECTS; PALATE; RISK; LIP; CONSUMPTION AB Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a hybrid design to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (19962001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures. C1 [Skare, Oivind; Jugessur, Astanand; Gjessing, Hakon Kristian] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Skare, Oivind; Lie, Rolv Terje; Lunde, Astrid; Gjessing, Hakon Kristian] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. [Jugessur, Astanand] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Lie, Rolv Terje; Truc Trung Nguyen] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. [Wilcox, Allen James] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Murray, Jeffrey Clark] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Murray, Jeffrey Clark] Univ Iowa, Dept Epidemiol & Biol Sci, Iowa City, IA 52242 USA. RP Skare, O (reprint author), Univ Oslo, Dept Biostat, Pb 1122 Blindern, N-0317 Oslo, Norway. EM oivind.skare@medisin.uio.no RI Gjessing, Hakon/A-5871-2012; Skare, Oivind/C-6330-2016; OI Skare, Oivind/0000-0001-8043-2820; Wilcox, Allen/0000-0002-3376-1311 FU National Institutes of Health [DE08559, P60 DE13076, NIH P30 ES05605, RO1 DE-11948-04]; Norwegian Research Council [NFR 177522/V50]; National Institute of Environmental Health Sciences (NIH/NIEHS); National Institutes of Health (NIH) [N01-HG-65403] FX This research was supported by the National Institutes of Health (DE08559, P60 DE13076, NIH P30 ES05605, and RO1 DE-11948-04), the Norwegian Research Council (NFR 177522/V50) and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIH/NIEHS). We thank all participating families who made this study possible, and Dr. Abee L. Boyles for her comments on an earlier draft of this manuscript. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, Contract Number N01-HG-65403. We thank Ivy McMullen, Corinne Boehm, Kim Doheny and other CIDR staff involved in this project. We also thank the US National Institute of Dental and Craniofacial Research (NIDCR) for underwriting a significant proportion of the genotyping costs by CIDR. NR 55 TC 4 Z9 5 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAY PY 2012 VL 76 BP 221 EP 236 DI 10.1111/j.1469-1809.2012.00707.x PN 3 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 924NE UT WOS:000302697800004 PM 22497478 ER PT J AU Brenner, M Laragione, T Shah, A Mello, A Remmers, EF Wilder, RL Gulko, PS AF Brenner, Max Laragione, Teresina Shah, Anish Mello, Adriana Remmers, Elaine F. Wilder, Ronald L. Gulko, Percio S. TI Identification of Two New Arthritis Severity Loci That Regulate Levels of Autoantibodies, Interleukin-1 beta, and Joint Damage in Pristane- and Collagen-Induced Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID EARLY RHEUMATOID-ARTHRITIS; QUANTITATIVE TRAIT LOCI; HISTOCOMPATIBILITY COMPLEX; DISEASE SEVERITY; II COLLAGEN; SYNOVIAL FIBROBLASTS; SUSCEPTIBILITY LOCI; RECEPTOR ANTAGONIST; PANNUS FORMATION; MAJOR ARTHRITIS AB Objective Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen- and pristane-induced arthritis (CIA and PIA). This study was undertaken to refine the Cia3 genecontaining interval toward gene identification and obtain insights into its mode of action. Methods Five DA.F344(Cia3) subcongenic rat strains were generated and studied using the PIA and CIA models. Levels of antibodies against type II collagen (both allo- and autoantibodies) were measured. Joints and synovial tissue were collected 32 days after the induction of PIA (chronic stage) for histologic and quantitative polymerase chain reaction analysis of interleukin-1 beta (IL-1 beta) and matrix metalloproteinase (MMP) levels. Results Three subcongenic strains sharing the centromeric Cia3d interval were protected and 2 subcongenic strains sharing the telomeric Cia3g interval, which did not overlap with Cia3d, were also protected, developing significantly less severe CIA and PIA. Normal joint architecture was preserved in DA.F344(Cia3) and DA.F344(Cia3d) congenic rats with PIA, while DA rats had pronounced synovial hyperplasia, angiogenesis, inflammatory infiltration, and bone or cartilage erosions. The DA.F344(Cia3d) and DA.F344(Cia3g) strains had significantly lower synovial levels of IL-1 beta (5-fold and nearly 2-fold, respectively [the latter not reaching statistical significance]), MMP-1 (expressed predominantly in DA rats), MMP-3 (79-fold and 8-fold, respectively), and MMP-14 (21-fold and 1.4-fold, respectively) and reduced levels of pathogenic autoantibodies against type II collagen, compared with DA rats. Conclusion We have identified 2 new arthritis severity and articular damage loci within Cia3. These loci regulate pathogenic processes in 2 different models of rheumatoid arthritis, and the identification of these genes has the potential to generate new targets for therapies aimed at reducing disease severity and articular damage, and may additionally have prognostic value. C1 [Gulko, Percio S.] Feinstein Inst Med Res, Lab Expt Rheumatol, Ctr Genom & Human Genet, Manhasset, NY 11030 USA. [Wilder, Ronald L.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Gulko, Percio S.] Elmezzi Grad Sch Mol Med N Shore LIJ, Manhasset, NY USA. RP Gulko, PS (reprint author), Feinstein Inst Med Res, Lab Expt Rheumatol, Ctr Genom & Human Genet, 350 Community Dr,Room 139, Manhasset, NY 11030 USA. EM pgulko@nshs.edu OI Brenner, Max/0000-0002-8010-148X FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [R01-AR-46213]; NIH (National Institute of Allergy and Infectious Diseases) [R01-AI-54348] FX Supported by grants to Dr. Gulko from the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01-AR-46213 and National Institute of Allergy and Infectious Diseases grant R01-AI-54348). NR 49 TC 5 Z9 5 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD MAY PY 2012 VL 64 IS 5 BP 1369 EP 1378 DI 10.1002/art.33468 PG 10 WC Rheumatology SC Rheumatology GA 931SG UT WOS:000303239000011 PM 22076633 ER PT J AU Baird, K Fry, TJ Steinberg, SM Bishop, MR Fowler, DH Delbrook, CP Humphrey, JL Rager, A Richards, K Wayne, AS Mackall, CL AF Baird, Kristin Fry, Terry J. Steinberg, Seth M. Bishop, Michael R. Fowler, Daniel H. Delbrook, Cynthia P. Humphrey, Jennifer L. Rager, Alison Richards, Kelly Wayne, Alan S. Mackall, Crystal L. TI Reduced-Intensity Allogeneic Stem Cell Transplantation in Children and Young Adults with Ultrahigh-Risk Pediatric Sarcomas SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Pediatric soft tissue sarcoma; Allogeneic stem cell transplantation; Reduced-intensity transplantation; Solid tumor ID BONE-MARROW-TRANSPLANTATION; METASTATIC SOLID TUMORS; TOTAL-BODY IRRADIATION; SOFT-TISSUE SARCOMAS; VERSUS-HOST-DISEASE; EWINGS-SARCOMA; PROGNOSTIC-FACTORS; EUROPEAN INTERGROUP; ADVANCED NEUROBLASTOMA; CONSOLIDATION THERAPY AB Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival (OS). Patients with ultrahigh-risk Ewing's sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma, or desmoplastic small round cell tumors received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen, and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT because of progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full-donor engraftment, with no peritransplantation mortality. Five of 23 alloHSCT recipients (22%) remain alive (OS of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 versus 29.0 months from alloHSCT for patients transplanted with versus without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared with 11.4 months for the 21 transplanted (P = .0003). We found prolonged survival after posttransplantation progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced antitumor effects from posttransplantation chemotherapy (objective response to pretransplantation EPOCH-F was 24% versus 67% to posttransplantation EOCH); however, this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radiosensitivity of tumors and normal tissues was observed posttransplantation. Biol Blood Marrow Transplant 18: 698-707 (2012) Published by Elsevier Inc on behalf of American Society for Blood and Marrow Transplantation C1 [Baird, Kristin; Fry, Terry J.; Delbrook, Cynthia P.; Richards, Kelly; Wayne, Alan S.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bishop, Michael R.; Fowler, Daniel H.] NCI, Expt Immunol & Transplantat Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Humphrey, Jennifer L.] Univ S Carolina, Sch Med, Columbia, SC USA. [Rager, Alison] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Rager, Alison] Duke Univ, Sch Med, Durham, NC USA. RP Baird, K (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1W-3940, Bethesda, MD 20892 USA. EM kbaird@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. The authors are employees of the United States Government, and as such, this work was done in that capacity. The views expressed do not necessarily represent the views of the National Institutes of Health or the United States Government. The authors thank Ronald E. Gress for his thoughtful insights. We also acknowledge the exhaustive efforts of Natasha Brunson, Keith O'Neil, Leon Schnabel, Joanne Derdak, Barbara Wise, our clinical fellows, and nursing staff. Finally, we express sincere gratitude to our patients and their families. NR 55 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2012 VL 18 IS 5 BP 698 EP 707 DI 10.1016/j.bbmt.2011.08.020 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 935YQ UT WOS:000303558500007 PM 21896345 ER PT J AU Moreno, C Hasin, DS Arango, C Oquendo, MA Vieta, E Liu, SM Grant, BF Blanco, C AF Moreno, Carmen Hasin, Deborah S. Arango, Celso Oquendo, Maria A. Vieta, Eduard Liu, Shangmin Grant, Bridget F. Blanco, Carlos TI Depression in bipolar disorder versus major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; clinical classifications; depression; epidemiology ID COMORBIDITY SURVEY REPLICATION; WEEKLY SYMPTOMATIC STATUS; TEST-RETEST RELIABILITY; II DISORDER; UNIPOLAR DEPRESSION; CLINICAL-FEATURES; NATURAL-HISTORY; DSM-V; INTERVIEW; PREVALENCE AB Moreno C, Hasin DS, Arango C, Oquendo MA, Vieta E, Liu S, Grant BF, Blanco C. Depression in bipolar disorder versus major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Bipolar Disord 2012: 14: 271282. (C) 2012 The Authors. Journal compilation (C) 2012 John Wiley & Sons A/S. Objectives: To compare the clinical features and course of major depressive episodes (MDEs) occurring in subjects with bipolar I disorder (BD-I), bipolar II disorder (BD-II), and major depressive disorder (MDD). Methods: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (2001-2002), a nationally representative face-to-face survey of more than 43000 adults in the USA, including 5695 subjects with lifetime MDD, 935 with BD-I and lifetime MDE, and 494 with BD-II and lifetime MDE. Differences on sociodemographic characteristics and clinical features, course, and treatment patterns of MDE were analyzed. Results: Most depressive symptoms, family psychiatric history, anxiety disorders, alcohol and drug use disorders, and personality disorders were more frequentand number of depressive symptoms per MDE was higheramong subjects with BD-I, followed by BD-II, and MDD. BD-I individuals experienced a higher number of lifetime MDEs, had a poorer quality of life, and received significantly more treatment for MDE than BD-II and MDD subjects. Individuals with BD-I and BD-II experienced their first mood episode about ten years earlier than those with MDD (21.2, 20.5, and 30.4 years, respectively). Conclusions: Our results support the existence of a spectrum of severity of MDE, with highest severity for BD-I, followed by BD-II and MDD, suggesting the utility of dimensional assessments in current categorical classifications. C1 [Moreno, Carmen; Arango, Celso] Hosp Gen Univ Gregorio Maranon, Dept Psiquiatria Nino & Adolescente, Ctr Invest Biomed Red Salud Mental, CIBERSAM, Madrid 28009, Spain. [Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Hasin, Deborah S.; Oquendo, Maria A.; Liu, Shangmin; Blanco, Carlos] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY USA. [Vieta, Eduard] Univ Barcelona, Bipolar Disorders Program, Inst Neurosci, Hosp Clin,IDIBAPS,CIBERSAM, Barcelona, Spain. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Moreno, C (reprint author), Hosp Gen Univ Gregorio Maranon, Dept Psiquiatria Nino & Adolescente, Ctr Invest Biomed Red Salud Mental, CIBERSAM, Ibiza 43, Madrid 28009, Spain. EM cmoreno@hggm.es RI Vieta, Eduard/I-6330-2013; Blanco, Carlos/I-4906-2013; Arango Lopez, Celso/H-6433-2015; OI Vieta, Eduard/0000-0002-0548-0053; Blanco, Carlos/0000-0001-6187-3057; Arango Lopez, Celso/0000-0003-3382-4754; Moreno, Carmen/0000-0003-0541-4846 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); NIAAA, National Institutes of Health (NIH); NIH [DA019606, DA020783, DA023200, MH076051, R01AA08159, R01DA018652, K05AA00161, MH 57910, MH 62185]; Alicia Koplowitz Foundation; American Foundation for Suicide Prevention; New York State Psychiatric Institute; CIBER de Salud Mental, Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III [CIBER07/09, CIBERSAM]; Fundacion Alicia Koplowitz; Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM); AstraZeneca; Bristol-Myers Squibb; Caja Navarra; Comunidad de Madrid; Fundacion Mutua Madrilena; Instituto de Salud Carlos III; CIBERSAM; NARSAD; Spanish Ministry of Education; Spanish Ministry of Science and Innovation; Spanish Ministry of Health; Stanley Foundation; Eli Lilly Co; Janssen; Almirall; European 7th Framework Program; GlaxoSmithKline; Janssen-Cilag; Novartis; Organon; Otsuka; Pfizer; Sanofi-aventis; Seny Foundation; Servier; Spanish Ministry of Health, the Spanish Ministry of Science and Innovation (CIBERSAM); Stanley Medical Research Institute FX The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health (NIH). This study was supported by NIH grants DA019606, DA020783, DA023200, and MH076051 (CB); R01AA08159, R01DA018652, and K05AA00161 (DSH); MH 57910 and MH 62185 (MAO); the Alicia Koplowitz Foundation (CM); the American Foundation for Suicide Prevention (CB); the New York State Psychiatric Institute (CB, DSH, MAO); and the CIBER de Salud Mental (CIBER07/09, CIBERSAM), Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (CM, CA, EV).; CM has received grant/research support from Fundacion Alicia Koplowitz and Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM); and has served as a consultant for Bristol-Myers Squibb. CA has received grant/research support from AstraZeneca, Bristol-Myers Squibb, Caja Navarra, Comunidad de Madrid, Fundacion Alicia Koplowitz, Fundacion Mutua Madrilena, Instituto de Salud Carlos III, CIBERSAM, NARSAD, the Spanish Ministry of Education, the Spanish Ministry of Science and Innovation, the Spanish Ministry of Health, and the Stanley Foundation; and has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Foundation Alicia Koplowitz, Fundacion Marcelino Botin, Janssen, Pfizer, Servier, the Spanish Ministry of Health, and the Spanish Ministry of Science and Innovation. MAO has received unrestricted educational grants from Eli Lilly & Co., AstraZeneca, and Janssen. EV has received grant/research support from Almirall, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., the European 7th Framework Program, GlaxoSmithKline, Janssen-Cilag, Novartis, Organon, Otsuka, Pfizer, Sanofi-aventis, Seny Foundation, Servier, the Spanish Ministry of Education, Social Policy and Sports, the Spanish Ministry of Health, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute; and has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Forest Research Institute, Geodon Richter, GlaxoSmithKline, Janssen, Jazz, Johnson & Johnson, Lundbeck, MSD, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier, Takeda, and UBC. CB has received research support from GlaxoSmithKline, Eli Lilly & Co., and Pfizer. DSH, SL, and BFG report no financial relationships with commercial interests. NR 50 TC 34 Z9 35 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAY PY 2012 VL 14 IS 3 BP 271 EP 282 DI 10.1111/j.1399-5618.2012.01009.x PG 12 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 934IO UT WOS:000303438000006 PM 22548900 ER PT J AU Little, MP Rajaraman, P Curtis, RE Devesa, SS Inskip, PD Check, DP Linet, MS AF Little, M. P. Rajaraman, P. Curtis, R. E. Devesa, S. S. Inskip, P. D. Check, D. P. Linet, M. S. TI Authors' reply to Kundi and Davis and colleagues SO BRITISH MEDICAL JOURNAL LA English DT Letter ID MOBILE; RISK C1 [Little, M. P.; Rajaraman, P.; Curtis, R. E.; Devesa, S. S.; Inskip, P. D.; Check, D. P.; Linet, M. S.] NCI, Rockville, MD 20852 USA. RP Little, MP (reprint author), NCI, Rockville, MD 20852 USA. EM mark.little@nih.gov RI Check, David/J-7184-2015 OI Check, David/0000-0003-3887-0493 NR 6 TC 0 Z9 0 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD MAY 1 PY 2012 VL 344 AR e3088 DI 10.1136/bmj.e3088 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 939MZ UT WOS:000303816700026 ER PT J AU Freeman, LEB DeRoos, AJ Koutros, S Blair, A Ward, MH Alavanja, M Hoppin, JA AF Freeman, Laura E. Beane DeRoos, Anneclaire J. Koutros, Stella Blair, Aaron Ward, Mary H. Alavanja, Michael Hoppin, Jane A. TI Poultry and livestock exposure and cancer risk among farmers in the agricultural health study SO CANCER CAUSES & CONTROL LA English DT Article DE Livestock; Poultry; Cancer; Cohort study; Agriculture ID NON-HODGKINS-LYMPHOMA; LUNG-CANCER; MULTIPLE-MYELOMA; OCCUPATIONAL-EXPOSURE; PET BIRDS; AVIAN EXPOSURE; MORTALITY; OPERATIONS; ENDOTOXIN; WORKERS AB The purpose of this study is to evaluate cancer risk associated with raising animals as commodities, which is associated with a variety of exposures, such as infectious agents and endotoxins. Information was available for 49,884 male farmers in the Agricultural Health Study, who reported livestock and poultry production at enrollment (1993-1997). Cancer incidence data were obtained through annual linkage to state registries. Using Poisson regression analyses, we evaluated whether the number and type of animals raised on the farm impacted cancer risk. Overall, 31,848 (63.8%) male farmers reported raising any animals. Lung cancer risk decreased with increasing number of livestock on the farm (p trend = 0.04) and with raising poultry (Relative Risk (RR) = 0.6; 95% confidence interval (CI): 0.4-0.97). Raising poultry was associated with an increased risk of colon cancer (RR = 1.4; 95% CI: 0.99-2.0) with further increased with larger flocks (p trend = 0.02). Risk of non-Hodgkin lymphoma was also elevated in those who raised poultry (RR = 1.6; 95% CI: 1.0-2.4), but there was no evidence of increased risk with larger flocks (p trend = 0.5). Raising sheep was associated with a significantly increased risk of multiple myeloma (RR = 4.9; 95% CI: 2.4-12.0). Performing veterinary services increased the risk of Hodgkin lymphoma (RR = 12.2; 95% CI: 1.6-96.3). We observed an inverse association between raising poultry and livestock and lung cancer risk and some evidence of increased risk of specific lymphohematopoietic malignancies with specific types of animals and performing veterinary services. Further research into associations between raising animals and cancer risk should focus on identification of etiologic agents. C1 [Freeman, Laura E. Beane; Koutros, Stella; Blair, Aaron; Ward, Mary H.; Alavanja, Michael] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Freeman, Laura E. Beane; Koutros, Stella; Blair, Aaron; Ward, Mary H.; Alavanja, Michael; Hoppin, Jane A.] Dept Hlth & Human Serv, Bethesda, MD USA. [DeRoos, Anneclaire J.] Univ Washington, Seattle, WA 98195 USA. [DeRoos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hoppin, Jane A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. RP Freeman, LEB (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,MSC 7240, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov FU National Institutes of Health (National Cancer Institute) [Z01 CP010119]; National Institutes of Health (National Institute of Environmental Health Sciences) [Z01 ES049030] FX This work was supported by funds from the Intramural Research Program of the National Institutes of Health (National Cancer Institute Z01 CP010119 and the National Institute of Environmental Health Sciences Z01 ES049030). All data used in these analyses were based on AHS data release P1REL201005.00. NR 32 TC 17 Z9 18 U1 0 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2012 VL 23 IS 5 BP 663 EP 670 DI 10.1007/s10552-012-9921-1 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 934CI UT WOS:000303418200001 ER PT J AU Reding, KW Chen, C Lowe, K Doody, DR Carlson, CS Chen, CT Houck, J Weiss, LK Marchbanks, PA Bernstein, L Spirtas, R McDonald, JA Strom, BL Burkman, RT Simon, MS Liff, JM Daling, JR Malone, KE AF Reding, Kerryn W. Chen, Chu Lowe, Kimberly Doody, David R. Carlson, Christopher S. Chen, Christina T. Houck, John Weiss, Linda K. Marchbanks, Polly A. Bernstein, Leslie Spirtas, Robert McDonald, Jill A. Strom, Brian L. Burkman, Ronald T. Simon, Michael S. Liff, Jonathan M. Daling, Janet R. Malone, Kathleen E. TI Estrogen-related genes and their contribution to racial differences in breast cancer risk SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Genetic variation; Racial disparities; Gene-environment interactions; Hormone therapy ID HORMONE-REPLACEMENT THERAPY; AFRICAN-AMERICAN WOMEN; MULTILOCUS GENOTYPE DATA; POPULATION-STRUCTURE; RECEPTOR STATUS; REPRODUCTIVE EXPERIENCES; TUMOR CHARACTERISTICS; METABOLISM GENOTYPES; ENDOGENOUS HORMONES; MULTIETHNIC COHORT AB Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent. C1 [Reding, Kerryn W.; Chen, Chu; Doody, David R.; Carlson, Christopher S.; Chen, Christina T.; Houck, John; Daling, Janet R.; Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Reding, Kerryn W.] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Chen, Chu; Carlson, Christopher S.; Malone, Kathleen E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lowe, Kimberly] Exponent, Seattle, WA USA. [Weiss, Linda K.] NCI, Canc Ctr Program, Rockville, MD USA. [Marchbanks, Polly A.; McDonald, Jill A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Spirtas, Robert] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Strom, Brian L.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Strom, Brian L.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Burkman, Ronald T.] Baystate Hlth, Dept Obstet & Gynecol, Springfield, MA USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Liff, Jonathan M.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Reding, KW (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,Mail Stop M4-B874, Seattle, WA 98109 USA. EM kreding@u.washington.edu FU National Institute of Child Health and Human Development; National Cancer Institute, through Emory University [N01 HD 3-3168]; Fred Hutchinson Cancer Research Center [N01 HD 2-3166]; Karmanos Cancer Institute at Wayne State University [N01 HD 3-3174]; University of Pennsylvania [N01 HD-3-3176]; University of Southern California [N01 HD 3-3175]; Centers for Disease Control and Prevention [Y01 HD 7022]; National Cancer Institute [R03 CA 123584]; Cancer Epidemiology and Biostatistics Training Grant [2 T32 CA 09168]; NINR [K99NR012232] FX The authors would like to thank the study participants for their contribution to this research. The CARE study was supported by the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, through contracts with Emory University (N01 HD 3-3168), the Fred Hutchinson Cancer Research Center (N01 HD 2-3166), Karmanos Cancer Institute at Wayne State University (N01 HD 3-3174), the University of Pennsylvania (N01 HD-3-3176), and the University of Southern California (N01 HD 3-3175) and through an intraagency agreement with the Centers for Disease Control and Prevention (Y01 HD 7022). The research generating the AIMs data was supported by the National Cancer Institute (R03 CA 123584). KWR was supported by the Cancer Epidemiology and Biostatistics Training Grant (2 T32 CA 09168) and NINR grant K99NR012232. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health or the Centers for Disease Control and Prevention. This research was supported by funding from the National Institute of Child Health and Human Development with additional support from the Centers for Disease Control and Prevention and the National Cancer Institute. NR 72 TC 18 Z9 19 U1 0 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2012 VL 23 IS 5 BP 671 EP 681 DI 10.1007/s10552-012-9925-x PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 934CI UT WOS:000303418200002 PM 22418777 ER PT J AU Dubrow, R Darefsky, AS Freedman, ND Hollenbeck, AR Sinha, R AF Dubrow, Robert Darefsky, Amy S. Freedman, Neal D. Hollenbeck, Albert R. Sinha, Rashmi TI Coffee, tea, soda, and caffeine intake in relation to risk of adult glioma in the NIH-AARP Diet and Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE Glioma; Brain neoplasms; Coffee; Tea; Soda; Caffeine ID BRAIN-TUMORS; ONSET GLIOMA; CANCER; COHORT; GLIOBLASTOMA; CONSUMPTION; DITERPENES; CALIFORNIA; NUTRITION; CAFESTOL AB We utilized the large, prospective NIH-AARP Diet and Health Study to further explore the hypothesis, suggested by two recent prospective cohort studies, that increased intake of coffee, tea, soda, and/or caffeine is associated with reduced adult glioma risk. At baseline in 1995-1996, dietary intake, including coffee, tea, and soda, was assessed with a food frequency questionnaire. We used Cox proportional hazards models to calculate adjusted hazard ratios (HR) and 95 % confidence intervals (CI) for glioma risk in relation to beverage intake. During follow-up of 545,771 participants through 2006, 904 participants were diagnosed with glioma. We found no trends of decreasing glioma risk with increasing intake of specific beverages or total caffeine. HR patterns for consumption of the caffeinated versus decaffeinated form of each beverage were inconsistent with a specific caffeine effect. HR patterns of reduced glioma risk for most categories of beverage intake greater than "none" prompted a post hoc analysis that revealed borderline-significant inverse associations for any versus no intake of tea (HR = 0.84; 95 % CI, 0.69-1.03), total coffee plus tea (HR = 0.70; 95 % CI, 0.48-1.03), and soda (HR = 0.82; 95 % CI, 0.67-1.01). The borderline-significant inverse associations could be explained by a threshold effect in which any beverage intake above a low level confers a beneficial effect, most likely due to beverage constituents other than caffeine. They could also be explained by non-drinkers of these beverages sharing unknown extraneous characteristics associated with increased glioma risk, or by chance. C1 [Dubrow, Robert; Darefsky, Amy S.] Yale Univ, Sch Med, Sch Publ Hlth, New Haven, CT 06520 USA. [Freedman, Neal D.; Sinha, Rashmi] NCI NIH DHHS, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Dubrow, R (reprint author), Yale Univ, Sch Med, Sch Publ Hlth, New Haven, CT 06520 USA. EM robert.dubrow@yale.edu RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU NIH, National Cancer Institute FX Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health, and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll and Jane Wang at Information Management Services for data support and analysis. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute. NR 27 TC 7 Z9 8 U1 0 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2012 VL 23 IS 5 BP 757 EP 768 DI 10.1007/s10552-012-9945-6 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 934CI UT WOS:000303418200011 PM 22457000 ER PT J AU Faupel-Badger, JM Wang, YP Staff, AC Karumanchi, SA Stanczyk, FZ Pollak, M Hoover, RN Troisi, R AF Faupel-Badger, Jessica M. Wang, Yuping Staff, Anne Cathrine Karumanchi, S. Ananth Stanczyk, Frank Z. Pollak, Michael Hoover, Robert N. Troisi, Rebecca TI Maternal and cord steroid sex hormones, angiogenic factors, and insulin-like growth factor axis in African-American preeclamptic and uncomplicated pregnancies SO CANCER CAUSES & CONTROL LA English DT Article DE Preeclampsia; African-American; sFlt-1; IGF; Leptin; Prolactin ID BREAST-CANCER RISK; FOR-GESTATIONAL-AGE; ANTIANGIOGENIC FACTORS; SOLUBLE ENDOGLIN; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; TYROSINE KINASE-1; NULLIPAROUS WOMEN; PATHOGENESIS; ESTROGEN AB A history of a preeclamptic pregnancy has been associated with subsequent increased risk of cardiovascular disease in the mother and decreased risk of breast cancer in both the mother and offspring. The concentrations of steroid sex hormones, angiogenic factors, and other proteins during pregnancy are important components of the in utero environment and may mediate the association of preeclampsia with later health outcomes. This study sought to compare an extensive profile of biological markers in both maternal and umbilical cord samples in preeclamptic and uncomplicated pregnancies of a predominantly African-American population. Steroid sex hormones, angiogenic factors, and components of the insulin-like growth factor axis were measured in maternal and umbilical cord sera from 48 pregnancies complicated by preeclampsia and 43 uncomplicated pregnancies. Regression models estimated the associations of these markers with preeclampsia, after adjusting for maternal and gestational age. Concentrations of androgens (testosterone p = 0.06 and androstenedione p = 0.08) and the anti-angiogenic factors soluble fms-like kinase 1 (p = 0.004) and soluble endoglin (p = 0.004) were higher in the maternal circulation of women diagnosed with preeclampsia. These findings also were noted when the analyses were restricted to only African-American participants (77% of overall study population). Furthermore, among African-Americans, cord insulin-like growth factor-1 was lower in preeclamptic pregnancies than in controls. The associations of maternal androgens and anti-angiogenic factors with preeclampsia are consistent with prior reports from predominantly Caucasian populations. Alterations in these analytes as well as other maternal and fetal biomarkers in preeclampsia could mediate the associations of preeclampsia with later health consequences. C1 [Faupel-Badger, Jessica M.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Bethesda, MD 20892 USA. [Faupel-Badger, Jessica M.; Hoover, Robert N.; Troisi, Rebecca] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wang, Yuping] Louisiana State Univ, Hlth Sci Ctr, Dept Obstet & Gynecol, Shreveport, LA 71105 USA. [Staff, Anne Cathrine] Oslo Univ Hosp, Dept Obstet & Gynaecol, Ulleval, Norway. [Staff, Anne Cathrine] Univ Oslo, Fac Med, Oslo, Norway. [Karumanchi, S. Ananth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Pollak, Michael] McGill Univ, Dept Med, Montreal, PQ, Canada. RP Faupel-Badger, JM (reprint author), NCI, Canc Prevent Fellowship Program, Ctr Canc Training, 6120 Execut Blvd EPS,Suite 150E,MSC 7105, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov RI Pollak, Michael/G-9094-2011 OI Pollak, Michael/0000-0003-3047-0604 FU National Cancer Institute (NCI), National Institutes of Health; Center for Cancer Training, NCI FX We would like to thank Lisa Philibert, RN and Kimberly Mandino, RN at LSUHSC-Shreveport for patient recruitment and clinical data collection for the study. We also thank Marianne Hyer and David Castenson at Information Management Systems for their contributions to data verification and analysis and Dr. Jun Zhang at NICHD for collaborating with us on the parent study. This research was supported in part by the intramural research program of the National Cancer Institute (NCI), National Institutes of Health and the Center for Cancer Training, Cancer Prevention Fellowship Program, NCI. NR 40 TC 8 Z9 8 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2012 VL 23 IS 5 BP 779 EP 784 DI 10.1007/s10552-012-9934-9 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 934CI UT WOS:000303418200013 PM 22418778 ER PT J AU Kapetanovic, IM Muzzio, M McCormick, DL Thompson, TN Johnson, WD Horn, TL Mohammed, A Rao, CV Kopelovich, L AF Kapetanovic, Izet M. Muzzio, Miguel McCormick, David L. Thompson, Thomas N. Johnson, William D. Horn, Thomas L. Mohammed, Altaf Rao, Chinthalapally V. Kopelovich, Levy TI Pharmacokinetics and tissue and tumor exposure of CP-31398, a p53-stabilizing agent, in rats SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE p53; Chemoprevention; Pharmacokinetics; Liver; Colon tumor; Rat ID MUTANT P53; CANCER; RESTORATION; SUPPRESSION; THERAPY; MICE AB CP-31398 (N'-[2-[(E)-2-(4-methoxyphenyl)ethenyl]quinazolin-4-yl]-N,N-dimethylpropane-1,3-diamine hydrochloride) is one of the new class of agents that can stabilize the DNA-binding domain of p53 and thereby maintain the activity of p53 as a tumor suppressor and transcription factor. Through its activity as a p53 stabilizer, CP-31398 demonstrates significant cancer preventive and therapeutic activity in several in vivo animal models. The objective of the current study was to describe the pharmacokinetic profile and tissue distribution of this novel agent following intravenous or oral (gavage and dietary) administration. CP-31398 was administered to male CD and F344 rats as a single intravenous bolus dose or by daily oral gavage dosing. Male F344 rats also received drug as an ad libitum dietary supplement. Plasma, liver, skin, colon, and colon tumor samples were collected after oral dosing. Concentrations of CP-31398 in plasma and tissue samples were analyzed using LC-MS/MS, and the resultant data were subjected to a non-compartmental pharmacokinetic analysis. Bioavailability (12-32%), elimination half-life (14-20 h), clearance (4.2-4.8 l/h/kg), and volume of distribution (70-82 l/kg) were determined. Tissue levels of CP-31398 after oral (gavage or diet) administration were several orders of magnitude higher than were corresponding plasma concentrations; CP-31398 levels were especially high in colon and liver. Levels of CP-31398 in tissues were higher after gavage dosing than after dietary administration. CP-31398 is bioavailable and has a relatively long elimination half-life, which supports the achievement of plasma steady-state levels with a once daily dosing regimen. CP-31398 exhibits a dramatically high volume of distribution, which is consistent with its tissue concentrations being much higher than corresponding plasma levels. It is accumulated in colon tumor tissues, albeit at lower concentrations than found in liver, skin, and colon. C1 [Kapetanovic, Izet M.; Kopelovich, Levy] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Muzzio, Miguel; McCormick, David L.; Johnson, William D.; Horn, Thomas L.] IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Mohammed, Altaf; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Chemoprevent & Drug Dev, Oklahoma City, OK 73104 USA. [Thompson, Thomas N.] R&D Serv Pharma Consulting, Omaha, NE 68154 USA. RP Kapetanovic, IM (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, 6130 Executive Blvd,Rm 2116, Bethesda, MD 20892 USA. EM kapetani@mail.nih.gov FU National Cancer Institute, Department of Health and Human Services [N01-CN-43304] FX These studies were supported by contract number N01-CN-43304 from the National Cancer Institute, Department of Health and Human Services. NR 19 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2012 VL 69 IS 5 BP 1301 EP 1306 DI 10.1007/s00280-011-1811-9 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 934CK UT WOS:000303418500021 PM 22302406 ER PT J AU Yewdell, JW Brooke, CB AF Yewdell, Jonathan W. Brooke, Christopher B. TI Monocytes, viruses and metaphors Hanging the Trojan horse SO CELL CYCLE LA English DT Editorial Material ID CELLS C1 [Yewdell, Jonathan W.; Brooke, Christopher B.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov FU Intramural NIH HHS NR 7 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 1 PY 2012 VL 11 IS 9 BP 1748 EP 1749 DI 10.4161/cc.20311 PG 2 WC Cell Biology SC Cell Biology GA 935OL UT WOS:000303528500011 PM 22517432 ER PT J AU Yamane, H Paul, WE AF Yamane, Hidehiro Paul, William E. TI Memory CD4(+) T Cells: fate determination, positive feedback and plasticity SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE T helper cell differentiation; Effector CD4(+) T cells; Memory CD4(+) T cells; T cell plasticity; T helper lineage-specific transcription factors; Positive feedback regulation by cytokines ID TRANSCRIPTION FACTOR GATA-3; INTERFERON-GAMMA; IN-VIVO; PRODUCE INTERLEUKIN-4; TH2 DIFFERENTIATION; HELPER-CELLS; IFN-GAMMA; EXPRESSION; IL-4; RESPONSES AB Na < ve CD4(+) T cells undergo massive cell proliferation upon encountering their cognate ligand. This proliferation depends upon appropriate cues from the antigen-presenting cells that have processed the antigen and present the peptide to the T cells, and requires the establishment of a cytokine environment that can support such proliferation. Expansion of antigen-specific CD4(+) T cells needs to be coupled with differentiation into one of several effector/regulatory phenotypes if the priming event is to result in cells that can initially act to control the particular pathogen that elicited the response, and later to serve as memory cells to insure an appropriate response upon reintroduction of the pathogen. Here, we discuss the initiation of T helper lineage commitment, the positive feedback regulation by the cytokine environment to enhance and stabilize the differentiation into distinct T helper subsets, and the biological significance of CD4(+) T cell plasticity and long-term CD4(+) T cell memory. C1 [Yamane, Hidehiro; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Yamane, H (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM hyamane@niaid.nih.gov; wpaul@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX The work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. We thank Dr. Ryoji Yagi for critical reading of the manuscript. NR 59 TC 15 Z9 16 U1 1 U2 14 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 MAY PY 2012 VL 69 IS 10 BP 1577 EP 1583 DI 10.1007/s00018-012-0966-9 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 935HN UT WOS:000303509800003 PM 22481436 ER PT J AU Hoffman, HJ Dobie, RA Ko, CW Themann, CL Murphy, WJ AF Hoffman, Howard J. Dobie, Robert A. Ko, Chia-Wen Themann, Christa L. Murphy, William J. TI Hearing Threshold Levels at Age 70 Years (65-74 Years) in the Unscreened Older Adult Population of the United States, 1959-1962 and 1999-2006 SO EAR AND HEARING LA English DT Article AB Objectives: To provide hearing threshold percentiles from unscreened older adults for creating new Annex B reference standards. Design: Percentiles are calculated, and 95% confidence intervals for medians from two U. S. surveys are compared graphically. Results: Median thresholds are lower (better) in the 1999-2006 National Health and Nutrition Examination Survey for men across all frequencies except 1 kHz. Results for women are similar; however, there is more overlap in confidence intervals across frequencies. Conclusions: The prevalence of hearing impairment in older adults, age 70 years (65-74 years), is lower in 1999-2006 compared with 19591962, consistent with our earlier findings for younger adults. C1 [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD 20892 USA. [Dobie, Robert A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Otolaryngol Head & Neck Surg, San Antonio, TX 78229 USA. [Ko, Chia-Wen] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Themann, Christa L.; Murphy, William J.] NIOSH, Hearing Loss Prevent Team, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. RP Hoffman, HJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Suite 400A,Execut Plaza S Bldg,6120 Execut Blvd, Bethesda, MD 20892 USA. EM hoffmanh@nidcd.nih.gov OI dobie, robert/0000-0003-3833-1772 FU National Institute on Deafness and Other Communication Disorders; National Institute for Occupational Safety and Health FX The National Health and Nutrition Examination Survey 1999-2006 audiometric data collection was funded with National Institute on Deafness and Other Communication Disorders research contract funds via an Interagency Agreement between the National Institute on Deafness and Other Communication Disorders and the National Center for Health Statistics. The National Institute for Occupational Safety and Health provided funding for the audiometric testing equipment, training and monitoring of technicians, and editing of preliminary data files. The National Institute for Occupational Safety and Healt collaboration was funded and managed via Interagency Agreements with the National Institute on Deafness and Other Communication Disorders and the National Center for Health Statistics. Audiometric testing was conducted in the field by health technicians employed by Westat, Inc., under contract with the National Center for Health Statistics. NR 15 TC 15 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD MAY-JUN PY 2012 VL 33 IS 3 BP 437 EP 440 DI 10.1097/AUD.0b013e3182362790 PG 4 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 934OT UT WOS:000303454400013 PM 22080933 ER PT J AU Oh, JY Choi, H Lee, RH Roddy, GW Ylostalo, JH Wawrousek, E Prockop, DJ AF Oh, Joo Youn Choi, Hosoon Lee, Ryang Hwa Roddy, Gavin W. Yloestalo, Joni H. Wawrousek, Eric Prockop, Darwin J. TI Identification of the HSPB4/TLR2/NF-?B axis in macrophage as a therapeutic target for sterile inflammation of the cornea SO EMBO MOLECULAR MEDICINE LA English DT Article DE cornea; HSPB4; inflammation; macrophage; toll-like receptor 2 ID ALPHA-A-CRYSTALLIN; HEAT-SHOCK-PROTEIN; OXIDATIVE STRESS; CELLS; SECRETONEURIN; RETINA; EYE; NEUROPEPTIDE; MECHANISMS; EXPRESSION AB Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular mechanisms triggering inflammatory responses. Neutrophil infiltration occurred in two phases: a small initial phase (Phase I) that began within 15?min after injury, and a larger second phase (Phase II) that peaked at 2448?h. Temporal analysis suggested that the neuropeptide secretoneurin initiated Phase I without involvement of resident macrophages. Phase II was initiated by the small heat shock protein HSPB4 that was released from injured keratocytes and that activated resident macrophages via the TLR2/NF-?B pathway. The Phase II inflammation was responsible for vision-threatening opacity and was markedly suppressed by different means of inhibition of the HSPB4/TLR2/NF-?B axis: in mice lacking HSPB4 or TLR2, by antibodies to HSPB4 or by TNF-a stimulated gene/protein 6 that CD44-dependently inhibits the TLR2/NF-?B pathway. Therefore, our data identified the HSPB4/TLR2/NF-?B axis in macrophages as an effective target for therapy of corneal inflammation. C1 [Oh, Joo Youn; Choi, Hosoon; Lee, Ryang Hwa; Roddy, Gavin W.; Yloestalo, Joni H.; Prockop, Darwin J.] Scott & White Mem Hosp & Clin, Coll Med, Texas A&M Hlth Sci Ctr, Inst Regenerat Med, Temple, TX 76508 USA. [Wawrousek, Eric] NEI, NIH, Bethesda, MD 20892 USA. RP Prockop, DJ (reprint author), Scott & White Mem Hosp & Clin, Coll Med, Texas A&M Hlth Sci Ctr, Inst Regenerat Med, Temple, TX 76508 USA. EM prockop@medicine.tamhsc.edu FU NIH [R21EY020962] FX This study was supported in part by NIH grant R21EY020962. We gratefully acknowledge help from Laura Quinlivan for assistance in animal experiments. NR 44 TC 16 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD MAY PY 2012 VL 4 IS 5 BP 435 EP 448 DI 10.1002/emmm.201200221 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 935DK UT WOS:000303498900009 PM 22359280 ER PT J AU Zannad, F Stough, WG Pocock, SJ Sleight, P Cushman, WC Cleland, JG McMurray, JJ Lonn, E Geller, NL Wedel, H Abadie, E Alonso-Garcia, A Pitt, B AF Zannad, Faiez Stough, Wendy Gattis Pocock, Stuart J. Sleight, Peter Cushman, William C. Cleland, John G. F. McMurray, John J. V. Lonn, Eva Geller, Nancy L. Wedel, Hans Abadie, Eric Alonso-Garcia, Angeles Pitt, Bertram TI Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements? SO EUROPEAN HEART JOURNAL LA English DT Review DE Diabetes mellitus; Cardiovascular disease; Clinical trials ID AMERICAN-HEART-ASSOCIATION; INTENSIVE GLYCEMIC CONTROL; BLOOD-GLUCOSE CONTROL; RANDOMIZED CONTROLLED-TRIALS; LONG-TERM COMPLICATIONS; ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; THIAZOLIDINEDIONE THERAPY; VASCULAR COMPLICATIONS AB Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs. C1 [Zannad, Faiez] Nancy Univ, Hop Jeanne dArc, INSERM, Ctr Invest Clin 9501, F-54200 Nancy, France. [Zannad, Faiez] Nancy Univ, Hop Jeanne dArc, Ctr Hosp Univ, Unite 961, F-54200 Nancy, France. [Zannad, Faiez] Nancy Univ, Hop Jeanne dArc, Dept Cardiol, F-54200 Nancy, France. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Pocock, Stuart J.] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. [Sleight, Peter] Univ Oxford, Nuffield Dept Med, Oxford OX3 9DU, England. [Cushman, William C.] Univ Tennessee, Coll Med, Vet Affairs Med Ctr, Memphis, TN USA. [Cleland, John G. F.] Castle Hill Hosp, Dept Cardiol, Kingston Upon Hull, Yorks, England. [McMurray, John J. V.] Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Lonn, Eva] McMaster Univ, Div Cardiol, Dept Med, Populat Hlth Res Inst, Hamilton, ON L8S 4L8, Canada. [Geller, Nancy L.] NHLBI, Bethesda, MD 20892 USA. [Wedel, Hans] Nord Sch Publ Hlth, Gothenburg, Sweden. [Abadie, Eric] French Agcy Safety Hlth Prod AFSSAPS, Paris, France. [Alonso-Garcia, Angeles] Sci Advice Working Party European Med Agcy, Madrid, Spain. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Zannad, F (reprint author), Nancy Univ, Hop Jeanne dArc, INSERM, Ctr Invest Clin 9501, F-54200 Nancy, France. EM f.zannad@chu-nancy.fr RI Stough, Wendy/R-4287-2016; OI Stough, Wendy/0000-0001-8290-1205; Cleland, John/0000-0002-1471-7016; mcmurray, john/0000-0002-6317-3975 FU Association de Recherche et d'Information en Cardiologie (ARISC) a non-profit educational organization, in Nancy, France; Novartis; GSK; Merck; FP7 FX This paper was generated from discussions during the 7th Global Cardiovascular Clinical Trialists (CVCT) Forum held in Paris, France, in December 2010. CVCT was organized by the Clinical Investigation Center (CIC) Inserm, CHU, and University Henri Poincare of Nancy, France and funded by an unrestricted educational grant from Association de Recherche et d'Information en Cardiologie (ARISC) a non-profit educational organization, in Nancy, France. ARISC had no involvement in preparation, review, or approval of the manuscript for publication.; All authors received travel expense reimbursement to attend the CVCT meeting from INSERM, Centre d'Investigation Clinique, Centre Hospitalier Universitaire, Nancy, France. Faiez Zannad: Pfizer, Inc. (Steering Committee). W.G.S.: INSERM, Centre d'Investigation Clinique, Centre Hospitalier Universitaire, Nancy, France (travel expense reimbursement to attend CVCT 2010; professional/project management/administrative time related to preparation of this paper). W.C.C.: Consultant to Takeda, Novartis, Merck, Sanofi-Aventis, BMS, Gilead, Daiichi-Sankyo, Theravance, and Noven; active or pending grants from Novartis, GSK, and Merck. J.G.F.C.: Active or pending grant from FP7. H.W.: Roche (Steering Committee member). B. P.: Consultant for Pfizer, Merck, Novartis, Takeda, Astra Zeneca, Bayer. NR 61 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD MAY PY 2012 VL 33 IS 9 BP 1049 EP U29 DI 10.1093/eurheartj/ehr437 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 937JD UT WOS:000303653900011 PM 22422830 ER PT J AU Jann, MW Spratlin, V Momary, K Zhang, HL Turner, D Penzak, SR Wright, A VanDenBerg, C AF Jann, Michael W. Spratlin, Vicky Momary, Kathryn Zhang, Hailing Turner, David Penzak, Scott R. Wright, Alan VanDenBerg, Chad TI Lack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavir SO EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Drug interaction; Venlafaxine XR; Desvenlafaxine XR; Indinavir; P-glycoprotein ID P-GLYCOPROTEIN; GRAPEFRUIT JUICE; HIV-INFECTION; IN-VITRO; INDINAVIR; METABOLITES; ABSORPTION; INHIBITORS; BARRIER; CYP2D6 AB To assess the effects of venlafaxine extended-release (XR) capsules and desvenlafaxine extended-release (XR) tablets upon indinavir pharmacokinetic properties when co-administrated to healthy volunteers. This was an open-label, two-period, fixed-dose study conducted at the clinical research unit located on a university campus. Twenty-four healthy volunteers enrolled in the study (mean age 28.3 +/- 8.0 years). Each subject received a single dose of indinavir 800 mg on day 1. Subsequently, subjects were then randomly assigned to either the venlafaxine XR group (N = 12) or the desvenlafaxine XR group (N = 12). Starting on day 2, venlafaxine XR was dosed at 37.5 mg/day for 4 days and increased to 75 mg/day for 6 days. Desvenlafaxine XR was dosed at 50 mg/day for 10 days. On day 12, indivanvir 800 mg was co-administered to both the venlafaxine XR and the desvenlafaxine XR groups. The pharmacokinetics of indinavir were determined both before and at the end of antidepressant dosing. Plasma indinavir, venlafaxine, and desvenlafaxine concentrations were assayed by high-performance liquid chromatography with ultra-violet (UV) detection. Indinavir pharmacokinetic parameters were calculated by noncompartmental analysis using validated computer software. Venlafaxine XR and desvenlafaxine XR did not produce any significant changes in indinavir disposition. Both antidepressants were well tolerated by the subjects with only minor adverse side effects. No pharmacokinetic drug-drug interaction was demonstrated between venlafaxine XR and indinavir or between desvenlafaxine XR and indinvair. The lack of interaction could be due to the venlafaxine and desvenlafaxine extended-release formulation. C1 [Jann, Michael W.; Spratlin, Vicky; Momary, Kathryn; Zhang, Hailing; Turner, David; Wright, Alan; VanDenBerg, Chad] Mercer Univ, Coll Pharm & Hlth Sci, Atlanta, GA 30341 USA. [Penzak, Scott R.] NIH, Clin Pharmacokinet Lab, Bethesda, MD 20892 USA. RP Jann, MW (reprint author), Mercer Univ, Coll Pharm & Hlth Sci, 3001 Mercer Univ Dr, Atlanta, GA 30341 USA. EM jann_mw@mercer.edu FU Pfizer, Inc.; Pfizer; Janssen Pharmaceuticals; Johnson/Johnson; Eli Lilly; Coca Cola Company FX This study was supported by Pfizer, Inc. through the investigator-initiated research study program. Dr. Jann has received research grants from Pfizer and Janssen Pharmaceuticals. Drs. Spratlin and VanDenBerg have received research grants from Pfizer, Johnson/Johnson, Eli Lilly, and the Coca Cola Company. Dr. Momary has received research funding from Pfizer. Dr. Zhang, Dr. Penzak, Dr. Wright, and Mr. Turner have nothing to disclose. NR 26 TC 2 Z9 4 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0031-6970 J9 EUR J CLIN PHARMACOL JI Eur. J. Clin. Pharmacol. PD MAY PY 2012 VL 68 IS 5 BP 715 EP 721 DI 10.1007/s00228-011-1180-7 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 934OD UT WOS:000303452800028 PM 22173281 ER PT J AU Feifel, D Shilling, PD Belcher, AM AF Feifel, David Shilling, Paul D. Belcher, Annabelle M. TI The effects of oxytocin and its analog, carbetocin, on genetic deficits in sensorimotor gating SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Schizophrenia; Antipsychotics; Prepulse inhibition; Brown-Norway; Animal models ID PREPULSE INHIBITION; SCHIZOPHRENIC-PATIENTS; CEREBROSPINAL-FLUID; RAT STRAIN; BEHAVIOR; VASOPRESSIN; AUTISM; BRAIN; MODEL AB Converging evidence from preclinical and clinical studies suggest that oxytocin has therapeutic potential for schizophrenia and other neuropsychiatric disorders. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating, an important brain function involved in filtering environmental information. We previously demonstrated that systemically administered oxytocin reversed psychostimulant-induced PPI deficits in rats suggesting that oxytocin can produce antipsychotic-like central effects. That finding was supported by a recent trial in humans, which found that intranasal oxytocin reduced symptoms of schizophrenia. The goal of this study was to extend this line of investigation by testing the effects of oxytocin, and a structural analog of oxytocin, carbetocin, on non-pharmacological deficits in PPI. In experiment 1, Brown Norway (BN) rats, a rat strain that has naturally low PPI, were given either saline or one of three doses of oxytocin (0.04-1.0 mg/kg, sc). In experiment 2, BN rats were given either saline, one of three doses of carbetocin (0.04-1.0 mg/kg) or oxytocin (1 mg/kg). PPI and acoustic startle response (ASR) of rats were tested. Oxytocin significantly increased PPI (P<0.01) and decreased ASR levels (P<0.01) in BN rats in a dose-dependent fashion. In contrast, carbetocin had no effect on PPI levels or ASR. The facilitation of BN PPI by oxytocin is similar to what we have previously observed with clozapine and thus further supports oxytocin having antipsychotic properties. In contrast to oxytocin, our data do not support the use of carbetocin as an antipsychotic drug. (C) 2011 Elsevier B.V. and ECNP. All rights reserved. C1 [Feifel, David; Shilling, Paul D.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Belcher, Annabelle M.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Feifel, D (reprint author), Univ Calif San Diego, Dept Psychiat, 200 W Arbor Dr, San Diego, CA 92103 USA. EM dfeifel@ucsd.edu FU NIHM [R01MH080910-01A2]; Abbott Labs; Astra Zeneca; Bristol Myers Squibb; Eli Lilly; Forest; Jansen; Merck; Otsuka; Pfizer; Sanofi; Shinogi; Shire; Sunovion FX Funding for this study was provided by NIHM Grant R01MH080910-01A2; the NIMH had no further rote in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.; In the past three years, Dr. Feifel has received funds in return for one or more of the following: conducting contracted research, conducting investigator-initiated research, advisory board participation, and speaking from the following pharmaceutical companies: Abbott Labs, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Forest, Jansen, Merck, Otsuka, Pfizer, Sanofi, Shinogi, Shire, and Sunovion. Dr. Feifel has no conflict of interest. Dr. Belcher and Dr. Shilling declare that, except for income received from their respective primary employers, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 27 TC 18 Z9 21 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAY PY 2012 VL 22 IS 5 BP 374 EP 378 DI 10.1016/j.euroneuro.2011.09.004 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 935WJ UT WOS:000303552600007 PM 21962914 ER PT J AU Plenz, D AF Plenz, D. TI Neuronal avalanches and coherence potentials SO EUROPEAN PHYSICAL JOURNAL-SPECIAL TOPICS LA English DT Article ID SELF-ORGANIZED CRITICALITY; FOREST-FIRE MODEL; CORTICAL ACTIVITY; SYNCHRONOUS SPIKING; NEURAL-NETWORKS; IN-VIVO; STIMULUS PROPERTIES; CELLULAR-AUTOMATA; CROSS-CORRELATION; CEREBRAL-CORTEX AB The mammalian cortex consists of a vast network of weakly interacting excitable cells called neurons. Neurons must synchronize their activities in order to trigger activity in neighboring neurons. Moreover, interactions must be carefully regulated to remain weak (but not too weak) such that cascades of active neuronal groups avoid explosive growth yet allow for activity propagation over long-distances. Such a balance is robustly realized for neuronal avalanches, which are defined as cortical activity cascades that follow precise power laws. In experiments, scale-invariant neuronal avalanche dynamics have been observed during spontaneous cortical activity in isolated preparations in vitro as well as in the ongoing cortical activity of awake animals and in humans. Theory, models, and experiments suggest that neuronal avalanches are the signature of brain function near criticality at which the cortex optimally responds to inputs and maximizes its information capacity. Importantly, avalanche dynamics allow for the emergence of a subset of avalanches, the coherence potentials. They emerge when the synchronization of a local neuronal group exceeds a local threshold, at which the system spawns replicas of the local group activity at distant network sites. The functional importance of coherence potentials will be discussed in the context of propagating structures, such as gliders in balanced cellular automata. Gliders constitute local population dynamics that replicate in space after a finite number of generations and are thought to provide cellular automata with universal computation. Avalanches and coherence potentials are proposed to constitute a modern framework of cortical synchronization dynamics that underlies brain function. C1 NIMH, Sect Crit Brain Dynam, NIH, Rockville, MD 20852 USA. RP Plenz, D (reprint author), NIMH, Sect Crit Brain Dynam, NIH, Rockville, MD 20852 USA. EM plenzd@mail.nih.gov FU National Institute of Mental Health, NIH FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, NIH. I thank Dr. Thiagarajan for the branching parameter analysis in vivo and members of my group for helpful discussions and critical reading of earlier versions of the manuscript. NR 147 TC 29 Z9 29 U1 2 U2 15 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1951-6355 EI 1951-6401 J9 EUR PHYS J-SPEC TOP JI Eur. Phys. J.-Spec. Top. PD MAY PY 2012 VL 205 IS 1 BP 259 EP 301 DI 10.1140/epjst/e2012-01575-5 PG 43 WC Physics, Multidisciplinary SC Physics GA 933CU UT WOS:000303337700017 ER PT J AU Lowell, SY Reynolds, RC Chen, G Horwitz, B Ludlow, CL AF Lowell, Soren Y. Reynolds, Richard C. Chen, Gang Horwitz, Barry Ludlow, Christy L. TI Functional connectivity and laterality of the motor and sensory components in the volitional swallowing network SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Swallowing; Neuroimaging; Functional connectivity; Correlations; fMRI ID CEREBRAL CORTICAL REPRESENTATION; HUMAN PARIETAL OPERCULUM; OROPHARYNGEAL DYSPHAGIA; CORTEX; STROKE; BRAIN; STIMULATION; ACTIVATION; ADULTS; HUMANS AB Functional neuroimaging has shown that multiple brain regions are active during volitional swallowing. Little is known, however, about which regions integrate motor execution and sensory feedback in the swallowing system. Although unilateral brain lesions in either hemisphere can produce swallowing deficits, some functional neuroimaging studies indicate that the left hemisphere has greater activation in certain sensory and motor-related swallowing regions. In this study, correlation coefficients were computed for five seed regions during volitional saliva swallowing to determine the functional relationships of these regions with the rest of the brain: the anterior and posterior insula, inferior frontal gyrus (BA44), primary sensory cortex (S1), and primary motor cortex (M1). A laterality index (LI) was derived that accounts for relative differences in total, positive connected voxels for the left/right hemisphere seeds. Clusters of significantly connected voxels were greater from the anterior and posterior insula than from the other three seed regions. Interactions of the insula with other brain regions were greater on the left than on the right during volitional swallowing. Group means showed laterality in the anterior insula (LI = 0.25) and the posterior insula (LI = 0.33). BA44 showed a lesser degree of difference in left versus right hemisphere interactions (LI = 0.12) while S1 did not show lateralization (LI = 0.02) and M1 showed some predominance of interactions in the right hemisphere (LI = -0.19). The greater connectivity from the left hemisphere insula to brain regions within and across hemispheres suggests that the insula is a primary integrative region for volitional swallowing in humans. C1 [Lowell, Soren Y.] Syracuse Univ, Dept Commun Sci & Disorders, Syracuse, NY 13210 USA. [Lowell, Soren Y.; Ludlow, Christy L.] Natl Inst Neurol Disorders & Stroke, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. [Reynolds, Richard C.; Chen, Gang] NIMH, NIH, Bethesda, MD 20892 USA. [Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Lowell, SY (reprint author), Syracuse Univ, Dept Commun Sci & Disorders, 805 S Crouse Ave, Syracuse, NY 13210 USA. EM slowell@syr.edu OI Ludlow, Christy/0000-0002-2015-6171 FU Divisions of Intramural Research of the National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders FX We thank Adam Gerson for his assistance on initial methods for this study. This research was supported by the Divisions of Intramural Research of the National Institute of Neurological Disorders and Stroke and of the National Institute on Deafness and Other Communication Disorders. NR 64 TC 20 Z9 25 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD MAY PY 2012 VL 219 IS 1 BP 85 EP 96 DI 10.1007/s00221-012-3069-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 934VP UT WOS:000303475100008 PM 22441258 ER PT J AU Yan, XX Cai, Y Zhang, XM Luo, XG Cai, HB Rose, GM Patrylo, PR AF Yan, Xiao-Xin Cai, Yan Zhang, Xue-Mei Luo, Xue-Gang Cai, Huaibin Rose, Gregory M. Patrylo, Peter R. TI BACE1 elevation is associated with aberrant limbic axonal sprouting in epileptic CD1 mice SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Aberrant neuroplasticity; Temporal lobe epilepsy; Mossy fiber sprouting; Dystrophic neurites; Beta-secretase; Alzheimer's disease ID AMYLOID PRECURSOR PROTEIN; TEMPORAL-LOBE EPILEPSY; GATED SODIUM-CHANNELS; ALZHEIMERS-DISEASE PATHOGENESIS; TRAUMATIC BRAIN-INJURY; PILOCARPINE MODEL; BETA-SECRETASE; SYNAPTIC PLASTICITY; MOSSY FIBER; NEURONAL-ACTIVITY AB The brain is capable of remarkable synaptic reorganization following stress and injury, often using the same molecular machinery that governs neurodevelopment. This form of plasticity is crucial for restoring and maintaining network function. However, neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis, as is seen in temporal lobe epilepsy and Alzheimer's disease. beta-Secretase-1 (BACE1) is a protease known for cleaving beta-amyloid precursor protein into beta-amyloid (A beta), a major constituent in amyloid plaques. Emerging evidence suggests that BACE1 is also involved with synaptic plasticity and nerve regeneration. Here we examined whether BACE1 immunoreactivity (IR) was altered in pilocarpine-induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis. BACE1-IR increased in the CA3 mossy fiber field and dentate inner molecular layer in pilocarpine-induced epileptic mice, relative to controls (saline-treated mice and mice 24-48 h after pilocarpine-status), and paralleled aberrant expression of neuropeptide Y. Regionally increased BACE1-IR also occurred in neuropil in hippocampal area CA1 and in subregions of the amygdala and temporal cortex in epileptic mice, colocalizing with increased IR for growth associated protein 43 (GAP43) and polysialylated-neural cell adhesion molecule (PSA-NCAM), but reduced IR for microtubule-associated protein 2 (MAP2). These findings suggest that BACE1 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy, warranting further investigation into the role of BACE1 in physiological vs. pathological neuronal plasticity. Published by Elsevier Inc. C1 [Yan, Xiao-Xin; Cai, Yan; Luo, Xue-Gang] Cent S Univ, Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. [Cai, Yan; Rose, Gregory M.; Patrylo, Peter R.] So Illinois Univ, Dept Physiol, Carbondale, IL 62901 USA. [Yan, Xiao-Xin; Rose, Gregory M.; Patrylo, Peter R.] So Illinois Univ, Ctr Integrated Res Cognit & Neural Sci, Carbondale, IL 62901 USA. [Zhang, Xue-Mei; Rose, Gregory M.; Patrylo, Peter R.] So Illinois Univ, Dept Anat, Carbondale, IL 62901 USA. [Zhang, Xue-Mei] Harbin Med Univ, Affiliated Hosp 2, Dept Neurol, Harbin 150086, Peoples R China. [Cai, Huaibin] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Yan, XX (reprint author), Cent S Univ, Xiangya Sch Med, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn; ppatrylo@siumed.edu RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU National Institute of Health [1R21NS056371]; Illinois Department of Public Health; Southern Illinois University Center for Alzheimer's disease and related disorders; National Institute on Aging; Central South University FX This study was supported by the National Institute of Health (1R21NS056371 to P.R.P., X.-X.Y.), the Illinois Department of Public Health (X.-X.Y.), the Southern Illinois University Center for Alzheimer's disease and related disorders (P.R.P., G.M.R, X.-X.Y.), the intramural program of the National Institute on Aging (H.C) and the Central South University (X.-X.Y.). NR 95 TC 11 Z9 12 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2012 VL 235 IS 1 BP 228 EP 237 DI 10.1016/j.expneurol.2012.01.003 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 934FZ UT WOS:000303430400024 PM 22265658 ER PT J AU Chen, CM Hu, ZG Liu, SB Tseng, H AF Chen, Chaomei Hu, Zhigang Liu, Shengbo Tseng, Hung TI Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE CiteSpace; co-citation analysis; induced pluripotent stem cells; regenerative medicine; scientometrics ID PLURIPOTENT STEM-CELLS; REPROGRAMMING FACTORS; SCIENTIFIC LITERATURE; HUMAN FIBROBLASTS; DEFINED FACTORS; RESEARCH FRONTS; GENERATION; MOUSE; STATE; PATIENT AB Introduction: Regenerative medicine involves research in a number of fields and disciplines such as stem cell research, tissue engineering and biological therapy in general. As research in these areas advances rapidly, it is critical to keep abreast of emerging trends and critical turns of the development of the collective knowledge. Areas covered: A progressively synthesized network is derived from 35,963 original research and review articles that cite 3875 articles obtained from an initial topic search on regenerative medicine between 2000 and 2011. CiteSpace is used to facilitate the analysis of the intellectual structure and emerging trends. Expert opinion: A major ongoing research trend is concerned with finding alternative reprogramming techniques as well as refining existing ones for induced pluripotent stem cells (iPSCs). A more recent emerging trend focuses on the structural and functional equivalence between iPSCs and human embryonic stem cells and potential clinical and therapeutic implications on regenerative medicine in a long run. The two trends overlap in terms of what they cite, but they are distinct and have different implications on future research. Visual analytics of the literature provides a valuable, timely, repeatable and flexible approach in addition to traditional systematic reviews so as to track the development of new emerging trends and identify critical evidence. C1 [Chen, Chaomei] Drexel Univ, Coll Informat Sci & Technol, Philadelphia, PA 19104 USA. [Hu, Zhigang; Liu, Shengbo] Dalian Univ Technol, WISELAB, Dalian, Peoples R China. [Tseng, Hung] NIAMSD, NIH, Div Skin & Rheumat Dis, Bethesda, MD 20892 USA. RP Chen, CM (reprint author), Drexel Univ, Coll Informat Sci & Technol, 3141 Chestnut St, Philadelphia, PA 19104 USA. EM chaomei.chen@drexel.edu RI Chen, Chaomei/A-1252-2007 OI Chen, Chaomei/0000-0001-8584-1041 NR 62 TC 45 Z9 56 U1 43 U2 307 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2012 VL 12 IS 5 BP 593 EP 608 DI 10.1517/14712598.2012.674507 PG 16 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 936ZA UT WOS:000303627600009 PM 22443895 ER PT J AU Hill, MJ Levens, ED Levy, G Ryan, ME Csokmay, JM DeCherney, AH Whitcomb, BW AF Hill, Micah J. Levens, Eric D. Levy, Gary Ryan, Mary E. Csokmay, John M. DeCherney, Alan H. Whitcomb, Brian W. TI The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis SO FERTILITY AND STERILITY LA English DT Review DE Recombinant luteinizing hormone; recombinant follicle stimulating hormone; in vitro fertilization; assisted reproductive technologies; advanced reproductive age ID IN-VITRO FERTILIZATION; FOLLICLE-STIMULATING-HORMONE; PREMATURE PROGESTERONE ELEVATION; HUMAN MENOPAUSAL GONADOTROPINS; CONTROLLED OVARIAN STIMULATION; HIGHLY PURIFIED HMG; LH SUPPLEMENTATION; CONTROLLED-TRIAL; PREGNANCY RATES; ANTAGONIST CYCLES AB Objective: To evaluate the effect of recombinant LH in assisted reproduction technology (ART) cycles in patients of advanced reproductive age. Design: A systematic review and meta-analysis. Setting: Published randomized controlled clinical trials comparing recombinant LH plus recombinant FSH versus recombinant FSH only in patients of advanced reproductive age. Patient(s): Patients 35 years and older undergoing assisted reproduction. Intervention(s): Recombinant LH plus recombinant FSH controlled ovarian hyperstimulation (COH) versus recombinant FSH stimulation only in assisted reproduction cycles. Main Outcome Measure(s): Implantation and clinical pregnancy. Result(s): Seven trials were identified that met inclusion criteria and comprised 902 assisted reproduction technology cycles. No differences in serum E-2 on the day of hCG administration were reported in any trials. Two trials reported lower oocyte yield and one trial reported lower metaphase II oocyte yield in the recombinant LH-supplemented group. One trial reported higher fertilization rates in the recombinant LH-supplemented group. In a fixed effect model, implantation was higher in the recombinant LH-supplemented group (odds ratio 1.36, 95% confidence interval 1.05-1.78). Similarly, clinical pregnancy was increased in the recombinant LH-supplemented group (odds ratio 1.37, 95% confidence interval 1.03-1.83). Conclusion(s): The addition of recombinant LH to ART cycles may improve implantation and clinical pregnancy in patients of advanced reproductive age. (Fertil Steril (R) 2012;97:1108-14. (C) 2012 by American Society for Reproductive Medicine.) C1 [Hill, Micah J.; Levens, Eric D.; Levy, Gary; Csokmay, John M.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Ryan, Mary E.] Natl Inst Hlth Lib, Bethesda, MD USA. [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. RP Levens, ED (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr,Bldg 10-CRC,Room 1E-3140, Bethesda, MD 20892 USA. EM Eric.Levens@Integramed.com FU National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 44 TC 33 Z9 39 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD MAY PY 2012 VL 97 IS 5 BP 1108 EP + DI 10.1016/j.fertnstert.2012.01.130 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 934RA UT WOS:000303461800029 PM 22365075 ER PT J AU Chen, LS Saccone, NL Culverhouse, RC Bracci, PM Chen, CH Dueker, N Han, Y Huang, HY Jin, GF Kohno, T Ma, JZ Przybeck, TR Sanders, AR Smith, JA Sung, YJ Wenzlaff, AS Wu, C Yoon, D Chen, YT Cheng, YC Cho, YS David, SP Duan, JB Eaton, CB Furberg, H Goate, AM Gu, DF Hansen, HM Hartz, S Hu, ZB Kim, YJ Kittner, SJ Levinson, DF Mosley, TH Payne, TJ Rao, DC Rice, JP Rice, TK Schwantes-An, TH Shete, SS Shi, JX Spitz, MR Sun, YV Tsai, FJ Wang, JC Wrensch, MR Xian, H Gejman, PV He, J Hunt, SC Kardia, SL Li, MD Lin, DX Mitchell, BD Park, T Schwartz, AG Shen, HB Wiencke, JK Wu, JY Yokota, J Amos, CI Bierut, LJ AF Chen, Li-Shiun Saccone, Nancy L. Culverhouse, Robert C. Bracci, Paige M. Chen, Chien-Hsiun Dueker, Nicole Han, Younghun Huang, Hongyan Jin, Guangfu Kohno, Takashi Ma, Jennie Z. Przybeck, Thomas R. Sanders, Alan R. Smith, Jennifer A. Sung, Yun Ju Wenzlaff, Angie S. Wu, Chen Yoon, Dankyu Chen, Ying-Ting Cheng, Yu-Ching Cho, Yoon Shin David, Sean P. Duan, Jubao Eaton, Charles B. Furberg, Helena Goate, Alison M. Gu, Dongfeng Hansen, Helen M. Hartz, Sarah Hu, Zhibin Kim, Young Jin Kittner, Steven J. Levinson, Douglas F. Mosley, Thomas H. Payne, Thomas J. Rao, D. C. Rice, John P. Rice, Treva K. Schwantes-An, Tae-Hwi Shete, Sanjay S. Shi, Jianxin Spitz, Margaret R. Sun, Yan V. Tsai, Fuu-Jen Wang, Jen C. Wrensch, Margaret R. Xian, Hong Gejman, Pablo V. He, Jiang Hunt, Steven C. Kardia, Sharon L. Li, Ming D. Lin, Dongxin Mitchell, Braxton D. Park, Taesung Schwartz, Ann G. Shen, Hongbing Wiencke, John K. Wu, Jer-Yuarn Yokota, Jun Amos, Christopher I. Bierut, Laura J. TI Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry-A Meta-Analysis of Chromosome 15q25 SO GENETIC EPIDEMIOLOGY LA English DT Article DE smoking; genetics; meta-analysis; cross-population ID LUNG-CANCER RISK; NICOTINE DEPENDENCE; CAUSAL VARIANTS; HEAVY SMOKING; ASSOCIATION; POLYMORPHISMS; DISEASE; IDENTIFICATION; BEHAVIOR; CLUSTER AB Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.251.42, P = 1.1 x 10-17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments. Genet. Epidemiol. 36:340351, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Chen, Li-Shiun; Przybeck, Thomas R.; Goate, Alison M.; Hartz, Sarah; Rice, John P.; Wang, Jen C.; Bierut, Laura J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Saccone, Nancy L.; Schwantes-An, Tae-Hwi] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Culverhouse, Robert C.; Xian, Hong] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Bracci, Paige M.] UCSF, Dept Epidemiol & Biostat, San Francisco, CA USA. [Chen, Chien-Hsiun; Chen, Ying-Ting; Wu, Jer-Yuarn] Acad Sinica, Inst Biomed Sci, Natl Genotyping Ctr, Taipei, Taiwan. [Chen, Chien-Hsiun; Wu, Jer-Yuarn] China Med Univ, Grad Inst Chinese Med Sci, Taichung, Taiwan. [Dueker, Nicole] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Han, Younghun; Shete, Sanjay S.; Spitz, Margaret R.; Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Huang, Hongyan; Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jin, Guangfu; Hu, Zhibin; Shen, Hongbing] Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Kohno, Takashi] Natl Canc Ctr, Div Genome Biol, Tokyo, Japan. [Ma, Jennie Z.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Sanders, Alan R.; Duan, Jubao; Gejman, Pablo V.] Univ Chicago, N Shore Univ Hlth Syst Res Inst, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA. [Smith, Jennifer A.; Mosley, Thomas H.; Sun, Yan V.; Kardia, Sharon L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Wenzlaff, Angie S.; Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, Dept Etiol, Beijing 100730, Peoples R China. [Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, Carcinogenesis Canc Inst, Beijing 100730, Peoples R China. [Yoon, Dankyu; Kim, Young Jin] Seoul Natl Univ, Coll Nat Sci, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Yoon, Dankyu] Natl Inst Hlth, Ctr Immunol & Pathol, Seoul, South Korea. [Cheng, Yu-Ching] Univ Maryland, Med Ctr, Dept Med, Baltimore, MD 21201 USA. [Cho, Yoon Shin; Mitchell, Braxton D.] Natl Inst Hlth, Ctr Genome Sci, Seoul, South Korea. [Cho, Yoon Shin] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea. [David, Sean P.; Kim, Young Jin] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [David, Sean P.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [David, Sean P.; Eaton, Charles B.] Brown Univ, Dept Family Med, Providence, RI 02912 USA. [Furberg, Helena] Mem Sloan Kettering Canc Ctr, Dept Epidemiol, New York, NY 10021 USA. [Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Hansen, Helen M.; Wrensch, Margaret R.; Wiencke, John K.] Helen Diller Family Canc Ctr, Neurol Surg Div Epidemiol, San Francisco, CA USA. [Kittner, Steven J.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Payne, Thomas J.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Tsai, Fuu-Jen] China Med Univ, Sch Postbaccalaureate Chinese Med, Taipei, Taiwan. [He, Jiang] Tulane Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Hunt, Steven C.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Li, Ming D.] Univ Virginia, Dept Psychiat & Neurobehav Sci, Charlottesville, VA USA. [Park, Taesung] Seoul Natl Univ, Coll Nat Sci, Dept Stat, Seoul 151742, South Korea. [Yokota, Jun] Natl Canc Ctr, Div Multistep Carcinogenesis, Tokyo, Japan. RP Chen, LS (reprint author), Washington Univ, Sch Med, Dept Psychiat, Box 8134,660 S Euclid Ave, St Louis, MO 63110 USA. EM chenli@psychiatry.wustl.edu RI Tsai, Fuu-Jen/J-4140-2015; OI David, Sean/0000-0002-4922-2603; Hartz, Sarah/0000-0002-5429-3799; Mitchell, Braxton/0000-0003-4920-4744; Smith, Jennifer/0000-0002-3575-5468 FU National Cancer Institute (NCI) [P01 CA089392]; National Human Genome Research Institute (NHGRI) [U01 HG04422-01]; National Institute on Drug Abuse (NIDA) [K02 DA021237]; NIDA [HHSN271200477471C, HHSN271200477451C]; National Institutes of Health (NIH) [HHSN268200782096]; NIH [MH61675, MH60879, MH81800, MH46276, MH46289, MH46318, MH79469, MH79470, HHSN268200625226C]; Cancer Prevention Research Institute of Texas [RP10043]; National Institutes of Health Genes, Environment and Health Initiative [U01 HG004436]; GENEVA consortium under GEI; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; Division of Adult and Community Health, Centers for Disease Control; National Institute of Neurological Disorders and Stroke (NINDS); NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]; Genetic Association Information Network (GAIN); Paul Michael Donovan Charitable Foundation; National Center for Research Resources [U54 RR020278]; National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health [HL54457, HL68737, HL087660]; NHLBI; National Human Genome Research Institute [U01HG004402]; State Key Basic Research Program [2002CB512902]; Korea National Institute of Health (Korea Center for Disease Control, Ministry for Health, Welfare and Family Affairs), Republic of Korea; Consortium for Large Scale Genome Wide Association Study; National Research Foundation [KRF-2008-313-C00086]; Ministry of Education, Japan; Ministry of Health, Labor and Welfare; Academia Sinica Genomic Medicine Multicenter Study; National Science Council, Taiwan (National Clinical Core) [NSC97-3112-B-001-014]; National Genotyping Center [NSC97-3112-B-001-015]; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland [U01HL072507]; National Institute of Environmental Health Sciences [R01 ES06717]; National Cancer Institute [R01 CA 52689]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; [KL2RR024994]; [K08DA030398]; [R01DA026911]; [R03DA023166]; [R21DA033827]; [U10]; [UL1RR025005]; [DA 017441]; [02733] FX Collaborative Genetic Study of Nicotine Dependence (COGEND): We thank the subjects who participated in this study. We wish to thank Hilary Davidson, Sherri Fisher, Tracey Richmond, and Heidi Kromrei for administrative support; and Louis Fox for data analysis. The Collaborative Genetic Study of Nicotine Dependence (COGEND) study investigators are Laura Bierut (PI), Michael Brent, Naomi Breslau, Robert Culverhouse, Alison Goate, Richard Grucza, Dorothy Hatsukami, Anthony Hinrichs, Eric Johnson, Sharon Murphy, John Rice, Nancy Saccone, Scott Saccone, Joe Henry Steinbach, Jerry Stitzel, and Jen-Chyong Wang. MD Anderson: We are grateful for the invaluable contributions of clinical information and tissue samples by the participants in this study, as well as for the dedicated work of the research staff at different clinical sites. Also, we wish to thank Dr. Qing Xu for performing SNP-typing on our samples. Mid-south Tobacco Family Study (MSTF): We are grateful for the invaluable contributions of clinical information and tissue samples by the participants in this study, as well as for the dedicated work of the research staff at different clinical sites. Molecular Genetics of Schizophrenia: We thank the study participants and the research staff at the study sites. Genetic Epidemiology Network of America (GENOA): Mayo Clinic (Rochester Field Center and Genotyping Center): Stephen T. Turner, Mariza de Andrade, Julie Cunningham. University of Texas Health Sciences Center (DNA lab): Eric Boerwinkle, Megan L. Grove-Gaona. University of Michigan (Analysis Center): Patricia Peyser, Lawrence Bielak, Wei Zhao. Hypertension Genetic Epidemiology Network (HyperGEN): University of Utah (Network Coordinating Center, Field Center, and Molecular Genetics Lab): Steven C. Hunt, Ph.D. (Network Director and Field Center P.I.); Mark F. Leppert, Ph.D. (Molecular Genetics P.I.); Jean-Marc Lalouel, M.D., D.Sc; Robert B. Weiss, Ph.D.; Roger R. Williams, M.D. (late); Janet Hood. University of Alabama at Birmingham (Field Center): Cora E. Lewis, M.D., M.S.P.H. (P.I.); Albert Oberman, M.D., M.P.H.; Donna Arnett, Ph.D.; Phillip Johnson; Christie Oden. Boston University (Field Center): Richard H. Myers, Ph.D. (P.I.); R. Curtis Ellison, M.D.; Yuqing Zhang, M.D.; Jemma B. Wilk, D.Sc.; Luc Djouss, M.D., D.Sc.; Jason M. Laramie; Greta Lee Splansky, M.S. University of Minnesota (Field Center and Biochemistry Lab): James S. Pankow, Ph.D. (Field Center P.I.); Michael B. Miller, Ph.D.; Michael Li, Ph.D.; John H. Eckfeldt, M.D., Ph.D.; Anthony a. Killeen, M.D., Ph.D.; Catherine Leiendecker-Foster, M.S.; Jean Bucksa; Greg Rynders. University of North Carolina (Field Center): Kari E. North, Ph.D. (P.I); Barry I. Freedman, M.D.; Gerardo Heiss, M.D. Washington University (Data Coordinating Center): D.C. Rao, Ph.D. (P.I.); Charles Gu, Ph.D.; Treva Rice, Ph.D; Aldi T. Kraja, D.Sc., Ph.D.; Gang Shi, Ph.D.; Yun Ju Sung, Ph.D.; Karen L. Schwander, M.S .; Matthew Brown; Michael A. Province, Ph.D.; Ingrid Borecki, Ph.D. Weil Cornell Medical College (Echo Reading Center): R.B. Devereux, M.D.; Giovanni de Simone, M.D., Jonathan N. Bella, M.D. National Heart, Lung, & Blood Institute: Cashell Jaquish, Ph.D.; Dina Paltoo, Ph.D. ARIC: The authors thank the staff and participants of the ARIC study for their important contributions. Japan: We thank Dr. Kouya Shiraishi for his help on genotype data processing. GenSalt: The GenSalt Study Steering Committee: Dongfeng Gu, JiangHe (Chair), James E. Hixson, Cashell E. Jaquish, Depei Liu, DC Rao, Paul K. Whelton, and Zhijian Yao.; GenSalt Collaborative Research Group: Tulane University Health Sciences Center, NewOrleans, USA: Jiang He (I), LydiaA. Bazzano, Chung- Shiuan Chen, Jing Chen, Lee Hamm, Paul Muntner, Kristi Reynolds, Jaqueline R. Reuben, Paul K. Whelton, and Wenjie Yang. Washington University School of Medicine, St. Louis, USA: DC Rao (PI), Matthew Brown, Charles Gu, Hongyan Huang, Treva Rice, Karen Schwander, Gang Shi, and Yun Ju Sung. Chinese Academy of Medical Sciences, Beijing, China: Dongfeng Gu (PI), Jie Cao, Jichun Chen, Xiufang Duan, Jianfeng Huang, Jinghan Huang, Jianxin Li, Depei Liu, Donghua Liu, Enchun Pan, YangWei, and Xiqui Wu. Shandong Academy ofMedical Sciences, Shandong, China: Fanghong Lu (PI), Shikuan Jin, Qingjie Meng, Fan Wu, and Yingxin Zhao; Shandong Center for Diseases Control and Prevention, Shandong, China: Jixiang Ma (PI), Weika Li, and Jiyu Zhang; Zhengzhou University: Dongsheng Hu (PI), Yaxin Ding, HongweiWen, Meixi Zhang, and Weidong Zhang; Xinle Traditional ChineseMedicine Hospital, Hebei, China: Xu Ji (PI), Rongyan Li, Haijun Zu; Nanjing University of Medical Sciences, Jiangsu, China: Cailiang Yao (PI), Yongchao Li, Chong Shen, and Jiayi Zhou; Xi'an Jiaotong University, Shanxi, China: Jianjun Mu (PI), Enrang Chen, Qinzhou Huang, and Man Wang. Chinese National Human Genome Center at Beijing: Zhi- Jian Yao (PI), Shufeng Chen, Dongfeng Gu, Hongfan Li, Laiyuan Wang, Penghua Zhang, Qi Zhao. University of Texas Health Sciences Center at Houston: James E. Hixson (PI) and Lawrence C. Shimmin. National Heart, Lung, and Blood Institute: Cashell E. Jaquish. Women's Health Initiative: This manuscript was prepared in collaboration with investigators of the WHI and has been reviewed and approved (MS1453) by the Women's Health Initiative (WHI) Publications & Presentations Committee. The authors thank Charles Kooperberg and the WHI investigators and staff and study participants for making the program possible. WHI investigators are listed at http://www.whiscience.org/ publications/WHI_investigators_ shortlist. pdf. Collaborative Genetic Study of Nicotine Dependence (COGEND): The COGEND contribution was supported by the National Cancer Institute (NCI; P01 CA089392), The National Human Genome Research Institute (NHGRI; U01 HG04422-01), and the National Institute on Drug Abuse (NIDA; K02 DA021237). COGEND genotyping was in part performed under NIDA Contract HHSN271200477471C; phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (PIs J Tischfield and J Rice); genotyping services were also provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096. Dr. LiShiun Chen was supported by KL2RR024994 and K08DA030398. Support was also provided by R01DA026911, R03DA023166, and R21DA033827. MD Anderson: Research was supported by NIH grants U19CA148127, R01CA121197S2, R01CA141716, R01CA127219, CA121197, R01CA133996, P30CA16672, P50CA70907, R01CA55769 and Cancer Prevention Research Institute of Texas grant RP10043. Midsouth Tobacco Family Study (MSTF): This project is supported in part by NIH Grant R01 DA012844 (PI: Ming Li). Wayne State University and the Karmanos Cancer Institute: Family Health Study; Women's Epidemiology of Lung Disease; EXHALE (Exploring Health Ancestry and Lung Epidemiology): This research was supported through NIH grants R01CA060691 and R01CA87895, and NIH contract PC35145.; University of Maryland: GEOS: The GEOS Study was supported by the National Institutes of Health Genes, Environment and Health Initiative (GEI) Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University (contract number HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce SWeir). Study recruitment and collection of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). Molecular Genetics of Schizophrenia: This study was supported by NIH R01 grants (MH67257 to Nancy G. Buccola, MH59588 to Bryan J. Mowry, MH59571 to Pablo V. Gejman, MH59565 to Robert Freedman, MH59587 to Farooq Amin, MH60870 to William F. Byerley, MH59566 to Donald W. Black, MH59586 to Jeremy M. Silverman, MH61675 to Douglas F. Levinson, MH60879 to C. Robert Cloninger, and MH81800 to Pablo V. Gejman), NIH U01 grants (MH46276 to C. Robert Cloninger, MH46289 to Charles Kaufmann, MH46318 to Ming T. Tsuang, MH79469 to Pablo V. Gejman, and MH79470 to Douglas F. Levinson), the Genetic Association Information Network (GAIN), and by The Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT (Stacy Gabriel and Daniel B. Mirel), which is supported by grant U54 RR020278 from the National Center for Research Resources. Genotyping of half of the EA sample and almost all the AA sample was carried out with support from GAIN. The GAIN quality control team (Goncalo R. Abecasis and Justin Paschall) made important contributions to the project. We thank Shaun Purcell for assistance with PLINK. Genetic Epidemiology Network of America (GENOA): The Genetic Epidemiology Network of Arteriopathy phenotyping and genome-wide genotyping is supported by the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (HL54457, HL68737, and HL087660). Hypertension Genetic Epidemiology Network (HyperGEN): The Hypertension Genetic Epidemiology Network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; Nanjing and Beijing: This work was supported by the Chinese National Natural Science Foundation grant 30230080 (Hongbing Shen) and the State Key Basic Research Program grants 2002CB512902 (Hongbing Shen). Dr. Dongxin Lin was supported by State Key Basic Research Program grant 2004CB518701. KARE (Korea Association Resource): The KARE data analyzed in this study were obtained from the Korean Genome Analysis Project (4845-301) which was funded by a grant from the Korea National Institute of Health (Korea Center for Disease Control, Ministry for Health, Welfare and Family Affairs), Republic of Korea. The work of TP was supported by the Consortium for Large Scale Genome Wide Association Study, the National Research Foundation (KRF-2008-313-C00086) and the Brain Korea 21 Project of the Ministry of Education, Japan: Grants-in-Aid from the Ministry of Health, Labor and Welfare for the 3rd-term Comprehensive 10-year Strategy for Cancer Control and for Cancer Research (19-9 and 19S-1). Taiwan: This study was supported by Academia Sinica Genomic Medicine Multicenter Study and National Research Program for Genomic Medicine, National Science Council, Taiwan (National Clinical Core, NSC97-3112-B-001-014 and National Genotyping Center, NSC97-3112-B-001-015). GenSalt: The Genetic Epidemiology Network of Salt Sensitivity is supported by a cooperative agreement project Grant (U01HL072507) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. University of California San Francisco: This work was supported by the National Institute of Environmental Health Sciences [R01 ES06717]; and the National Cancer Institute [R01 CA 52689 to MW]. Women's Health Initiative: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. SPD is supported by DA 017441 and 02733. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CONFLICT OF INTEREST DISCLOSURE: LB Bierut, AM Goate, JP Rice, and JC Wang are listed as inventors on Issued U.S. Patent. 8,080,371, "Markers for Addiction" covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Ming Li serves as a scientific advisor to ADial Pharmaceuticals. NR 33 TC 38 Z9 39 U1 0 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2012 VL 36 IS 4 BP 340 EP 351 DI 10.1002/gepi.21627 PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 932VZ UT WOS:000303319900006 PM 22539395 ER PT J AU Shi, JX Li, P AF Shi, Jianxin Li, Peng TI An Integrative Segmentation Method for Detecting Germline Copy Number Variations in SNP Arrays SO GENETIC EPIDEMIOLOGY LA English DT Article DE copy number variations; segmentation method; change point detection; B allele frequency ID HIDDEN-MARKOV MODEL; GENOTYPING DATA; CGH DATA; POPULATION; PLATFORMS; SEQUENCES; DELETIONS; WAVES; MAP AB Germline copy number variations (CNVs) are a major source of genetic variation in humans. In large-scale studies of complex diseases, CNVs are usually detected from data generated by single nucleotide polymorphism (SNP) genotyping arrays. In this paper, we develop an integrative segmentation method, SegCNV, for detecting CNVs integrating both log R ratio (LRR) and B allele frequency (BAF). Based on simulation studies, SegCNV had modestly better power to detect deletions and substantially better power to detect duplications compared with circular binary segmentation (CBS) that relies purely on LRRs; and it had better power to detect deletions and a comparable performance to detect duplications compared with PennCNV and QuantiSNP. In two Hapmap subjects with deep sequence data available as a gold standard, SegCNV detected more true short deletions than PennCNV and QuantiSNP. For 21 short duplications validated experimentally in the AGRE dataset, SegCNV, QuantiSNP, and PennCNV detected all of them while CBS detected only three. SegCNV is much faster than the HMM-based (where HMM is hidden Markov model) methods, taking only several seconds to analyze genome-wide data for one subject. Genet. Epidemiol. 36:373-383, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Shi, Jianxin; Li, Peng] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20854 USA. RP Shi, JX (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20854 USA. EM jianxin.shi@nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health; National Institute of Mental Health [1U24MH081810] FX The authors are supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M.L. (PI). 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). The authors declare no conflicts of interest. NR 25 TC 3 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2012 VL 36 IS 4 BP 373 EP 383 DI 10.1002/gepi.21631 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 932VZ UT WOS:000303319900010 PM 22539397 ER PT J AU Rasmussen-Torvik, LJ Guo, XQ Bowden, DW Bertoni, AG Sale, MM Yao, J Bluemke, DA Goodarzi, MO Chen, YI Vaidya, D Raffel, LJ Papanicolaou, GJ Meigs, JB Pankow, JS AF Rasmussen-Torvik, Laura J. Guo, Xiuqing Bowden, Donald W. Bertoni, Alain G. Sale, Michele M. Yao, Jie Bluemke, David A. Goodarzi, Mark O. Chen, Y. Ida Vaidya, Dhananjay Raffel, Leslie J. Papanicolaou, George J. Meigs, James B. Pankow, James S. TI Fasting Glucose GWAS Candidate Region Analysis Across Ethnic Groups in the Multiethnic Study of Atherosclerosis (MESA) SO GENETIC EPIDEMIOLOGY LA English DT Article DE GWAS; fasting glucose; SNP ID GENOME-WIDE ASSOCIATION; TYPE-2 DIABETES RISK; PLASMA-GLUCOSE; INSULIN-RESISTANCE; MTNR1B; POLYMORPHISM; VARIANT; GENE; INDIVIDUALS; POPULATION AB Genetic variants associated with fasting glucose in European ancestry populations are increasingly well understood. However, the nature of the associations between these single nucleotide polymorphisms (SNPs) and fasting glucose in other racial and ethnic groups is unclear. We sought to examine regions previously identified to be associated with fasting glucose in Caucasian genome-wide association studies (GWAS) across multiple ethnicities in the Multiethnic Study of Atherosclerosis (MESA). Nondiabetic MESA participants with fasting glucose measured at the baseline exam and with GWAS genotyping were included; 2,349 Caucasians, 664 individuals of Chinese descent, 1,366 African Americans, and 1,171 Hispanics. Genotype data were generated from the Affymetrix 6.0 array and imputation in IMPUTE. Fasting glucose was regressed on SNP dosage data in each ethnic group adjusting for age, gender, MESA study center, and ethnic-specific principal components. SNPs from the three gene regions with the strongest associations to fasting glucose in previous Caucasian GWAS (MTNR1B / GCK / G6PC2) were examined in depth. There was limited power to replicate associations in other ethnic groups due to smaller allele frequencies and limited sample size; SNP associations may also have differed across ethnic groups due to differing linkage disequilibrium patterns with causal variants. rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude and direction of association with fasting glucose across ethnic groups, although the associations were often not nominally significant. In conclusion, certain SNPs in MTNR1B and GCK demonstrate consistent effects across four racial and ethnic groups, narrowing the putative region for these causal variants. Genet. Epidemiol. 36:384-391, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Guo, Xiuqing; Yao, Jie; Goodarzi, Mark O.; Chen, Y. Ida; Raffel, Leslie J.] Med Genet Res Inst, Los Angeles, CA USA. [Bowden, Donald W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. [Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Ctr Clin, NIH, Bethesda, MD USA. [Vaidya, Dhananjay] Johns Hopkins Sch Med, Dept Gen Internal Med, Baltimore, MD USA. [Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Div Gen Med, Boston, MA USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Rasmussen-Torvik, LJ (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM ljrtorvik@northwestern.edu OI Bluemke, David/0000-0002-8323-8086; Vaidya, Dhananjay/0000-0002-7164-1601; Pankow, James/0000-0001-7076-483X FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95159, N01-HC-95169, R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259]; NIDDK [K24 DK080140] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute (NHLBI). The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Genotyping was funded by the following NHLBI grants: R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259. JBM is supported by NIDDK K24 DK080140. NR 29 TC 14 Z9 15 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2012 VL 36 IS 4 BP 384 EP 391 DI 10.1002/gepi.21632 PG 8 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 932VZ UT WOS:000303319900011 PM 22508271 ER PT J AU Murray, T Taub, MA Ruczinski, I Scott, AF Hetmanski, JB Schwender, H Patel, P Zhang, TX Munger, RG Wilcox, AJ Ye, XQ Wang, H Wu, T Wu-Chou, YH Shi, B Jee, SH Chong, S Yeow, V Murray, JC Marazita, ML Beaty, TH AF Murray, Tanda Taub, Margaret A. Ruczinski, Ingo Scott, Alan F. Hetmanski, Jacqueline B. Schwender, Holger Patel, Poorav Zhang, Tian Xiao Munger, Ronald G. Wilcox, Allen J. Ye, Xiaoqian Wang, Hong Wu, Tao Wu-Chou, Yah Huei Shi, Bing Jee, Sun Ha Chong, Samuel Yeow, Vincent Murray, Jeffrey C. Marazita, Mary L. Beaty, Terri H. TI Examining Markers in 8q24 to Explain Differences in Evidence for Association With Cleft Lip With/Without Cleft Palate Between Asians and Europeans SO GENETIC EPIDEMIOLOGY LA English DT Article DE cleft lip with; without cleft palate; 8q24; genome-wide association; imputation ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCUS; CHROMOSOME 8Q24; CANCER-RISK; POPULATION; VARIANTS AB In a recent genome-wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among nonsyndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, United States, and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving P < 10-6 in the allelic transmission disequilibrium test (TDT) showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians. Genet. Epidemiol. 36:392399, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Murray, Tanda; Hetmanski, Jacqueline B.; Patel, Poorav; Zhang, Tian Xiao; Beaty, Terri H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Taub, Margaret A.; Ruczinski, Ingo; Schwender, Holger] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Scott, Alan F.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD USA. [Schwender, Holger] TU Dortmund Univ, Fac Stat, Dortmund, Germany. [Munger, Ronald G.] Utah State Univ, Logan, UT 84322 USA. [Wilcox, Allen J.] NIEHS, NIH, Epidemiol Branch, Durham, NC USA. [Ye, Xiaoqian] Wuhan Univ, Sch Stomatol, Wuhan 430072, Peoples R China. [Ye, Xiaoqian] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Wang, Hong; Wu, Tao] Peking Univ, Hlth Sci Ctr, Beijing 100871, Peoples R China. [Wu-Chou, Yah Huei] Chang Gung Mem Hosp, Tao Yuan, Taiwan. [Shi, Bing] Sichuan Univ, W China Coll Stomatol, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. [Jee, Sun Ha] Yonsei Univ, Dept Epidemiol & Hlth Promot, Seoul 120749, South Korea. [Chong, Samuel] Natl Univ Singapore, Singapore 117548, Singapore. [Yeow, Vincent] KK Womens & Childrens Hosp, Singapore, Singapore. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Childrens Hosp, Iowa City, IA 52242 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA. RP Beaty, TH (reprint author), Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM tbeaty@jhsph.edu RI Chong, Samuel/D-8098-2015; OI Wilcox, Allen/0000-0002-3376-1311 FU National Human Genome Research Institute (NHGRI); US National Institutes of Health (NIH) [HHSN268200782096C]; NIDCR [U01-DE-018993]; NIH, National Institute of Environmental Health Sciences; [R01-DE-014581]; [R37-DE08559]; [R01-DE016148]; [P50-DE016215]; [R21-DE016930] FX We sincerely thank all of the families at each recruitment site for participating in this international study, and we gratefully acknowledge the invaluable assistance of clinical, field, and laboratory staff whose contributions made this work possible. Funding to support data collection, genotyping, and analysis came from several sources, some to individual investigators and some to the cleft consortium itself. The International Cleft Consortium was part of the Gene, Environment Association Studies (GENEVA) Consortium funded by the National Human Genome Research Institute (NHGRI) to enhance communication and collaboration among researchers conducting genome-wide studies of complex diseases. Our group benefited greatly from the work and efforts of the entire consortium, especially the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington) in data cleaning and preparation for submission to the Database for Genotypes and Phenotypes (dbGaP). We also acknowledge the leadership of T. Manolio of NHGRI and E. Harris of National Institute of Dental and Craniofacial Research (NIDCR). Genotyping services were provided by the Center for Inherited Disease Research (CIDR), funded through a federal contract from the US National Institutes of Health (NIH) to Johns Hopkins University (contract number HHSN268200782096C), and we wish to thank Drs. K. Doheny, E. W. Pugh, and H. Ling in particular. The GWAS was supported by the NIDCR through U01-DE-018993; "International Consortium to Identify Genes & Interactions Controlling Oral Clefts," TH Beaty, PI. Funding for individual investigators include: R01-DE-014581 (T.H.B.); R37-DE08559 (J.C.M., M.L.M.), R01-DE016148 (M.L.M.), P50-DE016215 (J.C.M., M.L.M.), R21-DE016930 (M.L.M.). Smile Train Foundation supported data collection in Chengdu (B.S.). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (A.J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR, nor the NIH. NR 22 TC 12 Z9 13 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2012 VL 36 IS 4 BP 392 EP 399 DI 10.1002/gepi.21633 PG 8 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 932VZ UT WOS:000303319900012 PM 22508319 ER PT J AU Sampson, JN Jacobs, K Wang, ZM Yeager, M Chanock, S Chatterjee, N AF Sampson, Joshua N. Jacobs, Kevin Wang, Zhaoming Yeager, Meredith Chanock, Stephen Chatterjee, Nilanjan TI A Two-Platform Design for Next Generation Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE GWAS; case-control study; power; study design; Omni2.5; imputation ID CANCER SCREENING TRIAL; GENOTYPE IMPUTATION; SUSCEPTIBILITY LOCI; MISSING GENOTYPES; METAANALYSIS; PROSTATE; RISK; PREVENTION; ACCURACY; POWER AB Genome-wide association studies (GWAS) have been successful in their search for common genetic variants associated with complex traits and diseases. With new advances in array technologies together with available genetic reference sets, the next generation of GWAS will extend the search for associations with uncommon SNPs (1% <= MAF <= 10%). Two possible approaches are genotyping all participants, a prohibitively expensive option for large GWAS, or using a combination of genotyping and imputation. Here, we consider a two platform method that genotypes all participants on a standard genotyping array, designed to identify common variants, and then supplements that data by genotyping only a small proportion of the participants on a platform that has higher coverage for uncommon SNPs. This subset of the study population is then included as part of the imputation reference set. To demonstrate the use of this two-platform design, we evaluate its potential efficiency using a newly available dataset containing 756 individuals genotyped on both the Illumina Human OmniExpress and Omni2.5 Quad. Although genotyping all individuals on the denser array would be ideal, we find that genotyping only 100 individuals on this array, in combination with imputation, leads to only a modest loss of power for detecting associations. However, the loss of power due to imputation can be more substantial if the relative risks for rare variants are significantly larger than those previously observed for common variants. Genet. Epidemiol. 36:400-408, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Sampson, Joshua N.; Chatterjee, Nilanjan] NCI, Biostat Branch, DCEG, Rockville, MD 20852 USA. [Jacobs, Kevin; Wang, Zhaoming; Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, DCEG, Gaithersburg, MD USA. [Chanock, Stephen] NCI, Lab Translat Genom, Gaithersburg, MD USA. RP Sampson, JN (reprint author), NCI, Biostat Branch, DCEG, 6120 Execut Blvd,8038 Rockville, Rockville, MD 20852 USA. EM joshua.sampson@nih.gov NR 40 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2012 VL 36 IS 4 BP 401 EP 409 DI 10.1002/gepi.21634 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 932VZ UT WOS:000303319900013 ER PT J AU Kong, HDH Oh, J Deming, C Conlan, S Grice, EA Beatson, MA Nomicos, E Polley, EC Komarow, HD Murray, PR Turner, ML Segre, JA AF Kong, Heidi H. Oh, Julia Deming, Clay Conlan, Sean Grice, Elizabeth A. Beatson, Melony A. Nomicos, Effie Polley, Eric C. Komarow, Hirsh D. Murray, Patrick R. Turner, Maria L. Segre, Julia A. CA NISC Comparative Sequence Program TI Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis SO GENOME RESEARCH LA English DT Article ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; PARTY DIAGNOSTIC-CRITERIA; ANTIMICROBIAL PEPTIDES; BINDING PROTEIN; SCORAD INDEX; ECZEMA; COLONIZATION; EPIDERMIDIS; BACTERIAL; INFECTIONS AB Atopic dermatitis (AD) has long been associated with Staphylococcus aureus skin colonization or infection and is typically managed with regimens that include antimicrobial therapies. However, the role of microbial communities in the pathogenesis of AD is incompletely characterized. To assess the relationship between skin microbiota and disease progression, 16S ribosomal RNA bacterial gene sequencing was performed on DNA obtained directly from serial skin sampling of children with AD. The composition of bacterial communities was analyzed during AD disease states to identify characteristics associated with AD flares and improvement post-treatment. We found that microbial community structures at sites of disease predilection were dramatically different in AD patients compared with controls. Microbial diversity during AD flares was dependent on the presence or absence of recent AD treatments, with even intermittent treatment linked to greater bacterial diversity than no recent treatment. Treatment-associated changes in skin bacterial diversity suggest that AD treatments diversify skin bacteria preceding improvements in disease activity. In AD, the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity. Representation of the skin commensal S. epidermidis also significantly increased during flares. Increases in Streptococcus, Propionibacterium, and Corynebacterium species were observed following therapy. These findings reveal linkages between microbial communities and inflammatory diseases such as AD, and demonstrate that as compared with culture-based studies, higher resolution examination of microbiota associated with human disease provides novel insights into global shifts of bacteria relevant to disease progression and treatment. C1 [Kong, Heidi H.; Beatson, Melony A.; Nomicos, Effie; Turner, Maria L.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Oh, Julia; Deming, Clay; Conlan, Sean; Grice, Elizabeth A.; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Polley, Eric C.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Komarow, Hirsh D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequence Program] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Murray, Patrick R.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kong, HDH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; jsegre@mail.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X; Grice, Elizabeth/0000-0003-3939-2200 FU NIH CC; NCI; NHGRI; National Institutes of Health [1UH2AR057504-01, 4UH3AR057504-02]; [1K99AR059222] FX We thank Mark C. Udey, Eric Green, and Evan Snitkin for helpful discussions; Pamela Thomas, Deborah Schoenfeld, Joie Davis, Roselyn Epps, Celeste Nelson, and Donna Gaskins for underlying contributions; and especially the patients and volunteers. This work was supported by NIH CC, NCI, and NHGRI Intramural Research Programs, and in part by 1K99AR059222 (H.H.K.). Sequencing and clinical research support was funded by grants from the National Institutes of Health Common Fund Human Microbiome Project (1UH2AR057504-01 and 4UH3AR057504-02). NR 55 TC 255 Z9 264 U1 7 U2 75 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2012 VL 22 IS 5 BP 850 EP 859 DI 10.1101/gr.131029.111 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 933NU UT WOS:000303369600005 PM 22310478 ER PT J AU Li, JF Akagi, K Hu, YJ Trivett, AL Hlynialuk, CJW Swing, DA Volfovsky, N Morgan, TC Golubeva, Y Stephens, RM Smith, DE Symer, DE AF Li, Jingfeng Akagi, Keiko Hu, Yongjun Trivett, Anna L. Hlynialuk, Christopher J. W. Swing, Deborah A. Volfovsky, Natalia Morgan, Tamara C. Golubeva, Yelena Stephens, Robert M. Smith, David E. Symer, David E. TI Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance SO GENOME RESEARCH LA English DT Article ID COPY NUMBER VARIATION; PEPT2 NULL MICE; TRANSPOSABLE ELEMENTS; GENE-EXPRESSION; CHOROID-PLEXUS; ALTERNATIVE POLYADENYLATION; PARTICLE GENES; HUMAN GENOME; HOST GENES; WILD-TYPE AB Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to similar to 5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 5'-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity. C1 [Li, Jingfeng; Akagi, Keiko; Hlynialuk, Christopher J. W.; Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. [Li, Jingfeng; Akagi, Keiko; Hlynialuk, Christopher J. W.; Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Hu, Yongjun; Smith, David E.] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. [Trivett, Anna L.] NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Swing, Deborah A.] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Volfovsky, Natalia; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, Informat Syst Program, Frederick, MD 21702 USA. [Morgan, Tamara C.; Golubeva, Yelena] NCI, Histotechnol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Columbus, OH 43210 USA. [Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Dept Biomed Informat, Columbus, OH 43210 USA. RP Symer, DE (reprint author), Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. EM david.symer@osumc.edu RI Symer, David/E-4173-2011 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; NIH [R01-GM035498]; National Cancer Institute [HHSN261200800001E]; Ohio State University Comprehensive Cancer Center FX We thank Drs. Albert de la Chapelle, Neal Copeland, and Maura Gillison for helpful comments; Robert Williams, Lu Lu, and Jesse F. Ingels (University of Tennessee) for help with the Gene Network and providing several BxD RI mouse strain genomic DNA samples; Holly Morris, Rob Koogle, and Sherry Rausch (National Cancer Institute) for superb maintenance of our mouse colony; Xiaolin Wu and Hongling Liao (SAIC Frederick) for assistance with exon microarray experiments; Clive Evans (Virginia Bioinformatics Institute) for 454 sequencing; and Richard Frederickson (SAIC Frederick) and Anthony Baker (OSU) for graphical illustration. This project was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (to J.L., K.A., A.L.T., D.A.S., T.C.M., D.E.Sy.); NIH research grant R01-GM035498 (to Y.H. and D.E.Sm.); contract no. HHSN261200800001E by the National Cancer Institute to SAIC, Inc. (to N.V., T.C.M., Y.G., and R.M.S.); and by The Ohio State University Comprehensive Cancer Center (to J.L., K.A., C.J.W.H., and D.E.Sy.). We thank the Ohio Supercomputer Center for providing computational resources (grant PAS0425-2 to K.A. and D.E.Sy.). 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. NCI-Frederick and OSU are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International and follow the U.S. Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals" (National Research Council, 1996, National Academy Press, Washington, DC). Mouse studies were performed following protocols approved by the Animal Care and Use Committee, NCI Frederick or by the Institutional Animal Care and Use Committee, OSU. NR 73 TC 26 Z9 26 U1 1 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2012 VL 22 IS 5 BP 870 EP 884 DI 10.1101/gr.130740.111 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 933NU UT WOS:000303369600007 PM 22367191 ER PT J AU Khil, PP Smagulova, F Brick, KM Camerini-Otero, RD Petukhova, GV AF Khil, Pavel P. Smagulova, Fatima Brick, Kevin M. Camerini-Otero, R. Daniel Petukhova, Galina V. TI Sensitive mapping of recombination hotspots using sequencing-based detection of ssDNA SO GENOME RESEARCH LA English DT Article ID MEIOTIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; HOT-SPOTS; STRAND EXCHANGE; DNA REVEALS; HUMAN-SPERM; MOUSE; YEAST; INITIATION; PROTEIN AB Meiotic DNA double-stranded breaks (DSBs) initiate genetic recombination in discrete areas of the genome called recombination hotspots. DSBs can be directly mapped using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Nevertheless, the genome-wide mapping of recombination hotspots in mammals is still a challenge due to the low frequency of recombination, high heterogeneity of the germ cell population, and the relatively low efficiency of ChIP. To overcome these limitations we have developed a novel method-single stranded DNA (ssDNA) sequencing (SSDS)-that specifically detects protein-bound single-stranded DNA at DSB ends. SSDS comprises a computational framework for the specific detection of ssDNA-derived reads in a sequencing library and a new library preparation procedure for the enrichment of fragments originating from ssDNA. The use of our technique reduces the nonspecific double-stranded DNA (dsDNA) background >10-fold. Our method can be extended to other systems where the identification of ssDNA or DSBs is desired. C1 [Khil, Pavel P.; Brick, Kevin M.; Camerini-Otero, R. Daniel] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Smagulova, Fatima; Petukhova, Galina V.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. RP Camerini-Otero, RD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov; gpetukhova@usuhs.mil RI Smagulova, Fatima/K-5459-2015; OI Brick, Kevin/0000-0002-9596-6400; Smagulova, Fatima/0000-0001-6883-1968; Khil, Pavel/0000-0002-4903-8777 FU NIDDK from the March of Dimes Foundation [5-FY07-667]; NIH from NIGMS [1R01GM084104-01A1]; USUHS [FS71HU, R071HU, CS71HU] FX We thank Peggy Hsieh and Michael Lichten for helpful discussion and Shaila Sharmeen for help with high-throughput sequencing. 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). This research was supported by the NIDDK Intramural Research Program; by Basil O'Connor Starter Scholar Research Award Grant No. 5-FY07-667 from the March of Dimes Foundation (G.V.P.); NIH grant 1R01GM084104-01A1 from NIGMS (G.V.P.); New Investigator Start-up Grants FS71HU, R071HU, and CS71HU from USUHS (G.V.P.). NR 30 TC 21 Z9 21 U1 1 U2 19 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2012 VL 22 IS 5 BP 957 EP 965 DI 10.1101/gr.130583.111 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 933NU UT WOS:000303369600014 PM 22367190 ER PT J AU Filipovych, R Resnick, SM Davatzikos, C AF Filipovych, Roman Resnick, Susan M. Davatzikos, Christos TI JointMMCC: Joint Maximum-Margin Classification and Clustering of Imaging Data SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Aging; clustering; magnetic resonance imaging (MRI); semi-supervised classification ID DIMENSIONAL PATTERN-CLASSIFICATION; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; BRAIN ATROPHY; OLDER-ADULTS; MCI PATIENTS; SCHIZOPHRENIA; AD; DECLINE AB A number of conditions are characterized by pathologies that form continuous or nearly-continuous spectra spanning from the absence of pathology to very pronounced pathological changes (e.g., normal aging, mild cognitive impairment, Alzheimer's). Moreover, diseases are often highly heterogeneous with a number of diagnostic subcategories or subconditions lying within the spectra (e.g., autism spectrum disorder, schizophrenia). Discovering coherent subpopulations of subjects within the spectrum of pathological changes may further our understanding of diseases, and potentially identify subconditions that require alternative or modified treatment options. In this paper, we propose an approach that aims at identifying coherent subpopulations with respect to the underlying MRI in the scenario where the condition is heterogeneous and pathological changes form a continuous spectrum. We describe a joint maximum-margin classification and clustering (JointMMCC) approach that jointly detects the pathologic population via semi-supervised classification, as well as disentangles heterogeneity of the pathological cohort by solving a clustering subproblem. We propose an efficient solution to the nonconvex optimization problem associated with JointMMCC. We apply our proposed approach to an medical resonance imaging study of aging, and identify coherent subpopulations (i.e., clusters) of cognitively less stable adults. C1 [Filipovych, Roman; Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Biomed Res Ctr 04B317, Baltimore, MD 21224 USA. RP Filipovych, R (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. EM roman.filipovych@uphs.upenn.edu; christos.davatzikos@uphs.upenn.edu FU National Institutes of Health (NIH), National Institute on Aging (NIA); [R01-AG14971]; [N01-AG-3-2124] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (NIA), and R01-AG14971, N01-AG-3-2124, N01-AG-3-2124. Asterisk indicates corresponding author. NR 65 TC 6 Z9 7 U1 3 U2 12 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD MAY PY 2012 VL 31 IS 5 BP 1124 EP 1140 DI 10.1109/TMI.2012.2186977 PG 17 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 935ES UT WOS:000303502400012 PM 22328179 ER PT J AU Wang, SJ McKenna, MT Nguyen, TB Burns, JE Petrick, N Sahiner, B Summers, RM AF Wang, Shijun McKenna, Matthew T. Nguyen, Tan B. Burns, Joseph E. Petrick, Nicholas Sahiner, Berkman Summers, Ronald M. TI Seeing Is Believing: Video Classification for Computed Tomographic Colonography Using Multiple-Instance Learning SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Computed tomographic colonography (CTC); multiple-instance learning; semidefinite programming; video analysis ID CT COLONOGRAPHY; AIDED DETECTION; POLYP DETECTION; VIRTUAL COLONOSCOPY; OBJECT RECOGNITION; COLONIC POLYPS; SYSTEM; FEATURES; ENDOSCOPY; EVOLUTION AB In this paper, we present development and testing results for a novel colonic polyp classification method for use as part of a computed tomographic colonography (CTC) computer-aided detection (CAD) system. Inspired by the interpretative methodology of radiologists using 3-D fly-through mode in CTC reading, we have developed an algorithm which utilizes sequences of images (referred to here as videos) for classification of CAD marks. For each CAD mark, we created a video composed of a series of intraluminal, volume-rendered images visualizing the detection from multiple viewpoints. We then framed the video classification question as a multiple-instance learning (MIL) problem. Since a positive (negative) bag may contain negative (positive) instances, which in our case depends on the viewing angles and camera distance to the target, we developed a novel MIL paradigm to accommodate this class of problems. We solved the new MIL problem by maximizing a L2-norm soft margin using semidefinite programming, which can optimize relevant parameters automatically. We tested our method by analyzing a CTC data set obtained from 50 patients from three medical centers. Our proposed method showed significantly better performance compared with several traditional MIL methods. C1 [Wang, Shijun; McKenna, Matthew T.; Nguyen, Tan B.; Summers, Ronald M.] NIH, Bethesda, MD 20892 USA. [Burns, Joseph E.] Univ Calif Irvine, Dept Radiol Sci, Orange, CA 92868 USA. [Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Summers, RM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM rms@nih.gov FU NIH Clinical Center; Food and Drug Administration FX This work was supported by the Intramural Research Programs of the NIH Clinical Center and the Food and Drug Administration. No official endorsement by the National Institutes of Health or the Food and Drug Administration of any equipment or product of any company mentioned in the publication should be inferred. Asterisk indicates corresponding author. NR 53 TC 9 Z9 9 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD MAY PY 2012 VL 31 IS 5 BP 1141 EP 1153 DI 10.1109/TMI.2012.2187304 PG 13 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 935ES UT WOS:000303502400013 PM 22552333 ER PT J AU Imboden, M Bouzigon, E Curjuric, I Ramasamy, A Kumar, A Hancock, DB Wilk, JB Vonk, JM Thun, GA Siroux, V Nadif, R Monier, F Gonzalez, JR Wjst, M Heinrich, J Loehr, LR Franceschini, N North, KE Altmuller, J Koppelman, GH Guerra, S Kronenberg, F Lathrop, M Moffatt, MF O'Connor, GT Strachan, DP Postma, DS London, SJ Schindler, C Kogevinas, M Kauffmann, F Jarvis, DL Demenais, F Probst-Hensch, NM AF Imboden, Medea Bouzigon, Emmanuelle Curjuric, Ivan Ramasamy, Adaikalavan Kumar, Ashish Hancock, Dana B. Wilk, Jemma B. Vonk, Judith M. Thun, Gian A. Siroux, Valerie Nadif, Rachel Monier, Florent Gonzalez, Juan R. Wjst, Matthias Heinrich, Joachim Loehr, Laura R. Franceschini, Nora North, Kari E. Altmueller, Janine Koppelman, Gerard H. Guerra, Stefano Kronenberg, Florian Lathrop, Mark Moffatt, Miriam F. O'Connor, George T. Strachan, David P. Postma, Dirkje S. London, Stephanie J. Schindler, Christian Kogevinas, Manolis Kauffmann, Francine Jarvis, Debbie L. Demenais, Florence Probst-Hensch, Nicole M. TI Genome-wide association study of lung function decline in adults with and without asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; cohort studies; genome-wide association; lung function decline; heterogeneity ID OBSTRUCTIVE PULMONARY-DISEASE; S-TRANSFERASE M1; LARGE-SCALE; GENERAL-POPULATION; CANDIDATE GENE; POLYMORPHISMS; LOCI; PHENOTYPES; CHILDREN; VARIANTS AB Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 x 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 x 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. (J Allergy Clin Immunol 2012;129:1218-28.) C1 [Imboden, Medea; Curjuric, Ivan; Kumar, Ashish; Thun, Gian A.; Schindler, Christian; Probst-Hensch, Nicole M.] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Imboden, Medea; Curjuric, Ivan; Kumar, Ashish; Thun, Gian A.; Schindler, Christian; Probst-Hensch, Nicole M.] Univ Basel, CH-4003 Basel, Switzerland. [Bouzigon, Emmanuelle; Monier, Florent; Demenais, Florence] INSERM, UMRS 946, Paris, France. [Bouzigon, Emmanuelle; Monier, Florent; Lathrop, Mark; Demenais, Florence] Fdn Jean Dausset, CEPH, Paris, France. [Bouzigon, Emmanuelle; Monier, Florent; Demenais, Florence] Univ Paris 07, Inst Univ Hematol, Paris, France. [Moffatt, Miriam F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Ramasamy, Adaikalavan; Jarvis, Debbie L.] MRC HPA Ctr Environm & Hlth, London, England. [Kumar, Ashish] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Hancock, Dana B.; London, Stephanie J.] NIEHS, Epidemiol Branch, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Hancock, Dana B.] Res Triangle Inst Int, Behav Hlth Epidemiol Program, Res Triangle Pk, NC USA. [Wilk, Jemma B.] 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. [Vonk, Judith M.; Koppelman, Gerard H.; Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol Pediat Pulmonol & Pediat Allergol, Beatrix Childrens Hosp,Groningen Res Inst Asthma, NL-9700 AB Groningen, Netherlands. [Siroux, Valerie] INSERM, U823, Team Environm Epidemiol Appl Reprod & Resp Hlth, Grenoble, France. [Siroux, Valerie] Univ Grenoble 1, Grenoble, France. [Nadif, Rachel; Kauffmann, Francine] CESP Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Resp & Environm Epidemiol Team, Villejuif, France. [Nadif, Rachel; Kauffmann, Francine] Univ Paris 11, UMRS 1018, Villejuif, France. [Gonzalez, Juan R.; Guerra, Stefano; Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona, Spain. [Gonzalez, Juan R.; Guerra, Stefano; Kogevinas, Manolis] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Wjst, Matthias; Heinrich, Joachim] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Loehr, Laura R.; Franceschini, Nora] Univ N Carolina Chapel Hill, UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina Chapel Hill, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Altmueller, Janine] Univ Cologne, CCG, Cologne, Germany. [Guerra, Stefano] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Kronenberg, Florian] Innsbruck Med Univ, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, Innsbruck, Austria. [Lathrop, Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London WC1E 7HU, England. [Guerra, Stefano; Kogevinas, Manolis] IMIM Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. RP Probst-Hensch, NM (reprint author), SwissTPH, Socinstr 57, CH-4002 Basel, Switzerland. EM Nicole.Probst@unibas.ch RI Ramasamy, Adaikalavan/G-2632-2010; Jarvis, Deborah/E-6494-2011; siroux, valerie/N-1865-2013; Demenais, Florence/G-3298-2013; Kronenberg, Florian/B-1736-2008; Schindler, Christian/D-3472-2015; Nadif, Rachel/R-2876-2016; Kogevinas, Manolis/C-3918-2017; OI London, Stephanie/0000-0003-4911-5290; Ramasamy, Adaikalavan/0000-0002-7598-2892; Kumar, Ashish/0000-0002-7075-5930; O'Connor, George/0000-0002-6476-3926; Hancock, Dana/0000-0003-2240-3604; Demenais, Florence/0000-0001-8361-0936; Kronenberg, Florian/0000-0003-2229-1120; Nadif, Rachel/0000-0003-4938-9339; Thun, Gian Andri/0000-0003-4436-3455 FU National Institutes of Health/National Heart, Lung, and Blood Institute; Flight Attendant Medical Research Institute; Netherlands Asthma Foundation; Top Institute Pharma; AstraZeneca; French Agency of Research; French Agency for Environmental and Occupational Health and Safety; INSERM-Ministry of Research "Cohortes et Collections" FX Disclosure of potential conflict of interest: J. B. Wilk has received research support from the National Institutes of Health/National Heart, Lung, and Blood Institute and the Flight Attendant Medical Research Institute. G. H. Koppelman has received research support from the Netherlands Asthma Foundation. D. S. Postma is a consultant for Nycomed and has received research support from the Top Institute Pharma and AstraZeneca. F. Kauffmann has received research support from the French Agency of Research, French Agency for Environmental and Occupational Health and Safety, and INSERM-Ministry of Research "Cohortes et Collections." The rest of the authors declare that they have no relevant conflicts of interest. NR 62 TC 48 Z9 48 U1 1 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2012 VL 129 IS 5 BP 1218 EP 1228 DI 10.1016/j.jaci.2012.01.074 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 934CG UT WOS:000303418000007 PM 22424883 ER PT J AU Liang, GQ Barker, T Xie, ZH Charles, N Rivera, J Druey, KM AF Liang, Genqing Barker, Tolga Xie, Zhihui Charles, Nicolas Rivera, Juan Druey, Kirk M. TI Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel T(H)2 immunity SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Chemokines; basophils; chemotaxis; T(H)2; allergens ID HELPER TYPE-2 RESPONSE; DENDRITIC CELLS; IN-VIVO; IL-4 PRODUCTION; BASOPHILS; DIFFERENTIATION; EXPRESSION; COMPLEXES; CYTOKINES; CCL17 AB Background: Sensitization to protease allergens, such as papain, or helminth infection is associated with basophil recruitment to draining lymph nodes (LNs). Basophils have the capacity to present antigen to naive T cells and promote T(H)2 differentiation directly or indirectly through IL-4 production. Objective: We studied how papain induces basophil migration to LNs and the contribution of various leukocytes to papain-induced immune responses. Methods: We immunized mice in the footpad with papain and studied leukocyte recruitment and inflammatory cytokine and chemokine production in the draining popliteal LNs. Results: Papain directly activated naive T cells through protease-activated receptor (PAR) 2 to initiate a chemokine/cytokine program that includes CCL17, CCL22, and IL-4. Papain-triggered innate immune responses were dependent on both CD4 T cells and PAR2 and were strongly reduced in the absence of CCR4, the primary receptor for CCL17/CCL22. Conclusion: These results elucidate a novel innate allergen-recognition pathway mediated by naive T cells through PAR2, which provide an immediate source of chemokines and IL-4 upstream of basophils and antigen-restricted T(H)2 differentiation. PAR2 antagonism might thus hold promise for the treatment of allergic disease. (J Allergy Clin Immunol 2012;129:1377-86.) C1 [Liang, Genqing; Barker, Tolga; Xie, Zhihui; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Charles, Nicolas; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,Rm 11N242, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases [AI000939] FX Supported in part by the Intramural Research Programs of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant no. AI000939 LAD to K. M. D.). NR 38 TC 19 Z9 19 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2012 VL 129 IS 5 BP 1377 EP U282 DI 10.1016/j.jaci.2012.02.035 PG 23 WC Allergy; Immunology SC Allergy; Immunology GA 934CG UT WOS:000303418000029 PM 22460072 ER PT J AU Udey, MC AF Udey, Mark C. TI Epidermal Langerhans cells tune skin reactivity to contact allergens SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID DERMAL DENDRITIC CELLS; T-CELLS; HYPERSENSITIVITY; DERMATITIS; DISTINCT; SENSITIZATION; TOLERANCE; RESPONSES; ABLATION; IMMUNITY AB Allergic contact dermatitis is a common disorder that has fascinated dermatologists and immunologists for decades. Extensive studies of contact sensitivity reactions in mice established a mechanistic paradigm that has been revisited in recent years, and the involvement of Langerhans cells (LCs), a population of epidermal dendritic cells, in immune responses to epicutaneously applied antigens has been questioned. In this issue of the JCI, Gomez de Aguero et al. describe an elegant series of experiments that implicate LCs in tolerance induction, positioning these cells as key regulators of immunologic barrier function. C1 NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, CCR, NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM udey@helix.nih.gov FU Intramural NIH HHS NR 23 TC 1 Z9 2 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2012 VL 122 IS 5 BP 1602 EP 1605 DI 10.1172/JCI63190 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 935BG UT WOS:000303491400008 PM 22523061 ER PT J AU Estes, JD AF Estes, Jacob D. TI Enhancing immune responses to limit chronic immune activation during SIV SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CD8 T-CELLS; CHRONIC INFECTION; RHESUS MACAQUES; PD-1 BLOCKADE; VIRUS-INFECTION; HIV-INFECTION; EXPRESSION; VACCINATION; EXHAUSTION; DISEASE AB The persistent immune activation that is typical of HIV-1 and Sly infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death-1 (PD-1). Targeting this exhaustion pathway could result in improved antiviral immune responses, but there have been concerns that it would also lead to increased inflammation and immunopathology. In this issue of the JCI, Dyavar Shetty et al. demonstrate that blocking PD-1 actually reduced proinflammatory responses and improved immunity in the gut of SIV-infected rhesus macaques, suggesting that this might have therapeutic potential to prevent opportunistic infections in HIV-infected patients. C1 NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Estes, JD (reprint author), NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM estesj@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 21 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2012 VL 122 IS 5 BP 1611 EP 1614 DI 10.1172/JCI63389 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 935BG UT WOS:000303491400011 PM 22523060 ER PT J AU Bibollet-Ruche, F Heigele, A Keele, BF Easlick, JL Decker, JM Takehisa, J Learn, G Sharp, PM Hahn, BH Kirchhoff, F AF Bibollet-Ruche, Frederic Heigele, Anke Keele, Brandon F. Easlick, Juliet L. Decker, Julie M. Takehisa, Jun Learn, Gerald Sharp, Paul M. Hahn, Beatrice H. Kirchhoff, Frank TI Efficient SIVcpz replication in human lymphoid tissue requires viral matrix protein adaptation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 GROUP O; PRIMATE LENTIVIRUSES; NONPANDEMIC HIV-1; WILD CHIMPANZEES; HUMAN TETHERIN; CELL-SURFACE; EX-VIVO; GAG; INFECTION AB SIVs infecting wild-living apes in west central Africa have crossed the species barrier to humans on at least four different occasions, one of which spawned the AIDS pandemic. Although the chimpanzee precursor of pandemic HIV-1 strains must have been able to infect humans, the capacity of SIVcpz strains to replicate in human lymphoid tissues (HLTs) is not known. Here, we show that SIVcpz strains from two chimpanzee subspecies are capable of replicating in human tonsillary explant cultures, albeit only at low titers. However, SIVcpz replication in HLT was significantly improved after introduction of a previously identified human-specific adaptation at position 30 in the viral Gag matrix protein. An Arg or Lys at this position significantly increased SIVcpz replication in HLT, while the same mutation reduced viral replication in chimpanzee-derived CD4(+) T cells. Thus, naturally occurring SIVcpz strains are capable of infecting HLTs, the major site of HIV-1 replication in vivo. However, efficient replication requires the acquisition of a host-specific adaptation in the viral matrix protein. These results identify Gag matrix as a major determinant of SIVcpz replication fitness in humans and suggest a critical role in the emergence of HIV/AIDS. C1 [Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Heigele, Anke; Kirchhoff, Frank] Univ Ulm, Med Ctr, Inst Mol Virol, D-89081 Ulm, Germany. [Keele, Brandon F.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Easlick, Juliet L.; Decker, Julie M.; Takehisa, Jun; Learn, Gerald] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Sharp, Paul M.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. RP Hahn, BH (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. EM bhahn@upenn.edu; frank.kirchhoff@uni-ulm.de RI Sharp, Paul/F-5783-2010 OI Sharp, Paul/0000-0001-9771-543X FU NIH [R21 AI080364, R01 A150529, R01 A158715, P30 Al27767]; Yerkes Regional Primate Research Center [RR000165]; Bristol Myers Freedom; Deutsche Forschungsgemeinschaft FX We thank Matthias H. Kraus, Rebecca S. Rudicell, Martha Mayer, and Birgit Ott for technical assistance. This work was supported in part by the NIH (R21 AI080364, RO1 A150529, R01 A158715, P30 Al27767), the Yerkes Regional Primate Research Center (RR000165), the Bristol Myers Freedom to Discover Program, and the Deutsche Forschungsgemeinschaft. NR 60 TC 15 Z9 15 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2012 VL 122 IS 5 BP 1644 EP 1652 DI 10.1172/JCI61429 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 935BG UT WOS:000303491400014 PM 22505456 ER PT J AU Khadra, A Yan, ZH Coddou, C Tomic, M Sherman, A Stojilkovic, SS AF Khadra, Anmar Yan, Zonghe Coddou, Claudio Tomic, Melanija Sherman, Arthur Stojilkovic, Stanko S. TI Gating properties of the P2X2a and P2X2b receptor channels: Experiments and mathematical modeling SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID P2X(2) RECEPTOR; PERMEABILITY DYNAMICS; CYTOSOLIC DOMAIN; ION-CHANNEL; DESENSITIZATION; IDENTIFICATION; TRANSDUCTION; ACTIVATION; EXPRESSION AB Adenosine triphosphate (ATP)-gated P2X2 receptors exhibit two opposite activation-dependent changes, pore dilation and pore closing (desensitization), through a process that is incompletely understood. To address this issue and to clarify the roles of calcium and the C-terminal domain in gating, we combined biophysical and mathematical approaches using two splice forms of receptors: the full-size form (P2X2aR) and the shorter form missing 69 residues in the C-terminal domain (P2X2bR). Both receptors developed conductivity for N-methyl-D-glucamine within 2-6 s of ATP application. However, pore dilation was accompanied with a decrease rather than an increase in the total conductance, which temporally coincided with rapid and partial desensitization. During sustained agonist application, receptors continued to desensitize in calcium-independent and calcium-dependent modes. Calcium-independent desensitization was more pronounced in P2X2bR, and calcium-dependent desensitization was more pronounced in P2X2aR. In whole cell recording, we also observed use-dependent facilitation of desensitization of both receptors. Such behavior was accounted for by a 16-state Markov kinetic model describing ATP binding/unbinding and activation/desensitization. The model assumes that naive receptors open when two to three ATP molecules bind and undergo calcium-independent desensitization, causing a decrease in the total conductance, or pore dilation, causing a shift in the reversal potential. In calcium-containing media, receptor desensitization is facilitated and the use-dependent desensitization can be modeled by a calcium-dependent toggle switch. The experiments and the model together provide a rationale for the lack of sustained current growth in dilating P2X2Rs and show that receptors in the dilated state can also desensitize in the presence of calcium. C1 [Khadra, Anmar; Sherman, Arthur] NIDDKD, Lab Biol Modeling, Bethesda, MD 20892 USA. [Yan, Zonghe; Coddou, Claudio; Tomic, Melanija; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Khadra, Anmar] McGill Univ, Dept Physiol, Montreal, PQ H3A 1Y6, Canada. RP Sherman, A (reprint author), NIDDKD, Lab Biol Modeling, Bethesda, MD 20892 USA. EM asherman@nih.gov RI Tomic, Melanija/C-3371-2016 FU National Institutes of Health, National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases FX The authors were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development (to Z. Yan, M. Tomic, C. Coddou, and S.S. Stojilkovic), and National Institute of Diabetes and Digestive and Kidney Diseases (to A. Khadra and A. Sherman). NR 26 TC 13 Z9 13 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD MAY PY 2012 VL 139 IS 5 BP 333 EP 348 DI 10.1085/jgp.201110716 PG 16 WC Physiology SC Physiology GA 934TF UT WOS:000303468900002 PM 22547664 ER PT J AU Zhao, HY Berger, AJ Brown, PH Kumar, J Balbo, A May, CA Casillas, E Laue, TM Patterson, GH Mayer, ML Schuck, P AF Zhao, Huaying Berger, Anthony J. Brown, Patrick H. Kumar, Janesh Balbo, Andrea May, Carrie A. Casillas, Ernesto, Jr. Laue, Thomas M. Patterson, George H. Mayer, Mark L. Schuck, Peter TI Analysis of high-affinity assembly for AMPA receptor amino-terminal domains SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; SEDIMENTATION EQUILIBRIUM-ANALYSIS; PROTEIN-PROTEIN INTERACTIONS; ANALYTICAL ULTRACENTRIFUGATION; DETECTED SEDIMENTATION; SUBUNIT ARRANGEMENT; CRYSTAL-STRUCTURE; NMDA RECEPTORS; CELL-LINE; VELOCITY AB Analytical ultracentrifugation (AUC) and steady-state fluorescence anisotropy were used to measure the equilibrium dissociation constant (K-d) for formation of dimers by the amino-terminal domains (ATDs) of the GluA2 and GluA3 subtypes of AMPA receptor. Previous reports on GluA2 dimerization differed in their estimate of the monomer-dimer K-d by a 2,400-fold range, with no consensus on whether the ATD forms tetramers in solution. We find by sedimentation velocity (SV) analysis performed using absorbance detection a narrow range of monomer-dimer K-d values for GluA2, from 5 to 11 nM for six independent experiments, with no detectable formation of tetramers and no effect of glycosylation or the polypeptide linker connecting the ATD and ligand-binding domains; for GluA3, the monomer-dimer K-d was 5.6 mu M, again with no detectable tetramer formation. For sedimentation equilibrium (SE) experiments, a wide range of K-d values was obtained for GluA2, from 13 to 284 nM, whereas for GluA3, the K-d of 3.1 mu M was less than twofold different from the SV value. Analysis of cell contents after the similar to 1-week centrifuge run by silver-stained gels revealed low molecular weight GluA2 breakdown products. Simulated data for SE runs demonstrate that the apparent K-d for GluA2 varies with the extent of proteolysis, leading to artificially high K-d values. SV experiments with fluorescence detection for GluA2 labeled with 5,6-carboxyfluorescein, and fluorescence anisotropy measurements for GluA2 labeled with DyLight405, yielded K-d values of 5 and 11 nM, consistent with those from SV with absorbance detection. However, the sedimentation coefficients measured by AUC using absorbance and fluorescence systems were strikingly different, and for the latter are not consistent with hydrodynamic protein models. Thus, for unknown reasons, the concentration dependence of sedimentation coefficients obtained with fluorescence detection SV may be unreliable, limiting the usefulness of this technique for quantitative analysis. C1 [Berger, Anthony J.; Kumar, Janesh; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20892 USA. [Casillas, Ernesto, Jr.; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, Bethesda, MD 20892 USA. [May, Carrie A.; Laue, Thomas M.] Univ New Hampshire, Dept Biochem, Durham, NH 03824 USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mark.mayer@nih.gov; schuckp@mail.nih.gov RI Zhao, Huaying/F-5716-2012; Mayer, Mark/H-5500-2013; OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering, NIH, Department of Health and Human Services FX This work was supported by the intramural research programs of National Institute of Child Health and Human Development and National Institute of Biomedical Imaging and Bioengineering, NIH, Department of Health and Human Services. NR 55 TC 26 Z9 26 U1 0 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD MAY PY 2012 VL 139 IS 5 BP 371 EP 388 DI 10.1085/jgp.201210770 PG 18 WC Physiology SC Physiology GA 934TF UT WOS:000303468900005 PM 22508847 ER PT J AU Kepka, DL Ulrich, AK Coronado, GD AF Kepka, Deanna L. Ulrich, Angela K. Coronado, Gloria D. TI Low Knowledge of the Three-Dose HPV Vaccine Series among Mothers of Rural Hispanic Adolescents SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Hispanic mothers; Hispanic adolescents; HPV vaccine uptake; cervical cancer; rural Hispanics; HPV vaccine education ID HUMAN-PAPILLOMAVIRUS VACCINATION; UNITED-STATES; ACCEPTANCE AB Background. Few previous investigations on correlates of HPV vaccine uptake have included Hispanics, a group known to have a disproportionately high risk of cervical cancer. Methods. Rural Hispanic mothers of daughters aged 9-17 (n=78) were recruited at local community events to participate in a standardized Spanish-language survey that examined factors related to vaccine uptake. Results. Approximately 35% of the mothers reported that their daughter had received at least one dose of the vaccine. Mothers who had heard of the HPV vaccine were more likely to have a vaccinated daughter (p<.01). Mothers who thought their daughter's father would approve were more likely to have a vaccinated daughter (p=.004). Contrary to expectation, parents who believed that only one injection is necessary were more likely to have a vaccinated daughter (p=.009). Conclusions. HPV vaccine education programs that target both parents are needed to ensure that Hispanic parents receive the complete HPV vaccine regimen. C1 [Kepka, Deanna L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ulrich, Angela K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Coronado, Gloria D.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. RP Kepka, DL (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4017,Mail Stop Code 7344, Bethesda, MD 20892 USA. EM deanna.kepka@nih.gov FU AHRQ HHS [T32 HS013853]; NCI NIH HHS [U01 CA114633, R25 CA92408] NR 18 TC 15 Z9 15 U1 1 U2 7 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD MAY PY 2012 VL 23 IS 2 BP 626 EP 635 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 934EY UT WOS:000303427600013 PM 22643612 ER PT J AU Takai, S Sabzevari, H Farsaci, B Schlom, J Greiner, JW AF Takai, Shinji Sabzevari, Helen Farsaci, Benedetto Schlom, Jeffrey Greiner, John W. TI Distinct Effects of Saracatinib on Memory CD8(+) T Cell Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; SRC/ABL KINASE INHIBITOR; CEA TRANSGENIC MICE; IN-VIVO; INFLUENZA NUCLEOPROTEIN; ANTITUMOR IMMUNITY; COMPLEX-FORMATION; DENDRITIC CELLS; SRC INHIBITOR; ACTIVATION AB Immunologic memory involving CD8(+) T cells is a hallmark of an adaptive Ag-specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T cell response has led to new approaches that target the magnitude and quality of the memory T cell response. In this article, we show that T cells from TCR transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases-priming, expansion, contraction, and memory-of an Ag-specific T cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62L(high)/CD44(high) central memory CD8(+) T cells and IFN-gamma production but suppressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8(+) T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine. The Journal of Immunology, 2012, 188: 4323-4333. C1 [Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto; Schlom, Jeffrey; Greiner, John W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10,Room 8B09,10 Ctr Dr, Bethesda, MD 20892 USA. EM jg117s@nih.gov RI Farsaci, Benedetto/L-9837-2014 OI Farsaci, Benedetto/0000-0001-8275-2561 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 50 TC 4 Z9 4 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 IS 9 BP 4323 EP 4333 DI 10.4049/jimmunol.1101439 PG 11 WC Immunology SC Immunology GA 932OH UT WOS:000303299900024 PM 22450814 ER PT J AU Falanga, YT Chaimowitz, NS Charles, N Finkelman, FD Pullen, NA Barbour, S Dholaria, K Faber, T Kolawole, M Huang, BN Odom, S Rivera, J Carlyon, J Conrad, DH Spiegel, S Oskeritzian, CA Ryan, JJ AF Falanga, Yves T. Chaimowitz, Natalia S. Charles, Nicolas Finkelman, Fred D. Pullen, Nicholas A. Barbour, Suzanne Dholaria, Kevin Faber, Travis Kolawole, Motunrayo Huang, Bernice Odom, Sandra Rivera, Juan Carlyon, Jason Conrad, Daniel H. Spiegel, Sarah Oskeritzian, Carole A. Ryan, John J. TI Lyn but Not Fyn Kinase Controls IgG-Mediated Systemic Anaphylaxis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; MAST-CELL ACTIVATION; CHRONIC ALLERGIC INFLAMMATION; GAMMA-RIII; TYROSINE KINASE; NEGATIVE REGULATION; CYTOKINE PRODUCTION; DEFICIENT MICE; IMPAIRED DEGRANULATION; LUPUS-ERYTHEMATOSUS AB Anaphylaxis is a rapid, life-threatening hypersensitivity reaction. Until recently, it was mainly attributed to histamine released by mast cells activated by allergen crosslinking (XL) of Fc epsilon RI-bound allergen-specific IgE. However, recent reports established that anaphylaxis could also be triggered by basophil, macrophage, and neutrophil secretion of platelet-activating factor subsequent to Fc gamma R stimulation by IgG/Ag complexes. We have investigated the contribution of Fyn and Lyn tyrosine kinases to Fc gamma RIIb and Fc gamma RIII signaling in the context of IgG-mediated passive systemic anaphylaxis (PSA). We found that mast cell IgG XL induced Fyn, Lyn, Akt, Erk, p38, and JNK phosphorylation. Additionally, IgG XL of mast cells, basophils, and macrophages resulted in Fyn- and Lyn-regulated mediator release in vitro. Fc gamma R-mediated activation was enhanced in Lyn-deficient (knockout [KO]) cells, but decreased in Fyn KO cells, compared with wild-type cells. More importantly, Lyn KO mice displayed significantly exacerbated PSA features whereas no change was observed for Fyn KO mice, compared with wild-type littermates. Intriguingly, we establish that mast cells account for most serum histamine in IgG-induced PSA. Taken together, our findings establish pivotal roles for Fyn and Lyn in the regulation of PSA and highlight their unsuspected functions in IgG-mediated pathologies. The Journal of Immunology, 2012, 188: 4360-4368. C1 [Falanga, Yves T.; Pullen, Nicholas A.; Dholaria, Kevin; Faber, Travis; Kolawole, Motunrayo; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Chaimowitz, Natalia S.; Barbour, Suzanne; Huang, Bernice; Carlyon, Jason; Conrad, Daniel H.] Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Charles, Nicolas] Univ Paris 07, Fac Med Xavier Bichat, INSERM, U699, F-75870 Paris 18, France. [Finkelman, Fred D.] Cincinnati Vet Affairs Med Ctr, Res Serv, Cincinnati, OH 45220 USA. [Finkelman, Fred D.] Univ Cincinnati, Coll Med, Div Immunol, Cincinnati, OH 45267 USA. [Finkelman, Fred D.] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. [Odom, Sandra; Rivera, Juan] NIAMSD, Lab Mol Immunogenet, NIH, Bethesda, MD 20892 USA. [Spiegel, Sarah; Oskeritzian, Carole A.] Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, 1000 W Cary St, Richmond, VA 23284 USA. EM jjryan@vcu.edu RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; National Institutes of Health [IR01AI59638, U19A1077435, KO1AR053186]; Veterans Affairs Merit Grant FX This work was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (to J.R.), and National Institutes of Health Grants IR01AI59638 and U19A1077435 (to JR.), KO1AR053186 (to C.A.O.), and a Veterans Affairs Merit Grant (to F.D.F.). NR 74 TC 16 Z9 16 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 IS 9 BP 4360 EP 4368 DI 10.4049/jimmunol.1003223 PG 9 WC Immunology SC Immunology GA 932OH UT WOS:000303299900028 PM 22450804 ER PT J AU Luz, NF Andrade, BB Feijo, DF Araujo-Santos, T Carvalho, GQ Andrade, D Abanades, DR Melo, EV Silva, AM Brodskyn, CI Barral-Netto, M Barral, A Soares, RP Ameida, RP Bozza, MT Borges, VM AF Luz, Nivea F. Andrade, Bruno B. Feijo, Daniel F. Araujo-Santos, Theo Carvalho, Graziele Q. Andrade, Daniela Abanades, Daniel R. Melo, Enaldo V. Silva, Angela M. Brodskyn, Claudia I. Barral-Netto, Manoel Barral, Aldina Soares, Rodrigo P. Ameida, Roque P. Bozza, Marcelo T. Borges, Valeria M. TI Heme Oxygenase-1 Promotes the Persistence of Leishmania chagasi Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN VISCERAL LEISHMANIASIS; TUMOR-NECROSIS-FACTOR; CARBON-MONOXIDE; HEMOPHAGOCYTIC SYNDROME; DIFFERENTIAL-DIAGNOSIS; SUPEROXIDE-DISMUTASE; MURINE MACROPHAGES; INTERFERON-GAMMA; VIRULENCE FACTOR; IMMUNE-RESPONSE AB Visceral leishmaniasis (VL) remains a major public health problem worldwide. This disease is highly associated with chronic inflammation and a lack of the cellular immune responses against Leishmania. It is important to identify major factors driving the successful establishment of the Leishmatzia infection to develop better tools for the disease control. Heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, and its role in VL has not been investigated. In this study, we evaluated the role of HO-1 in the infection by Leishmatzia infantum chagasi, the causative agent of VL cases in Brazil. We found that L. chagasi infection or lipophosphoglycan isolated from promastigotes triggered HO-1 production by murine macrophages. Interestingly, cobalt protoporphyrin IX, an HO-1 inductor, increased the parasite burden in both mouse and human-derived macrophages. Upon L. chagasi infection, macrophages from Hmox1 knockout mice presented significantly lower parasite loads when compared with those from wild-type mice. Furthermore, upregulation of HO-1 by cobalt protoporphyrin IX diminished the production of TNF-alpha and reactive oxygen species by infected murine macrophages and increased Cu/Zn superoxide dismutase expression in human monocytes. Finally, patients with VL presented higher systemic concentrations of HO-1 than healthy individuals, and this increase of HO-1 was reduced after antileishmanial treatment, suggesting that HO-1 is associated with disease susceptibility. Our data argue that HO-1 has a critical role in the L. chagasi infection and is strongly associated with the inflammatory imbalance during VL. Manipulation of HO-1 pathways during VL could serve as an adjunctive therapeutic approach. The Journal of Immunology, 2012, 188: 4460-4467. C1 [Luz, Nivea F.; Araujo-Santos, Theo; Carvalho, Graziele Q.; Andrade, Daniela; Abanades, Daniel R.; Brodskyn, Claudia I.; Barral-Netto, Manoel; Barral, Aldina; Borges, Valeria M.] Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, BR-40295001 Salvador, BA, Brazil. [Luz, Nivea F.; Araujo-Santos, Theo; Carvalho, Graziele Q.; Andrade, Daniela; Abanades, Daniel R.; Brodskyn, Claudia I.; Barral-Netto, Manoel; Barral, Aldina; Borges, Valeria M.] Univ Fed Bahia, BR-40110060 Salvador, BA, Brazil. [Andrade, Bruno B.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Feijo, Daniel F.; Bozza, Marcelo T.] Univ Fed Rio de Janeiro, Inst Microbiol, Dept Imunol, BR-21941590 Rio De Janeiro, Brazil. [Melo, Enaldo V.; Silva, Angela M.; Ameida, Roque P.] Univ Fed Sergipe, Univ Hosp, Dept Med, BR-49010390 Aracaju, Brazil. [Brodskyn, Claudia I.; Barral-Netto, Manoel; Barral, Aldina; Ameida, Roque P.; Borges, Valeria M.] Inst Nacl Ciencia & Tecnol Invest Imunol, BR-40110100 Salvador, BA, Brazil. [Soares, Rodrigo P.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG, Brazil. RP Borges, VM (reprint author), Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Rua Waldemar Falcao 121, BR-40295001 Salvador, BA, Brazil. EM vborges@bahia.fiocruz.br RI Andrade, Bruno/J-9111-2012; Barral Netto, Manoel/B-3904-2009; Imunologia, Inct/I-2124-2013; Araujo-Santos, Theo/F-9807-2014; Borges, Valeria/G-2009-2014; OI Borges, Valeria/0000-0002-2775-5409; Andrade, Bruno/0000-0001-6833-3811; Barral Netto, Manoel/0000-0002-5823-7903; Araujo-Santos, Theo/0000-0001-9861-6660; Farias Luz, Nivea/0000-0003-1958-7043 FU Fundacao de Amparo a Pesquisa do Estado da Bahia; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior; National Institute for Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by Fundacao de Amparo a Pesquisa do Estado da Bahia, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), and Instituto Nacional de Ciencia e Tecnologia de Investigacao em Imunologia. N.F.L., D.F.F. TA-S., and G.Q.C. are recipients of CNPq fellowships. D.A. received a fellowship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior. C.I.B., R.P.S., M.B.-N., A.B., R.P.A., M.T.B., and V.M.B. are senior investigators from CNPq. The work of B.B.A. is supported by the intramural research program of the National Institute for Allergy and Infectious Diseases, National Institutes of Health. NR 67 TC 20 Z9 20 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 MAY 1 PY 2012 VL 188 IS 9 BP 4460 EP 4467 DI 10.4049/jimmunol.1103072 PG 8 WC Immunology SC Immunology GA 932OH UT WOS:000303299900039 PM 22461696 ER PT J AU Guerrero-Beltran, CE Mukhopadhyay, P Horvath, B Rajesh, M Tapia, E Garcia-Torres, I Pedraza-Chaverri, J Pacher, P AF Enrique Guerrero-Beltran, Carlos Mukhopadhyay, Partha Horvath, Bela Rajesh, Mohanraj Tapia, Edilia Garcia-Torres, Itzhel Pedraza-Chaverri, Jose Pacher, Pal TI Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Sulforaphane; Natural compound; Nephropathy; Inflammation; Cell death; Cisplatin ID ISCHEMIA-REPERFUSION INJURY; RAT-KIDNEY MITOCHONDRIA; ACUTE-RENAL-FAILURE; P38 MAP KINASE; NF-KAPPA-B; CISPLATIN NEPHROTOXICITY; OXIDATIVE STRESS; ISOTHIOCYANATE SULFORAPHANE; ISCHEMIA/REPERFUSION INJURY; IN-VITRO AB Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity. Cell death and inflammation play a key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of prosurvival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways [p53, Jun N-terminal kinase (JNK), and p38-alpha mitogen-activated protein kinase (MAPK)] and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling), associated with attenuation of various prosurvival signaling pathways [e.g., extracellular signal-regulated kinase (ERK) and p38-beta MAPK]. Cisplatin also markedly enhanced inflammation in the kidneys [promoted NF-kappa B activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-alpha (TNF-alpha) levels and inflammatory cell infiltration]. These effects were significantly attenuated by pretreatment of rodents with SFN. Thus, the cisplatin-induced nephropathy is associated with activation of various cell death and proinflammatory pathways (p53. JNK, p38-alpha, TNF-alpha and NF-kappa B) and impairments of key prosurvival signaling mechanisms (ERK and p38-beta). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of chemotherapy. Published by Elsevier Inc. C1 [Enrique Guerrero-Beltran, Carlos; Mukhopadhyay, Partha; Horvath, Bela; Rajesh, Mohanraj; Pedraza-Chaverri, Jose; Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Enrique Guerrero-Beltran, Carlos; Pedraza-Chaverri, Jose] Univ Nacl Autonoma Mexico, Dept Biol, Fac Quim, Mexico City 04510, DF, Mexico. [Horvath, Bela] Semmelweis Univ, Inst Human Physiol & Clin Expt Res, H-1089 Budapest, Hungary. [Tapia, Edilia] Inst Nacl Cardiol, Dept Nefrol, Mexico City 04510, DF, Mexico. [Garcia-Torres, Itzhel] Inst Nacl Pediat, Lab Bioquim Genet, Mexico City 04510, DF, Mexico. RP Pedraza-Chaverri, J (reprint author), NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM pedraza@unam.mx; pacher@mail.nih.gov RI MUKHOPADHYAY, PARTHA/G-3890-2010; Horvath, Bela/A-7368-2009; Pacher, Pal/B-6378-2008; OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Guerrero-Beltran, Carlos Enrique/0000-0002-5001-0093; Garcia, Itzhel/0000-0002-3018-060X FU NIH/NIAAA; Consejo Nacional de Ciencia y Tecnologia (CONACYT) [129838]; Direccion General de Asuntos del Personal Academic (DGAPA) [201910]; Hungarian Research Scientific Fund (OTKA) fellowship [MB08-A 80238] FX Grants, sponsors and funding sources: This work was supported by the Intramural Research Program of NIH/NIAAA (to Pacher P), Consejo Nacional de Ciencia y Tecnologia (CONACYT) 129838 and Direccion General de Asuntos del Personal Academic (DGAPA) 201910 (to Pedraza-Chaverri J). Dr. Horvath was supported by a Hungarian Research Scientific Fund (OTKA) fellowship (MB08-A 80238). The study sponsors had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 53 TC 37 Z9 38 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD MAY PY 2012 VL 23 IS 5 BP 494 EP 500 DI 10.1016/j.jnutbio.2011.02.004 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 937ED UT WOS:000303640900011 PM 21684138 ER PT J AU Kaufmann, P AF Kaufmann, Petra TI Clinical research for neuropathies SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Article DE clinical research; clinical trials; data sharing; neuropathy; research infrastructure AB The National Institutes of Health (NIH) has a long-standing commitment to neuropathy research. From 20052009, the NIH has committed US $115 million each year. A collaborative effort between researchers and patients can accelerate the translation of pre-clinical discoveries into better treatments for neuropathy patients. Clinical trials are needed to test these new treatments, but they can only be implemented in a timely fashion if patients with neuropathies are willing to participate. This perspective focuses on the value of having various outlets for informing both the patients and the physicians about existing clinical research opportunities and on the potential benefit of establishing patient registries to help with trial recruitment. Once data have been collected, there is a need to broadly share the data in order to inform future trials, and a first step would be to harmonize data collection by using Common Data Elements (CDEs). C1 Natl Inst Neurol Disorders & Stroke, Off Clin Res, NSC, Bethesda, MD 20892 USA. RP Kaufmann, P (reprint author), Natl Inst Neurol Disorders & Stroke, Off Clin Res, NSC, 6001 Execut Blvd,Room 2216, Bethesda, MD 20892 USA. EM petra.kaufman@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD MAY PY 2012 VL 17 SU 2 SI SI BP 40 EP 42 DI 10.1111/j.1529-8027.2012.00394.x PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 934JU UT WOS:000303441200008 PM 22548622 ER PT J AU Kristinsson, SY Goldin, L Turesson, I Hultcrantz, M Bjorkholm, M Landgren, O AF Kristinsson, S. Y. Goldin, L. Turesson, I. Hultcrantz, M. Bjorkholm, M. Landgren, O. TI Family history of venous thromboembolism is associated with increased risk for thrombosis in multiple myeloma: a population-based study SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Letter ID DEEP-VEIN THROMBOSIS; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; PLUS DEXAMETHASONE; THALIDOMIDE; LENALIDOMIDE; PREVENTION; SWEDEN C1 [Kristinsson, S. Y.; Hultcrantz, M.; Bjorkholm, M.] Karolinska Univ Hosp, Div Hematol, Dept Med, Solna, Sweden. [Goldin, L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Turesson, I.] Skane Univ Hosp, Malmo, Sweden. [Landgren, O.] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Kristinsson, S. Y.; Hultcrantz, M.; Bjorkholm, M.] Karolinska Inst, Stockholm, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Intramural NIH HHS NR 21 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD MAY PY 2012 VL 10 IS 5 BP 962 EP 964 DI 10.1111/j.1538-7836.2012.04676.x PG 3 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 934KK UT WOS:000303442800030 PM 22372994 ER PT J AU Lin, YH Salem, N Wells, EM Zhou, WY Loewke, JD Brown, JA Lands, WEM Goldman, LR Hibbeln, JR AF Lin, Yu Hong Salem, Norman, Jr. Wells, Ellen M. Zhou, Weiyin Loewke, James D. Brown, James A. Lands, William E. M. Goldman, Lynn R. Hibbeln, Joseph R. TI Automated High-Throughput Fatty Acid Analysis of Umbilical Cord Serum and Application to an Epidemiological Study SO LIPIDS LA English DT Article DE Gas chromatography; Automation; Robot; Fatty acid; Transesterification ID GAS-CHROMATOGRAPHY; CONTROLLED-TRIAL; BLOOD-SERUM; TRANSESTERIFICATION; CHILDHOOD; FISH; AGE; CONSUMPTION; PREVENTION; FINGERTIP AB Large population studies show that polyunsaturated fatty acids are important for human health, but determining relationships between the health benefits and the fatty acid content has been hampered by the unavailability of labor-effective high-throughput technologies. An automated high throughput fatty acid analysis was developed from a previous procedure based on direct transesterification including the automation of chemical procedures, data acquisition and automatic data processing. The method was validated and applied to umbilical cord serum samples in an epidemiological study. The method was linear in the range of 1-600 mu g/mL serum with r (2) a parts per thousand yen0.99. The within-run CV was < 5.4% for 23 fatty acids and a range of recoveries over three concentrations were 76-119% in a low-lipid matrix with the exception of 14:0. The fatty acid concentration as measured by the robotic method for human plasma was in good agreement with the Lepage & Roy method. The fatty acid profile in umbilical cord serum from American subjects (n = 287) showed an average of 38.0, 24.9, 32.0 and 4.6% of total fatty acids for saturates, monounsaturates, n-6 and n-3 polyunsaturates, respectively. This is the first report of a complete, validated, cost-effective, automated, high throughput fatty acid measurement method along with application to a population-based study. Automated fatty acid analysis coupled with automated data processing greatly facilitates the high throughput, 72 samples transesterified in 6 h, required for large population-based studies. C1 [Lin, Yu Hong; Salem, Norman, Jr.; Zhou, Weiyin; Loewke, James D.; Brown, James A.; Lands, William E. M.; Hibbeln, Joseph R.] NIAAA, Sec Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Wells, Ellen M.] Case Western Reserve Univ, Sch Med, Dept Environm Hlth Sci, Cleveland, OH 44106 USA. [Wells, Ellen M.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Goldman, Lynn R.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Lin, YH (reprint author), NIAAA, Sec Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N-07,MSC 9410, Bethesda, MD 20892 USA. EM yulin@mail.nih.gov OI Wells, Ellen/0000-0002-7293-1395 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; National Oceanic and Atmospheric Administration FX This research was supported, in part, by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; and the National Oceanic and Atmospheric Administration. Thanks to Dr. Shui-Lin Niu for helping with the preparation of the low lipid serum, and Mr. Brian Brown for his assistance with manuscript editing. NR 34 TC 19 Z9 20 U1 2 U2 17 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD MAY PY 2012 VL 47 IS 5 BP 527 EP 539 DI 10.1007/s11745-012-3661-6 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 933IP UT WOS:000303354400009 PM 22430941 ER PT J AU Linguraru, MG Pura, JA Pamulapati, V Summers, RM AF Linguraru, Marius George Pura, John A. Pamulapati, Vivek Summers, Ronald M. TI Statistical 4D graphs for multi-organ abdominal segmentation from multiphase CT SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Multiphase CT; 4D graph; Multi-organ segmentation; Enhancement; Shape ID AUTOMATED SEGMENTATION; PROBABILISTIC ATLAS; LIVER SEGMENTATION; IMAGE SEGMENTATION; SHAPE PRIORS; MR-IMAGES; CUTS; MODEL; CLASSIFICATION; CONSTRUCTION AB The interpretation of medical images benefits from anatomical and physiological priors to optimize computer-aided diagnosis applications. Diagnosis also relies on the comprehensive analysis of multiple organs and quantitative measures of soft tissue. An automated method optimized for medical image data is presented for the simultaneous segmentation of four abdominal organs from 4D CT data using graph cuts. Contrast-enhanced CT scans were obtained at two phases: non-contrast and portal venous. Intra-patient data were spatially normalized by non-linear registration. Then 4D convolution using population training information of contrast-enhanced liver, spleen and kidneys was applied to multiphase data to initialize the 4D graph and adapt to patient-specific data. CT enhancement information and constraints on shape, from Parzen windows, and location, from a probabilistic atlas, were input into a new formulation of a 4D graph. Comparative results demonstrate the effects of appearance, enhancement, shape and location on organ segmentation. All four abdominal organs were segmented robustly and accurately with volume overlaps over 93.6% and average surface distances below 1.1 mm. Published by Elsevier B.V. C1 [Linguraru, Marius George] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Linguraru, Marius George; Pura, John A.; Pamulapati, Vivek; Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Linguraru, MG (reprint author), Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, 111 Michigan Ave NW, Washington, DC 20010 USA. EM mlingura@cnmc.org; rms@nih.gov FU National Institutes of Health, Clinical Center FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, Clinical Center. The authors would like to thank Ananda S. Chowdhury, PhD, Jesse K. Sandberg, Visal Desai and Javed Aman for helping with the data analysis. NR 62 TC 43 Z9 45 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD MAY PY 2012 VL 16 IS 4 BP 904 EP 914 DI 10.1016/j.media.2012.02.001 PG 11 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 937EP UT WOS:000303642100012 PM 22377657 ER PT J AU Roberts, WC Taylor, MA Shirani, J AF Roberts, William C. Taylor, Marc A. Shirani, Jamshid TI Cardiac Findings at Necropsy in Patients With Chronic Kidney Disease Maintained on Chronic Hemodialysis SO MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; LONG-TERM HEMODIALYSIS; ABDOMINAL AORTIC CALCIFICATION; CARDIOVASCULAR-DISEASE; DIALYSIS PATIENTS; VASCULAR CALCIFICATION; ALL-CAUSE; MAINTENANCE HEMODIALYSIS; CLINICAL EPIDEMIOLOGY; MITRAL-VALVE AB Studies of multiple hearts at necropsy are lacking in patients who have been on chronic hemodialysis for chronic kidney disease (CKD). We studied at necropsy 120 patients who had been treated with hemodialysis for more than 1 year (mean, 5.25 +/- 4.33 yr). Their ages ranged from 24 to 81 years (mean, 53 yr); 91 (76%) were men. Calcific deposits were present in the heart at necropsy in 74 (62%) patients: in the epicardial coronary arteries in all 74 (62%); in the mitral annular region in 52 (42%) patients, and in the aortic valve cusps in 42 (35%) patients. The frequency and quantity of the cardiac calcific deposits were significantly greater in the older compared with the younger patients, and in those with longer durations of hemodialysis compared with those with shorter durations. Despite the calcific deposits, which were sometimes huge, only 47 (39%) patients had 1 or more coronary arteries narrowed more than 75% in cross-sectional area by atherosclerotic plaques, apparently no patient had clinical evidence of mitral stenosis, and 9 patients had clinical evidence of aortic valve stenosis. Thus, we found that CKD treated with hemodialysis is a major producer of cardiac calcific deposits, some of which can be massive. Only a minority of the calcific deposits, however, appeared to lead to cardiac dysfunction or myocardial ischemia during life. C1 [Roberts, William C.] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX 75246 USA. [Roberts, William C.; Taylor, Marc A.; Shirani, Jamshid] NHLBI, NIH, Bethesda, MD 20892 USA. RP Roberts, WC (reprint author), Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, 3500 Gaston Ave,Suite H-030, Dallas, TX 75246 USA. EM wc.roberts@baylorhealth.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; Baylor Health Care System Foundation, Dallas, TX FX This study was supported by the National Heart, Lung, and Blood Institute, Intramural Program, National Institutes of Health, Bethesda, MD; and the Baylor Health Care System Foundation, Dallas, TX. NR 55 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD MAY PY 2012 VL 91 IS 3 BP 165 EP 178 DI 10.1097/MD.0b013e318256e076 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 936QK UT WOS:000303604900006 PM 22549132 ER PT J AU Wu, MX Yu, KF Liu, AY Ma, TF AF Wu, Mi-Xia Yu, Kai-Fun Liu, Aiyi Ma, Tie-Feng TI Simultaneous optimal estimation in linear mixed models SO METRIKA LA English DT Article DE Least squares estimator; Analysis of variance estimator; Minimum variance unbiased estimator; Linear mixed model ID VARIANCE AB Simultaneous optimal estimation in linear mixed models is considered. A necessary and sufficient condition is presented for the least squares estimator of the fixed effects and the analysis of variance estimator of the variance components to be of uniformly minimum variance simultaneously in a general variance components model. That is, the matrix obtained by orthogonally projecting the covariance matrix onto the orthogonal complement space of the column space of the design matrix is symmetric, each eigenvalue of the matrix is a linear combinations of the variance components and the number of all distinct eigenvalues of the matrix is equal to the the number of the variance components. Under this condition, uniformly optimal unbiased tests and uniformly most accurate unbiased confidence intervals are constructed for the parameters of interest. A necessary and sufficient condition is also given for the equivalence of several common estimators of variance components. Two examples of their application are given. C1 [Wu, Mi-Xia] Beijing Univ Technol, Coll Appl Sci, Beijing 100124, Peoples R China. [Yu, Kai-Fun; Liu, Aiyi] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. [Ma, Tie-Feng] SW Univ Finance & Econ, Sch Stat, Chengdu 611130, Sichuan, Peoples R China. RP Wu, MX (reprint author), Beijing Univ Technol, Coll Appl Sci, Beijing 100124, Peoples R China. EM wumixia@bjut.edu.cn OI Liu, Aiyi/0000-0002-6618-5082 FU National Natural Science Foundation of China [10801005, 11026214]; Natural Science Foundation of Beijing [1102010]; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry; Training Programme Foundation for the Beijing Municipal Excellent Talents [PYZZ090421001156]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Wu's research is partially supported by National Natural Science Foundation of China (10801005, 11026214), Natural Science Foundation of Beijing (1102010), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and Training Programme Foundation for the Beijing Municipal Excellent Talents (PYZZ090421001156). Research of A. Liu and K. F. Yu is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors are grateful to the two referees for their detailed suggestions which considerably improved the quality of the paper. NR 22 TC 1 Z9 2 U1 0 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0026-1335 J9 METRIKA JI Metrika PD MAY PY 2012 VL 75 IS 4 BP 471 EP 489 DI 10.1007/s00184-010-0337-1 PG 19 WC Statistics & Probability SC Mathematics GA 935GZ UT WOS:000303508400003 ER PT J AU Ebmeier, SE Tan, IS Clapham, KR Ramamurthi, KS AF Ebmeier, Sarah E. Tan, Irene S. Clapham, Katie Rose Ramamurthi, Kumaran S. TI Small proteins link coat and cortex assembly during sporulation in Bacillus subtilis SO MOLECULAR MICROBIOLOGY LA English DT Article ID SPORE COAT; SUBCELLULAR-LOCALIZATION; MORPHOGENETIC PROTEIN; PEPTIDOGLYCAN SYNTHESIS; ASPOROGENOUS MUTANTS; TRANSCRIPTION FACTOR; ENDOSPORE FORMATION; GENE; MEMBRANE; CLONING AB Mature spores of the bacterium Bacillus subtilis are encased by two concentric shells: an inner shell (the cortex), made of peptidoglycan; and an outer proteinaceous shell (the coat), whose basement layer is anchored to the surface of the developing spore via a 26-amino-acid-long protein called SpoVM. During sporulation, initiation of cortex assembly depends on the successful initiation of coat assembly, but the mechanisms that co-ordinate the morphogenesis of both structures are largely unknown. Here, we describe a sporulation pathway involving SpoVM and a 37-amino-acid-long protein named CmpA that is encoded by a previously un-annotated gene and is expressed under control of two sporulation-specific transcription factors (sE and SpoIIID). CmpA localized to the surface of the developing spore and deletion of cmpA resulted in cells progressing through the sporulation programme more quickly. Overproduction of CmpA did not affect normal growth or cell division, but delayed entry into sporulation and abrogated cortex assembly. In those cells that had successfully initiated coat assembly, CmpA was removed by a post-translational mechanism, presumably in order to overcome the sporulation inhibition it imposed. We propose a model in which CmpA participates in a developmental checkpoint that ensures the proper orchestration of coat and cortex morphogenesis by repressing cortex assembly until coat assembly successfully initiates. C1 [Ebmeier, Sarah E.; Tan, Irene S.; Clapham, Katie Rose; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Tan, Irene S.] Johns Hopkins Univ, NIH, Grad Partnerships Program, Baltimore, MD 21218 USA. RP Ramamurthi, KS (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ramamurthiks@mail.nih.gov RI Ramamurthi, Kumaran/P-3516-2015 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank S. Gottesman, D. Popham, V. Lee and members of the laboratory for comments on the manuscript; R. Losick for helpful discussion and advice; N. Majdalani and A. Battesti for training; K. Nagashima of the Electron Microscopy Laboratory (NCI Frederick) for assistance with electron microscopy; and the anonymous reviewer who notified us about the SpoIIID binding site upstream of cmpA. This work was funded by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 66 TC 15 Z9 15 U1 2 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2012 VL 84 IS 4 BP 682 EP 696 DI 10.1111/j.1365-2958.2012.08052.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 936MO UT WOS:000303594700007 PM 22463703 ER PT J AU Morgan, RA AF Morgan, Richard A. TI Human Tumor Xenografts: The Good, the Bad, and the Ugly SO MOLECULAR THERAPY LA English DT Editorial Material ID MOUSE MODELS; NUDE-MOUSE; MICE; CANCER; CELLS; METASTASIS C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Bldg 10,CRC Room 3-5940,10 Ctr Dr,MSC1201, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov NR 23 TC 8 Z9 8 U1 0 U2 2 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 MAY PY 2012 VL 20 IS 5 BP 882 EP 884 DI 10.1038/mt.2012.73 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YS UT WOS:000303484300002 PM 22549804 ER PT J AU Kariko, K Muramatsu, H Keller, JM Weissman, D AF Kariko, Katalin Muramatsu, Hiromi Keller, Jason M. Weissman, Drew TI Increased Erythropoiesis in Mice Injected With Submicrogram Quantities of Pseudouridine-containing mRNA Encoding Erythropoietin SO MOLECULAR THERAPY LA English DT Article ID RED-CELL APLASIA; GENE-THERAPY; ANTIERYTHROPOIETIN ANTIBODIES; RECOMBINANT ERYTHROPOIETIN; NUCLEOSIDE MODIFICATIONS; AUTOIMMUNE ANEMIA; VACCINATION TRIAL; T-CELLS; EXPRESSION; ACTIVATION AB Advances in the optimization of in vitro-transcribed mRNA are bringing mRNA-mediated therapy closer to reality. In cultured cells, we recently achieved high levels of translation with high-performance liquid chromatography (HPLC)-purified, in vitro-transcribed mRNAs containing the modified nucleoside pseudouridine. Importantly, pseudouridine rendered the mRNA non-immunogenic. Here, using erythropoietin (EPO)-encoding mRNA complexed with TransIT-mRNA, we evaluated this new generation of mRNA in vivo. A single injection of 100 ng (0.005 mg/kg) mRNA elevated serum EPO levels in mice significantly by 6 hours and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10-100-fold lower levels of EPO lasting only 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. As little as 1 0 ng mRNA doubled reticulocyte numbers. Weekly injection of 100 ng of EPO mRNA was sufficient to increase the hematocrit from 43 to 57%, which was maintained with continued treatment. Even when a large amount of pseudouridine-mRNA was injected, no inflammatory cytokines were detectable in plasma. Using macaques, we could also detect significantly-increased serum EPO levels following intraperitoneal injection of rhesus EPO mRNA. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications. C1 [Kariko, Katalin; Muramatsu, Hiromi] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Keller, Jason M.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Weissman, Drew] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Kariko, K (reprint author), Univ Penn, Dept Neurosurg, 36th & Hamilton Walk, Philadelphia, PA 19104 USA. EM kariko@mail.med.upenn.edu FU National Institutes of Health [R01NS029331, R42HL87688, R01AI50484, R21DE019059] FX We thank Houping Ni for technical assistance, Magdolna Sebestyen (Roche Madison, Madison, WI) for advice on the macaque study, and Mark Lewis and Bioqual, Inc, Rockville, MD for performing the macaque studies. This work was supported by National Institutes of Health (grant number R01NS029331 and R42HL87688 to K.K.; R01AI50484 and R21DE019059 to D.W.). K.K. and D.W. have formed a small biotech company RNARx that receives funding from the National Institutes of Health (R42HL87688) to explore the use of nucleoside-modified mRNA for gene therapy. NR 34 TC 63 Z9 65 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 MAY PY 2012 VL 20 IS 5 BP 948 EP 953 DI 10.1038/mt.2012.7 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YS UT WOS:000303484300010 PM 22334017 ER PT J AU Neschadim, A Wang, JCM Sato, T Fowler, DH Lavie, A Medin, JA AF Neschadim, Anton Wang, James C. M. Sato, Takeya Fowler, Daniel H. Lavie, Arnon Medin, Jeffrey A. TI Cell Fate Control Gene Therapy Based on Engineered Variants of Human Deoxycytidine Kinase SO MOLECULAR THERAPY LA English DT Article ID VIRUS-THYMIDINE KINASE; DONOR T-CELLS; SUICIDE GENE; THYMIDYLATE SYNTHASE; GANCICLOVIR RESISTANCE; VARICELLA-ZOSTER; STRUCTURAL BASIS; FUSION PROTEIN; SAFETY SWITCH; HOST-DISEASE AB The safety of cell therapy applications can be enhanced by the introduction of Cell Fate Control (CFC) elements, which encode pharmacologically controlled cellular suicide switches. CFC Gene Therapy (CFCGT) offers the possibility of establishing control over gene-modified cells (GMCs) with regards to their proliferation, differentiation, or function. However, enzymes commonly employed in these approaches often possess poor kinetics and high immunogenicity. We describe a novel CFCGT system based on engineered variants of human deoxyCytidine Kinase (dCK) that overcomes limitations of current modalities. Mutants of dCK with rationally designed active sites that make them thymidine-activating were stably introduced into cells by recombinant lentiviral vectors (LVs). Transduced cells maintained growth kinetics and function. These dCK mutants efficiently activate bromovinyl-deoxyuridine (BVdU), L-deoxythymidine (LdT), and L-deoxyuridine (LdU), which are otherwise not toxic to wild-type cells. We show that mutant dCK-expressing Jurkat, Molt-4, and U87mg cells could be efficiently eliminated in vitro and in xenogeneic leukemia and tumor models in vivo. We also describe a fusion construct of the thymidine-activating dCK to the cytoplasmic tail-truncated LNGFR molecule and applications to in vivo eradication of primary human T cells. This novel CFCGT system offers unique plasticity with respect to the wide range of prodrugs it can potentiate, and can be used as a reliable safety switch in cell and gene therapy. C1 [Medin, Jeffrey A.] Univ Hlth Network, Toronto, ON M5G 2M1, Canada. [Neschadim, Anton; Medin, Jeffrey A.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Wang, James C. M.; Medin, Jeffrey A.] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. [Sato, Takeya] Tohoku Univ, Sendai, Miyagi 980, Japan. [Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Lavie, Arnon] Univ Illinois, Chicago, IL USA. RP Medin, JA (reprint author), Univ Hlth Network, 67 Coll St,4th Floor,Room 406, Toronto, ON M5G 2M1, Canada. EM jmedin@uhnres.utoronto.ca RI Lavie, Arnon/H-4927-2012; OI Neschadim, Anton/0000-0003-1750-9703 FU CIHR FX The authors acknowledge Sean P. Devine (Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada), Matthew Scaife (Department of Medical Biophysics, University of Toronto), and Orlay Lopez-Perez (University Health Network) for their assistance with methods development. Funding for A.N. was provided by the CIHR Training Program in Regenerative Medicine (TPRM). The authors declared no conflict of interest. NR 51 TC 9 Z9 10 U1 0 U2 2 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 MAY PY 2012 VL 20 IS 5 BP 1002 EP 1013 DI 10.1038/mt.2011.298 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YS UT WOS:000303484300016 PM 22273576 ER PT J AU Abate-Daga, D Rosenberg, SA Morgan, RA AF Abate-Daga, Daniel Rosenberg, Steven A. Morgan, Richard A. TI Analysis of Gene Expression in Adoptively Transferred TCR-Engineered Lymphocytes SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Abate-Daga, Daniel; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 190 BP S75 EP S75 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600191 ER PT J AU Barese, CN Krouse, AE Metzger, ME Sellers, S Spenser, D Farrell, T Di Stasi, AB Donahue, RE Brenner, MK Dunbar, CE AF Barese, Cecilia N. Krouse, Allen E. Metzger, Mark E. Sellers, Stephanie Spenser, David Farrell, Tom Di Stasi, Antonio B. Donahue, Robert E. Brenner, Malcom K. Dunbar, Cynthia E. TI Inducible Caspase 9 as Safety Switch in Gene Therapies Targeting Hematopoietic Stem Cells SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Barese, Cecilia N.; Krouse, Allen E.; Metzger, Mark E.; Sellers, Stephanie; Donahue, Robert E.; Dunbar, Cynthia E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Di Stasi, Antonio B.; Brenner, Malcom K.] Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 MAY PY 2012 VL 20 SU 1 MA 218 BP S85 EP S86 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600219 ER PT J AU Barrett, JA Weber, G Gerdemann, U Kerkar, S Muranski, P Hensel, NF Leen, A Melenhorst, JJ Bollard, CM AF Barrett, John A. Weber, Gerrit Gerdemann, Ulrike Kerkar, Sid Muranski, Pawel Hensel, Nancy F. Leen, Ann Melenhorst, Jos J. Bollard, Cath M. TI Donor T Cells Specific for Multiple Leukemia Antigens for Adoptive Immunotherapy of Myeloid Leukemias after Stem Cell Transplantation SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Barrett, John A.; Weber, Gerrit; Kerkar, Sid; Muranski, Pawel; Hensel, Nancy F.; Melenhorst, Jos J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Gerdemann, Ulrike; Leen, Ann; Bollard, Cath M.] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 532 BP S205 EP S205 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600532 ER PT J AU Bauer, TR Tuschong, LM Russell, DW Hickstein, DD AF Bauer, Thomas R., Jr. Tuschong, Laura M. Russell, David W. Hickstein, Dennis D. TI Efficacy and Safety of the Foamy Viral Vector Delta Phi MscvCD18 in Long-Term Follow-Up (4-6 years) of Four Dogs with Canine Leukocyte Adhesion Deficiency SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Bauer, Thomas R., Jr.; Tuschong, Laura M.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Russell, David W.] Univ Washington, Div Hematol, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 MAY PY 2012 VL 20 SU 1 MA 221 BP S87 EP S87 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600222 ER PT J AU Cecchini, S Virag, T Kotin, R AF Cecchini, Sylvain Virag, Tamas Kotin, Robert TI Reproducible and Scalable Production Processes of Recombinant Adeno-Associated Virus Compatible with Current Good Manufacturing Practice SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Cecchini, Sylvain; Virag, Tamas; Kotin, Robert] NHLBI, Mol Virol & Gene Therapy Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 MAY PY 2012 VL 20 SU 1 MA 588 BP S228 EP S228 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600588 ER PT J AU Chandler, RJ Venditti, CP AF Chandler, Randy J. Venditti, Charles P. TI Demonstration of Pre-Clinical Efficacy of rAAV8 Gene Transfer as a Treatment for Methylmalonic Acidemia Using a Vector Suitable for Human Clinical Trials SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Chandler, Randy J.; Venditti, Charles P.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 145 BP S58 EP S58 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600146 ER PT J AU Choi, U Koontz, S Malech, HL AF Choi, Uimook Koontz, Sherry Malech, Harry L. TI Comparison of Different Internal Promoter Performance in the CL20 SIN HIV Lentivector Used To Correct Human X-Linked Chronic Granulomatous Disease as Evaluated Ex Vivo and in NSG Mice Transplanted with Transduced Patient CD34+Stem Cells SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Choi, Uimook; Koontz, Sherry; Malech, Harry L.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 7 BP S3 EP S4 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600008 ER PT J AU Cruz, C Micklethwaite, K Savoldo, B Ku, S Krance, R Diouf, O Kamble, R Kennedy-Nasser, A Barrett, J Shpall, E Heslop, H Rooney, C Brenner, M Bollard, C Dotti, G AF Cruz, Conrad Micklethwaite, Kenneth Savoldo, Barbara Ku, Stephanie Krance, Robert Diouf, Oumar Kamble, Rammurti Kennedy-Nasser, Alana Barrett, John Shpall, Elizabeth Heslop, Helen Rooney, Cliona Brenner, Malcolm Bollard, Catherine Dotti, Gianpietro TI Infusion of CD19-Directed/Multivirus-Specific CTLs Post HSCT for B Cell Malignancies SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Cruz, Conrad; Micklethwaite, Kenneth; Savoldo, Barbara; Ku, Stephanie; Krance, Robert; Diouf, Oumar; Kamble, Rammurti; Kennedy-Nasser, Alana; Heslop, Helen; Rooney, Cliona; Brenner, Malcolm; Bollard, Catherine; Dotti, Gianpietro] Texas Childrens Hosp, Baylor Coll Med, Methodist Hosp, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Barrett, John] NHLBI, NIH, Bethesda, MD 20892 USA. [Shpall, Elizabeth] UT MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2012 VL 20 SU 1 MA 536 BP S207 EP S207 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600536 ER PT J AU Donsante, A Haddad, MR Kaler, SG AF Donsante, Anthony Haddad, Marie Reine Kaler, Stephen G. TI Directed Evolution To Create Choroid Plexus-Permissive AAV Capsid Variants: Toward Novel Clinical Management of Lysosomal Storage Disorders SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Donsante, Anthony] NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 591 BP S229 EP S229 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600591 ER PT J AU Haddad, MR Zerfas, PM Donsante, A Kaler, SG AF Haddad, Marie Reine Zerfas, Patricia M. Donsante, Anthony Kaler, Stephen G. TI In Utero Brain-Directed AAV5 Gene Therapy Results in Rapid, Robust, and Specific Transduction of Choroid Plexus Epithelia: Implications for Rescue of Prenatal Lethal Mouse Models of Neurometabolic Disease SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Haddad, Marie Reine; Donsante, Anthony; Kaler, Stephen G.] NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2012 VL 20 SU 1 MA 164 BP S66 EP S66 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600165 ER PT J AU Hunter, MJ Zhao, HF Tuschong, LM Kapoor, V Burkholder, TH Persons, DA Hickstein, DD AF Hunter, Michael J. Zhao, Huifen Tuschong, Laura M. Kapoor, Veena Burkholder, Tanya H. Persons, Derek A. Hickstein, Dennis D. TI Human Versus Murine Phosphoglycerate Kinase (PGK) Promoter/Enhancer in Canine Leukocyte Adhesion Deficiency SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Hunter, Michael J.; Tuschong, Laura M.; Kapoor, Veena; Hickstein, Dennis D.] NCI, NIH, Bethesda, MD 20892 USA. [Zhao, Huifen; Persons, Derek A.] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA. [Burkholder, Tanya H.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 141 BP S57 EP S57 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600142 ER PT J AU Ikawa, Y Uchiyama, T Jagadeesh, J Candotti, F AF Ikawa, Yasuhiro Uchiyama, Toru Jagadeesh, Jayashree Candotti, Fabio TI Comparison of Safety and Effectiveness between Gamma-Retroviral, Lentiviral and Foamy Virus Gene Transfer Vectors SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Ikawa, Yasuhiro; Uchiyama, Toru; Jagadeesh, Jayashree; Candotti, Fabio] NHGRI, GMBB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 493 BP S191 EP S191 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600493 ER PT J AU Kouprina, N AF Kouprina, Natalay TI Human Artificial Chromosome (HAC) Vector with a Conditional Centromere for Correction of Genetic Deficiencies in Human Cells SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Kouprina, Natalay] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 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 MAY PY 2012 VL 20 SU 1 MA 124 BP S50 EP S51 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600125 ER PT J AU Lee, YM Jun, HS Pan, CJ Lin, SR Wilson, LH Mansfield, BC Chou, JY AF Lee, Young Mok Jun, Hyun Sik Pan, Chi-Jiunn Lin, Su Ru Wilson, Lane H. Mansfield, Brian C. Chou, Janice Y. TI Prevention of Hepatocellular Adenoma and Correction of Metabolic Abnormalities in Murine Glycogen Storage Disease Type la by Gene Therapy SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Lee, Young Mok; Jun, Hyun Sik; Pan, Chi-Jiunn; Lin, Su Ru; Wilson, Lane H.; Mansfield, Brian C.; Chou, Janice Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Bethesda, MD USA. RI Jun, Hyun Sik/C-6799-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 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 MAY PY 2012 VL 20 SU 1 MA 132 BP S53 EP S54 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600133 ER PT J AU Li, LN Levy, JR Yang, Y Dimitriadis, EK Garcia, L Kotin, RM AF Li, Lina Levy, Justin R. Yang, Yu Dimitriadis, Emilios K. Garcia, Luis Kotin, Robert M. TI Closed-Ended Linear Duplex AAV (celdAAV) DNA for Non-Viral Gene Transfer SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Li, Lina; Levy, Justin R.; Yang, Yu; Kotin, Robert M.] NHLBI, Mol Virol & Gene Therapy Lab, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Garcia, Luis] INSERM, U974, Inst Myol, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 613 BP S236 EP S236 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600611 ER PT J AU Mingozzi, F Chen, YF Zhou, SZ Murphy, S Mezger, M Donahue, R Wright, F Dunbar, C High, K AF Mingozzi, Federico Chen, Yifeng Zhou, Shangzhen Murphy, Samuel Mezger, Mark Donahue, Robert Wright, Fraser Dunbar, Cynthia High, Katherine TI Pharmacological Modulation of Humoral Immunity in a Non-Human Primate Model of AAV Gene Transfer for Hemophilia B SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Mingozzi, Federico; Chen, Yifeng; Zhou, Shangzhen; Murphy, Samuel; Wright, Fraser; High, Katherine] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Chen, Yifeng; High, Katherine] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Mezger, Mark; Donahue, Robert; Dunbar, Cynthia] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 556 BP S215 EP S215 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600556 ER PT J AU Senac, JS Sysol, JR Venditti, CP AF Senac, Julien S. Sysol, Justin R. Venditti, Charles P. TI Hepatocyte Therapy for MUT Methylmalonic Acidemia SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Senac, Julien S.; Sysol, Justin R.; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 146 BP S59 EP S59 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600147 ER PT J AU Shaw, KL Sokolic, R Mishra, S Geiger, S Garabedian, E de Oliveira, S Carbonaro, DA Muul, L Silvin, C Jagadeesh, J Fu, PY Crooks, GM Moore, T Candotti, F Kohn, DB AF Shaw, Kit L. Sokolic, Robert Mishra, Suparna Geiger, Sabine Garabedian, Elizabeth de Oliveira, Satiro Carbonaro, Denise A. Muul, Linda Silvin, Chris Jagadeesh, Jayashree Fu, Pei-Yu Crooks, Gay M. Moore, Theodore Candotti, Fabio Kohn, Donald B. TI Update on the US Clinical Gene Therapy Trial for Adenosine Deaminase Deficient Severe Combined Immune Deficiency (ADA-SCID) SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Shaw, Kit L.; Mishra, Suparna; Geiger, Sabine; de Oliveira, Satiro; Carbonaro, Denise A.; Fu, Pei-Yu; Crooks, Gay M.; Moore, Theodore; Kohn, Donald B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Sokolic, Robert; Garabedian, Elizabeth; Muul, Linda; Silvin, Chris; Jagadeesh, Jayashree; Candotti, Fabio] NHGRI, NIH, Bethesda, MD 20892 USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 0 Z9 0 U1 0 U2 5 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 MAY PY 2012 VL 20 SU 1 MA 53 BP S22 EP S22 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600054 ER PT J AU Sweeney, CL Merling, RK Choi, U Wang, HM Holland, SM Malech, HL AF Sweeney, Colin L. Merling, Randall K. Choi, Uimook Wang, Hongmei Holland, Steven M. Malech, Harry L. TI Extreme Skewing of X-Chromosome Inactivation in Female Carriers of X-CGD Can Be Reversed during iPSC Reprogramming To Restore Neutrophil Function SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Sweeney, Colin L.; Merling, Randall K.; Choi, Uimook; Wang, Hongmei; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 566 BP S219 EP S220 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600566 ER PT J AU Templeton, NS Ko, E Burgess, K Phalon, C Chen, L Roberts, DD Jay, CM Brunicardi, FC Maples, PB Senzer, N Nemunaitis, J AF Templeton, Nancy S. Ko, Eunhwa Burgess, Kevin Phalon, Connor Chen, Li Roberts, David D. Jay, Chris M. Brunicardi, F. C. Maples, Phillip B. Senzer, Neil Nemunaitis, John TI Recent Advances Using Small Molecule Targeting for Bilamellar Invaginated Vesicle (BIV) Delivery SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Templeton, Nancy S.; Phalon, Connor; Chen, Li; Jay, Chris M.; Maples, Phillip B.; Senzer, Neil; Nemunaitis, John] Gradalis Inc, Dallas, TX USA. [Ko, Eunhwa; Burgess, Kevin] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. [Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Brunicardi, F. C.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Senzer, Neil; Nemunaitis, John] Mary Crowley Canc Res Ctr, Dallas, TX USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 398 BP S155 EP S156 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600399 ER PT J AU Uchida, N Tisdale, JF AF Uchida, Naoya Tisdale, John F. TI A Hematopoietic Stem Cell Expansion Medium Increased Transduction Efficiency for Human CD34+Cells SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Uchida, Naoya; Tisdale, John F.] NHLBI, MCHB, NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2012 VL 20 SU 1 MA 494 BP S191 EP S192 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600494 ER PT J AU Wellman, JA Mingozzi, F Ozelo, MC Arruda, V Podsakoff, G Chen, YF Konkle, BA Blatt, PM Hoots, K Raffini, LJ Rasko, J Ragni, MV High, KA AF Wellman, Jennifer A. Mingozzi, Federico Ozelo, Margareth C. Arruda, Valder Podsakoff, Greg Chen, Yifeng Konkle, Barbara A. Blatt, Philip M. Hoots, Keith Raffini, Leslie J. Rasko, John Ragni, Margaret V. High, Katherine A. TI Results from the Long-Term Follow-Up of Severe Hemophilia B Subjects Previously Enrolled in a Clinical Study of AAV2-FIX Gene Transfer to the Liver SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Wellman, Jennifer A.; Mingozzi, Federico; Arruda, Valder; Podsakoff, Greg; Chen, Yifeng; High, Katherine A.] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA USA. [Ozelo, Margareth C.] Univ Estadual Campinas, Campinas, Brazil. [Konkle, Barbara A.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Blatt, Philip M.] Duke Univ, Durham, NC USA. [Hoots, Keith] NHLBI, NIH, Bethesda, MD 20892 USA. [Rasko, John] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Ragni, Margaret V.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [High, Katherine A.] HHMI, Chevy Chase, MD USA. RI Ozelo, Margareth/K-5819-2012 OI Ozelo, Margareth/0000-0001-5938-0675 NR 0 TC 3 Z9 3 U1 0 U2 3 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 MAY PY 2012 VL 20 SU 1 MA 69 BP S28 EP S29 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600070 ER PT J AU Yang, SC Karne, NK Goff, SL Black, MA Xu, H Bischof, D Cornetta, K Rosenberg, SA Morgan, RA Feldman, SA AF Yang, Shicheng Karne, Neel K. Goff, Stephanie L. Black, Mary A. Xu, Hui Bischof, Daniela Cornetta, Kenneth Rosenberg, Steven A. Morgan, Richard A. Feldman, Steven A. TI A Simple and Effective Method To Generate Lentiviral Vectors for Ex Vivo Gene Delivery to Mature Human Peripheral Blood Lymphocytes SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Yang, Shicheng; Karne, Neel K.; Goff, Stephanie L.; Black, Mary A.; Xu, Hui; Rosenberg, Steven A.; Morgan, Richard A.; Feldman, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Yang, Shicheng] Duke Univ, Dept Surg, Durham, NC USA. [Karne, Neel K.] SUNY Upstate Med Univ, Dept Surg Gen Surg, Syracuse, NY USA. [Goff, Stephanie L.] Columbia Univ, Dept Surg, New York, NY USA. [Bischof, Daniela; Cornetta, Kenneth] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Cornetta, Kenneth] Indiana Univ Sch Med, Dept Immunol & Microbiol, Indianapolis, IN USA. [Cornetta, Kenneth] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 MAY PY 2012 VL 20 SU 1 MA 753 BP S290 EP S290 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600748 ER PT J AU Zhang, JY Thorgeirsson, SS Jessup, JM AF Zhang, Jingyu Thorgeirsson, Snorri S. Jessup, J. Milburn TI Allele-Specific Inhibition of Nanog Family Members Inhibits Three-Dimensional (3-D) Growth of Human Colorectal Carcinoma (CRC) In Vitro SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Zhang, Jingyu; Thorgeirsson, Snorri S.; Jessup, J. Milburn] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 473 BP S184 EP S184 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600474 ER PT J AU Zhang, L Zheng, ZL Yu, ZY Dudley, ME Falgout, JA Restifo, NP Rosenberg, SA Morgan, RA AF Zhang, Ling Zheng, Zhili Yu, Zhiya Dudley, Mark E. Falgout, Jeffery A. Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. TI TGF-beta as a Modifier of Response to Adoptive Cell Therapy for Melanoma: Enhanced Tumor Treatment in Animal Models and a Highly Significant Correlation between Clinical Response and TGF-beta Genotypes SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Zhang, Ling; Zheng, Zhili; Yu, Zhiya; Dudley, Mark E.; Falgout, Jeffery A.; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.] NIH, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 20 SU 1 MA 534 BP S206 EP S206 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600534 ER PT J AU Zou, JZ Sweeney, CL Malech, HL Cheng, LZ AF Zou, Jizhong Sweeney, Colin L. Malech, Harry L. Cheng, Linzhao TI Generation of Integration-Free iPSCs from an X-CGD Patient's Blood Cells as Clinically Relevant Target for Gene-Repair Using Designer ZFN or TALEN SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 16-19, 2012 CL Philadelphia, PA SP Amer Soc Gene & Cell Therapy (ASGCT) C1 [Zou, Jizhong; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Sweeney, Colin L.; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 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 MAY PY 2012 VL 20 SU 1 MA 280 BP S110 EP S111 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 934YU UT WOS:000303484600281 ER PT J AU Clarke, L Zheng-Bradley, X Smith, R Kulesha, E Xiao, CL Toneva, I Vaughan, B Preuss, D Leinonen, R Shumway, M Sherry, S Flicek, P AF Clarke, Laura Zheng-Bradley, Xiangqun Smith, Richard Kulesha, Eugene Xiao, Chunlin Toneva, Iliana Vaughan, Brendan Preuss, Don Leinonen, Rasko Shumway, Martin Sherry, Stephen Flicek, Paul CA 1000 Genomes Project Consortium TI The 1000 Genomes Project: data management and community access SO NATURE METHODS LA English DT Article ID VARIANTS; FORMAT AB The 1000 Genomes Project was launched as one of the largest distributed data collection and analysis projects ever undertaken in biology. In addition to the primary scientific goals of creating both a deep catalog of human genetic variation and extensive methods to accurately discover and characterize variation using new sequencing technologies, the project makes all of its data publicly available. Members of the project data coordination center have developed and deployed several tools to enable widespread data access. C1 [Clarke, Laura; Zheng-Bradley, Xiangqun; Smith, Richard; Kulesha, Eugene; Toneva, Iliana; Vaughan, Brendan; Leinonen, Rasko; Flicek, Paul] European Bioinformat Inst, Cambridge, England. [Xiao, Chunlin; Preuss, Don; Shumway, Martin; Sherry, Stephen] US Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD USA. RP Flicek, P (reprint author), European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge, England. EM flicek@ebi.ac.uk RI Khurana, Ekta/C-4933-2013; Ding, Jun/G-3918-2011; Altshuler, David/A-4476-2009; Rosenstiel, Philip/A-5137-2009; Ye, Kai/B-3640-2012; Myers, Simon/A-6792-2015; Browning, Brian/A-1178-2010; Dahl, Andreas/E-3783-2017; OI Hinrichs, Angie/0000-0002-1697-1130; Keane, Thomas/0000-0001-7532-6898; Zheng Bradley, Xiangqun/0000-0002-9324-2708; Sebat, Jonathan/0000-0002-9087-526X; Leinonen, Rasko/0000-0002-2639-7187; Haraksingh, Rajini/0000-0002-6644-8874; Vaughan, Brendan/0000-0002-2199-1267; Herrero, Javier/0000-0001-7313-717X; Clarke, Laura/0000-0002-5989-6898; Flicek, Paul/0000-0002-3897-7955; McLaren, William/0000-0001-6218-1116; Walter, Klaudia/0000-0003-4448-0301; Keenan, Stephen/0000-0002-9141-7690; Altshuler, David/0000-0002-7250-4107; Rosenstiel, Philip/0000-0002-9692-8828; Myers, Simon/0000-0002-2585-9626; Browning, Brian/0000-0001-6454-6633; Dahl, Andreas/0000-0002-2668-8371; Kulesha, Eugene/0000-0002-4285-6232; Zalunin, Vadim/0000-0002-7722-1958; Radhakrishnan, Rajesh/0000-0001-7170-699X FU Wellcome Trust [WT085532]; European Molecular Biology Laboratory; US National Institutes of Health National Library of Medicine FX For early work and support to the DCC, we thank Z. Iqbal, H. Khouri, F. Cunningham, Y. Chen, W. McLaren, V. Zalunin, R. Radhakrishnan, D. Smirnov, J. Paschall, Z. Belaia, R. Sanders, C. O'Sullivan, S. Keenan, G. Ritchie and G. Cochrane. For maintenance of the EBI computer infrastructure, we acknowledge J. Barker, V. Silventoinen, G. Kellman and P. Jokinen. Funding support at the EBI is provided by the Wellcome Trust (grant WT085532) and the European Molecular Biology Laboratory. This research was supported in part by the Intramural Research Program of the US National Institutes of Health National Library of Medicine. NR 16 TC 92 Z9 96 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD MAY PY 2012 VL 9 IS 5 BP 1 EP 4 DI 10.1038/NMETH.1974 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 935TU UT WOS:000303544800021 PM 22543379 ER PT J AU Pajevic, S Plenz, D AF Pajevic, Sinisa Plenz, Dietmar TI The organization of strong links in complex networks SO NATURE PHYSICS LA English DT Article ID SMALL-WORLD NETWORKS; NEURONAL AVALANCHES; TOPOLOGY; WEAK AB Many complex systems reveal a small-world topology, which allows simultaneously local and global efficiency in the interaction between system constituents. Here, we report the results of a comprehensive study that investigates the relation between the clustering properties in such small-world systems and the strength of interactions between its constituents, quantified by the link weight. For brain, gene, social and language networks, we find a local integrative weight organization in which strong links preferentially occur between nodes with overlapping neighbourhoods; we relate this to global robustness of the clustering to removal of the weakest links. Furthermore, we identify local learning rules that establish integrative networks and improve network traffic in response to past traffic failures. Our findings identify a general organization for complex systems that strikes a balance between efficient local and global communication in their strong interactions, while allowing for robust, exploratory development of weak interactions. C1 [Pajevic, Sinisa] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Plenz, Dietmar] NIH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Pajevic, S (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM pajevic@nih.gov FU NIH of the NIMH; DCB/CIT FX We thank M. Boguna and members of the Section on Critical Brain Dynamics, NIMH, NIH, for constructive comments during this work. We also thank S. Yu for providing some of the monkey data and J. Alstott for Matlab implementation of one of the social network models. This work was supported by the NIH Intramural Research Program of the NIMH and the DCB/CIT. NR 41 TC 17 Z9 19 U1 0 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1745-2473 J9 NAT PHYS JI Nat. Phys. PD MAY PY 2012 VL 8 IS 5 BP 429 EP 436 DI 10.1038/NPHYS2257 PG 8 WC Physics, Multidisciplinary SC Physics GA 936OF UT WOS:000303599200025 ER PT J AU Maecker, HT McCoy, JP Nussenblatt, R AF Maecker, Holden T. McCoy, J. Philip Nussenblatt, Robert TI Reducing variability in flow cytometry SO NATURE REVIEWS IMMUNOLOGY LA English DT Letter C1 [Maecker, Holden T.] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [McCoy, J. Philip; Nussenblatt, Robert] Natl Inst Hlth, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [McCoy, J. Philip] Natl Heart Lung & Blood Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. [Nussenblatt, Robert] NEI, Natl Inst Hlth, Bethesda, MD 20893 USA. RP Maecker, HT (reprint author), Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. EM maecker@stanford.edu NR 4 TC 3 Z9 3 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD MAY PY 2012 VL 12 IS 5 DI 10.1038/nri3158-c2 PG 1 WC Immunology SC Immunology GA 933ET UT WOS:000303343300015 ER PT J AU Boyden, SE Mahoney, LJ Kawahara, G Myers, JA Mitsuhashi, S Estrella, EA Duncan, AR Dey, F DeChene, ET Blasko-Goehringer, JM Bonnemann, CG Darras, BT Mendell, JR Lidov, HGW Nishino, I Beggs, AH Kunkel, LM Kang, PB AF Boyden, Steven E. Mahoney, Lane J. Kawahara, Genri Myers, Jennifer A. Mitsuhashi, Satomi Estrella, Elicia A. Duncan, Anna R. Dey, Friederike DeChene, Elizabeth T. Blasko-Goehringer, Jessica M. Boennemann, Carsten G. Darras, Basil T. Mendell, Jerry R. Lidov, Hart G. W. Nishino, Ichizo Beggs, Alan H. Kunkel, Louis M. Kang, Peter B. TI Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores SO NEUROGENETICS LA English DT Article DE MEGF10; Whole genome sequencing; Linkage analysis; Congenital myopathy; Satellite cells; Cleft palate ID SKELETAL-MUSCLE REGENERATION; FIBER-TYPE DISPROPORTION; MUSCULAR-DYSTROPHY; ZEBRAFISH; DISEASE; PROTEIN; CED-1; IDENTIFICATION; SPECIFICATION; ORGANIZATION AB We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism. C1 [Darras, Basil T.; Kang, Peter B.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Boyden, Steven E.; Kunkel, Louis M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Boyden, Steven E.; Mahoney, Lane J.; Kawahara, Genri; Myers, Jennifer A.; Mitsuhashi, Satomi; Estrella, Elicia A.; Duncan, Anna R.; Dey, Friederike; DeChene, Elizabeth T.; Blasko-Goehringer, Jessica M.; Lidov, Hart G. W.; Beggs, Alan H.; Kunkel, Louis M.; Kang, Peter B.] Childrens Hosp, Div Genet, Program Genom, Boston, MA 02115 USA. [Boyden, Steven E.; Mahoney, Lane J.; Kawahara, Genri; Myers, Jennifer A.; Mitsuhashi, Satomi; Estrella, Elicia A.; Duncan, Anna R.; Dey, Friederike; DeChene, Elizabeth T.; Blasko-Goehringer, Jessica M.; Lidov, Hart G. W.; Beggs, Alan H.; Kunkel, Louis M.; Kang, Peter B.] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Mitsuhashi, Satomi; Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Dept Neuromuscular Res, Natl Inst Neurosci, Tokyo, Japan. [Boennemann, Carsten G.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Mendell, Jerry R.] Nationwide Childrens Hosp, Ctr Gene Therapy Res Inst, Columbus, OH USA. [Lidov, Hart G. W.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Beggs, Alan H.; Kunkel, Louis M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Kang, PB (reprint author), Childrens Hosp, Dept Neurol, 300 Longwood Ave, Boston, MA 02115 USA. EM peter.kang@childrens.harvard.edu OI Beggs, Alan/0000-0001-8818-0568; Nishino, Ichizo/0000-0001-9452-112X FU NIH [K08 NS048180, R01 AR044345, P50 NS40828]; Genise Goldenson Fund; Children's Hospital Boston; Muscular Dystrophy Association [186796, 201302]; Bernard F. and Alva B. Gimbel Foundation; Lee and Penny Anderson Family Foundation; Professor-Dr.Adolf-Schmidtmann-Stiftung; NIH through the Intellectual and Developmental Disabilities Research Center [P30 HD18655] FX The authors thank the patients and their families for their participation in this study, as well as Hal Schneider, Laura Moody, Susan Kim, Sachiko Kajino, Kanako Goto, and Yukiko Hayashi for technical assistance, Michael Lawlor and Pankaj Agrawal for helpful discussions, Fedik Rahimov for critical reading of the manuscript, and Timothy Yu and Christopher Walsh for contribution of control genome sequence data. This work was supported by NIH K08 NS048180 (PBK), the Genise Goldenson Fund (PBK), a Children's Hospital Boston Pilot Grant (PBK), Muscular Dystrophy Association Research Grants 186796 (PBK) and 201302 (AHB), the Bernard F. and Alva B. Gimbel Foundation (LMK), NIH R01 AR044345 (AHB), the Lee and Penny Anderson Family Foundation (AHB), and the Professor-Dr.-Adolf-Schmidtmann-Stiftung (FD). Microarray genotyping and Sanger DNA sequencing experiments were performed in the Molecular Genetics Core Facility at Children's Hospital Boston, supported by NIH P30 HD18655 through the Intellectual and Developmental Disabilities Research Center and NIH P50 NS40828 through the Neuromuscular Disease Project. Electron microscopy was performed at the Harvard Medical School EM Core Facility with the assistance of Maria Ericsson, Louise Trakimas, and Elizabeth Benecchi. NR 48 TC 18 Z9 20 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD MAY PY 2012 VL 13 IS 2 BP 115 EP 124 DI 10.1007/s10048-012-0315-z PG 10 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 933ZY UT WOS:000303408600002 PM 22371254 ER PT J AU Callacondo, D Garcia, HH Gonzales, I Escalante, D Nash, TE AF Callacondo, D. Garcia, H. H. Gonzales, I. Escalante, D. Nash, T. E. CA Cysticercosis Working Grp Peru TI High frequency of spinal involvement in patients with basal subarachnoid neurocysticercosis SO NEUROLOGY LA English DT Article ID EXTRAPARENCHYMAL NEUROCYSTICERCOSIS; FOLLOW-UP; CYSTICERCOSIS; DISEASE; HYDROCEPHALUS; THERAPY AB Objective: To determine the frequency of spinal neurocysticercosis (NCC) in patients with basal subarachnoid NCC compared with that in individuals with viable limited intraparenchymal NCC (<= 20 live cysts in the brain). Methods: We performed a prospective observational case-control study of patients with NCC involving the basal cisterns or patients with only limited intraparenchymal NCC. All patients underwent MRI examinations of the brain and the entire spinal cord to assess spinal involvement. Results: Twenty-seven patients with limited intraparenchymal NCC, and 28 patients with basal subarachnoid NCC were included in the study. Spinal involvement was found in 17 patients with basal subarachnoid NCC and in only one patient with limited intraparenchymal NCC (odds ratio 40.18, 95% confidence interval 4.74-340.31; p < 0.0001). All patients had extramedullary (intradural) spinal NCC, and the lumbosacral region was the most frequently involved (89%). Patients with extensive spinal NCC more frequently had ventriculoperitoneal shunt placement (7 of 7 vs 3 of 11; p = 0.004) and tended to have a longer duration of neurologic symptoms than those with regional involvement (72 months vs 24 months; p = 0.062). Conclusions: The spinal subarachnoid space is commonly involved in patients with basal subarachnoid NCC, compared with those with only intraparenchymal brain cysts. Spinal cord involvement probably explains serious late complications including chronic meningitis and gait disorders that were described before the introduction of antiparasitic therapy. MRI of the spine should be performed in basal subarachnoid disease to document spinal involvement, prevent complications, and monitor for recurrent disease. Neurology (R) 2012;78:1394-1400 C1 [Nash, T. E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Callacondo, D.] Univ Peruana Cayetano Heredia, Labs Invest & Desarrollo, Lima, Peru. [Callacondo, D.; Garcia, H. H.] Univ Peruana Cayetano Heredia, Dept Microbiol, Lima, Peru. [Garcia, H. H.] Univ Peruana Cayetano Heredia, Ctr Global Hlth Tumbes, Lima, Peru. [Garcia, H. H.; Gonzales, I.] Inst Nacl Ciencias Neurol, Dept Transmissible Dis, Cysticercosis Unit, Lima, Peru. [Escalante, D.] RESOCENTRO, Lima, Peru. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. EM tnash@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH; Fogarty International Center/NIH [D43 TW001140] FX Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, and by Fogarty International Center/NIH (Training Grant D43 TW001140). H.H.G. is now a Wellcome Trust International Senior Research Fellow. NR 28 TC 19 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY PY 2012 VL 78 IS 18 BP 1394 EP 1400 DI 10.1212/WNL.0b013e318253d641 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 935DB UT WOS:000303498000009 PM 22517102 ER PT J AU Bergman, HE Hunt, YM Augustson, E AF Bergman, Hannah E. Hunt, Yvonne M. Augustson, Erik TI Smokeless Tobacco Use in the United States Military: A Systematic Review SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID CARDIOVASCULAR-DISEASE; SMOKING-CESSATION; ORAL LEUKOPLAKIA; ACTIVE-DUTY; AIR-FORCE; DUAL-USE; PERSONNEL; POPULATION; RECRUITS; PREVALENCE AB Smokeless tobacco (ST) use represents an important target for intervention in the U.S. military population because it impairs "military readiness" and harms the health of the military. This paper aims to provide a systematic review of ST studies conducted in the U.S. military population in order to assess the content of existing ST research in this population, provide estimates of prevalence and clinically relevant use patterns, and discuss how these findings might be used to guide future ST research among this population. We reviewed articles published through December 2010 using PubMed and PsycINFO databases, Google Scholar, and any relevant articles' reference lists. Inclusion criteria included focus on a U.S. military sample, English language, measured tobacco use, and ST prevalence was reported or could be calculated. To the extent possible, each article was coded for demographics, socioeconomic status, prevalence, amount, frequency, and length of use, and quit intentions/attempts. Thirty-nine articles met criteria for inclusion. Less than half focused primarily on ST use among military personnel. The remaining studies measured ST use in the context of other behaviors. Findings related to clinically relevant behaviors included a need for more cohort and intervention studies, a better understanding of ST use in combination with cigarettes (i.e., concurrent use), and identifying risk factors for ST initiation and use. ST use is prevalent among military personnel, as is concurrent use of cigarettes and ST. We provide a number of recommendations to guide future research in this important, yet understudied, area. C1 [Bergman, Hannah E.; Hunt, Yvonne M.; Augustson, Erik] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Bergman, HE (reprint author), Case Western Reserve Univ, Dept Psychol Sci, Psychol Program, 11220 Belleflower Rd,Mather Mem 109, Cleveland, OH 44106 USA. EM hannah.bergman87@gmail.com FU NCI, National Institutes of Health FX The corresponding author was funded as a Cancer Research Training Award Fellow at the NCI, National Institutes of Health, from September 2009 to August 2011. NR 56 TC 1 Z9 1 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAY PY 2012 VL 14 IS 5 BP 507 EP 515 DI 10.1093/ntr/ntr216 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 933BS UT WOS:000303334800001 PM 22123789 ER PT J AU Huskins, WC Sullivan, CD Wang, J Aitken, M Alexander, SR Epstein, LG Hoberman, A Neufeld, E Philipps, A Shanley, TP Szilagyi, P Purucker, M Barkin, SL AF Huskins, W. Charles Sullivan, Clare D. Wang, Janey Aitken, Mary Alexander, Steven R. Epstein, Leon G. Hoberman, Alejandro Neufeld, Ellis Philipps, Anthony Shanley, Thomas P. Szilagyi, Peter Purucker, Mary Barkin, Shari L. TI Tracking the impact of the National Institutes of Health Clinical and Translational Science Awards on child health research: developing and evaluating a measurement strategy SO PEDIATRIC RESEARCH LA English DT Article ID SUPPORT C1 [Huskins, W. Charles] Mayo Clin, Div Pediat Infect Dis, Rochester, MN 55905 USA. [Sullivan, Clare D.; Wang, Janey] Vanderbilt Inst Clin & Translat Res, Nashville, TN USA. [Aitken, Mary] Arkansas Childrens Hosp Res Inst, Little Rock, AR USA. [Alexander, Steven R.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Epstein, Leon G.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hoberman, Alejandro] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. [Neufeld, Ellis] Childrens Hosp, Boston, MA 02115 USA. [Neufeld, Ellis] Harvard Univ, Sch Med, Boston, MA USA. [Philipps, Anthony] Univ Calif Davis, Dept Pediat, Sch Med, Sacramento, CA 95817 USA. [Shanley, Thomas P.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Szilagyi, Peter] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Purucker, Mary] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Barkin, Shari L.] Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN USA. RP Huskins, WC (reprint author), Mayo Clin, Div Pediat Infect Dis, Rochester, MN 55905 USA. EM huskins.charles@mayo.edu OI Huskins, W. Charles/0000-0002-9989-175X FU National Institutes of Health (NIH)/National Center for Research Resources [UL1 RR024150, UL1 RR024975, UL1 RR029884, UL1 RR025744, UL1 RR025741, UL1 RR024153, UL1 RR025758, UL1 RR024146, UL1 RR024986, UL1 RR024160] FX This publication was supported by National Institutes of Health (NIH)/National Center for Research Resources Clinical and Translational Science Award grant nos. UL1 RR024150 (Mayo Center for Translational Science Activities, Mayo Clinic); UL1 RR024975 (Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University); UL1 RR029884 (Arkansas Center for Clinical and Translational Research, University of Arkansas for Medical Sciences); UL1 RR025744 (The Stanford Center for Clinical and Translational Education and Research, Stanford University); UL1 RR025741 (Northwestern University Clinical and Translational Sciences Institute, Northwestern University); UL1 RR024153 (University of Pittsburgh Clinical and Translational Science Institute, University of Pittsburgh); UL1 RR025758 (Harvard Catalyst: The Harvard Clinical and Translational Science Center, Harvard University); UL1 RR024146 (UC Davis Clinical and Translational Science Center, University of California, Davis); UL1 RR024986 (Michigan Institute for Clinical and Health Research, University of Michigan at Ann Arbor); and UL1 RR024160 (University of Rochester Clinical and Translational Sciences Institute, University of Rochester School of Medicine and Dentistry). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 13 TC 3 Z9 3 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAY PY 2012 VL 71 IS 5 BP 619 EP 624 DI 10.1038/pr.2012.5 PG 6 WC Pediatrics SC Pediatrics GA 933PC UT WOS:000303373300014 PM 22398699 ER PT J AU Pickens, CL Cifani, C Navarre, BM Eichenbaum, H Theberge, FR Baumann, MH Calu, DJ Shaham, Y AF Pickens, Charles L. Cifani, Carlo Navarre, Brittany M. Eichenbaum, Hila Theberge, Florence R. Baumann, Michael H. Calu, Donna J. Shaham, Yavin TI Effect of fenfluramine on reinstatement of food seeking in female and male rats: implications for the predictive validity of the reinstatement model SO PSYCHOPHARMACOLOGY LA English DT Article DE Animal models; Fenfluramine; Diet; Food self-administration; Predictive validity; Reinstatement; Relapse; Stress ID ANXIOGENIC DRUG YOHIMBINE; RECEPTOR PARTIAL AGONIST; CORTICOTROPIN-RELEASING FACTOR; CUE-INDUCED REINSTATEMENT; STRESS-INDUCED RELAPSE; COCAINE-SEEKING; ALCOHOL DEPENDENCE; SMOKING-CESSATION; ETHANOL-SEEKING; EATING BEHAVIOR AB Relapse to old unhealthy eating habits while dieting is often provoked by stress or acute exposure to palatable foods. We adapted a rat reinstatement model, which is used to study drug relapse, to study mechanisms of relapse to palatable food seeking induced by food-pellet priming (non-contingent exposure to a small amount of food pellets) or injections of yohimbine (an alpha-2 adrenoceptor antagonist that causes stress-like responses in humans and non-humans). Here, we assessed the predictive validity of the food reinstatement model by studying the effects of fenfluramine, a serotonin releaser with known anorectic effects, on reinstatement of food seeking. We trained food-restricted female and male rats to lever-press for 45-mg food pellets (3-h sessions) and first assessed the effect of fenfluramine (0.75, 1.5, and 3.0 mg/kg, i.p.) on food-reinforced responding. Subsequently, we extinguished the food-reinforced responding and tested the effect of fenfluramine (1.5 and 3.0 mg/kg) on reinstatement of food seeking induced by yohimbine injections (2 mg/kg, i.p.) or pellet priming (four non-contingent pellets). Fenfluramine decreased yohimbine- and pellet-priming-induced reinstatement. As expected, fenfluramine also decreased food-reinforced responding, but a control condition in which we assessed fenfluramine's effect on high-rate operant responding indicated that the drug's effect on reinstatement was not due to performance deficits. The present data support the predictive validity of the food reinstatement model and suggest that this model could be used to identify medications for prevention of relapse induced by stress or acute exposure to palatable food during dietary treatments. C1 [Pickens, Charles L.; Cifani, Carlo; Navarre, Brittany M.; Eichenbaum, Hila; Theberge, Florence R.; Baumann, Michael H.; Calu, Donna J.; Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pickens, CL (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM pickensc@nida.nih.gov; yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Cifani, Carlo/0000-0001-6180-828X; Calu, Donna/0000-0003-2377-9494 FU National Institute on Drug Abuse FX The work was supported by the Intramural Research Program of the National Institute on Drug Abuse. CLP, CC, and BMN equally contributed to this paper. NR 107 TC 19 Z9 19 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2012 VL 221 IS 2 BP 341 EP 353 DI 10.1007/s00213-011-2585-9 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 934PT UT WOS:000303457600014 PM 22134478 ER PT J AU Nadyrov, E Rozhko, A Kravtsov, V Mabuchi, K Hatch, M Nakamura, N Nikonovich, S Aleksanin, S AF Nadyrov, Eldar Rozhko, Alexander Kravtsov, Viacheslav Mabuchi, Kiyohiko Hatch, Maureen Nakamura, Nori Nikonovich, Sergey Aleksanin, Sergey TI Karyopathological traits of thyrocytes and exposure to radioiodines in Belarusian children and adolescents following the accident at the Chernobyl nuclear power plant SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article DE Thyroid gland; Thyrocytes; Nuclear abnormalities; Chernobyl fallout; Belarus ID THYROID-CANCER; CARCINOMA; UKRAINE; CELLS AB The Belarus-American (BelAm) thyroid study cohort consists of persons who were 0-18 years of age at the time of exposure to radioactive iodine fallout from the 1986 Chernobyl nuclear power plant accident and who have undergone serial thyroid screenings with referral for fine-needle aspiration biopsy (FNAB) using standardized criteria. We investigated thyrocyte nuclear abnormalities in cytological samples from FNABs in 75 BelAm subjects with single and multiple thyroid nodules and 47 nodular goiter patients from Leningrad, Russia, unexposed to Chernobyl fallout. Nuclear abnormalities examined included internuclear chromosome bridges and derivative nuclei with broken bridges (i.e., "tailed" nuclei), which are formed from dicentric and ring chromosomes and thus may be cellular markers of radiation exposure. Among subjects with single-nodular goiter, thyrocytes with bridges were present in 86.8% of the exposed BelAm cohort compared with 27.0% of unexposed controls. The average frequency of thyrocytes with bridges and with tailed nuclei was also significantly higher in the BelAm subjects than in controls. Among subjects with multinodular goiters, thyrocytes with bridges were present in 75.7% of exposed BelAm patients compared with 16.7% of unexposed controls; thyrocytes with tailed nuclei were observed in all of the BelAm subjects but in only 40% of controls, and the mean frequencies of bridges and tailed nuclei were significantly higher in the exposed group. Unusually, long bridges were detected in 29% of BelAm patients with single-nodular goiters and 35% of those with multinodular goiters, while no such abnormalities were observed among patients from the Leningrad region. In the exposed subjects from BelAm, we also found positive correlations between their estimated dose of Iodine-131 from Chernobyl fallout and the frequency of tailed nuclei (p = 0.008) and bridges (p = 0.09). Further study is needed to confirm that these phenomena represent consequences of radiation exposure in the human organism. C1 [Mabuchi, Kiyohiko; Hatch, Maureen] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Nadyrov, Eldar; Rozhko, Alexander; Nikonovich, Sergey] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [Kravtsov, Viacheslav; Aleksanin, Sergey] EMERCOM Russia, Nikiforov Russian Ctr Emergency & Radiat Med, St Petersburg, Russia. [Nakamura, Nori] Radiat Effects Res Fdn, Hiroshima, Japan. RP Hatch, M (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. EM hatchm@mail.nih.gov FU U.S. National Cancer Institute, NIH, DHHS; Department of Energy; U.S. Nuclear Regulatory Program; Ministry of Health of the Republic of Belarus FX This work was supported by the Intramural Research Program of the U.S. National Cancer Institute, NIH, DHHS, and the Department of Energy, with initial funds for equipment provided by the U.S. Nuclear Regulatory Program. Support has also been provided by the Ministry of Health of the Republic of Belarus within the limits of Government program performance. NR 16 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAY PY 2012 VL 51 IS 2 BP 187 EP 193 DI 10.1007/s00411-012-0407-z PG 7 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 934RQ UT WOS:000303464400008 PM 22382464 ER PT J AU Little, MP AF Little, Mark P. TI Heterogeneity of variation of relative risk by age at exposure in the Japanese atomic bomb survivors (vol 48, pg 253, 2009) SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Correction C1 NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. EM mark.little@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAY PY 2012 VL 51 IS 2 BP 223 EP 223 DI 10.1007/s00411-012-0408-y PG 1 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 934RQ UT WOS:000303464400012 ER PT J AU Toy, BC Koo, E Cukras, C Meyerle, CB Chew, EY Wong, WT AF Toy, Brian C. Koo, Euna Cukras, Catherine Meyerle, Catherine B. Chew, Emily Y. Wong, Wai T. TI TREATMENT OF NONNEOVASCULAR IDIOPATHIC MACULAR TELANGIECTASIA TYPE 2 WITH INTRAVITREAL RANIBIZUMAB Results of a Phase II Clinical Trial SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE anti-VEGF; clinical trial; idiopathic macular telangiectasia; IMT2; ranibizumab ID OPTICAL COHERENCE TOMOGRAPHY; SUBRETINAL NEOVASCULARIZATION SECONDARY; JUXTAFOVEOLAR RETINAL TELANGIECTASIS; BEVACIZUMAB AVASTIN; FOLLOW-UP; MEMBRANE; THERAPY; MICROPERIMETRY; PREVALENCE; VEGF AB Purpose: To evaluate the safety and preliminary efficacy of intravitreal ranibizumab for nonneovascular idiopathic macular telangiectasia Type 2. Methods: Single-center, open-label Phase II clinical trial enrolling five participants with bilateral nonneovascular idiopathic macular telangiectasia Type 2. Intravitreal ranibizumab (0.5 mg) was administered every 4 weeks in the study eye for 12 months with the contralateral eye observed. Outcome measures included changes in best-corrected visual acuity, area of late-phase leakage on fluorescein angiography, and retinal thickness on optical coherence tomography. Results: The study treatment was well tolerated and associated with few adverse events. Change in best-corrected visual acuity at 12 months was not significantly different between treated study eyes (0.0 +/- 7.5 letters) and control fellow eyes (+2.2 +/- 1.9 letters). However, decreases in the area of late-phase fluorescein angiography leakage (-33 +/- 20% for study eyes, +1 +/- 8% for fellow eyes) and in optical coherence tomography central subfield retinal thickness (-11.7 +/- 7.0% for study eyes and -2.9 +/- 3.5% for fellow eyes) were greater in study eyes compared with fellow eyes. Conclusion: Despite significant anatomical responses to treatment, functional improvement in visual acuity was not detected. Intravitreal ranibizumab administered monthly over a time course of 12 months is unlikely to provide a general and significant benefit to patients with nonneovascular idiopathic macular telangiectasia Type 2. RETINA 32:996-1006, 2012 C1 [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Toy, Brian C.; Koo, Euna; Cukras, Catherine; Meyerle, Catherine B.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Off Sci Director, NIH, 6 Ctr Dr,Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute; Clinical Research Training Program; National Institutes of Health; Pfizer Inc FX Supported by the National Eye Institute Intramural Research Program. B. C. Toy and E. Koo were supported by the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health and Pfizer Inc (via a grant to the Foundation for National Institutes of Health from Pfizer). NR 36 TC 12 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD MAY PY 2012 VL 32 IS 5 BP 996 EP 1006 DI 10.1097/IAE.0b013e31824690a8 PG 11 WC Ophthalmology SC Ophthalmology GA 935EQ UT WOS:000303502200018 PM 22266930 ER PT J AU Taveira-DaSilva, AM Moss, J AF Taveira-DaSilva, A. M. Moss, J. TI Progress in the treatment of lymphangioleiomyomatosis: From bench to bedside SO REVISTA PORTUGUESA DE PNEUMOLOGIA LA English DT Editorial Material DE Lymphangioleiomyomatosis; Sirolimus therapy; mTOR ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; LUNG-FUNCTION; SIROLIMUS; MUTATIONS; RAPAMYCIN; TSC2 C1 [Taveira-DaSilva, A. M.; Moss, J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Taveira-DaSilva, AM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL002541-17] NR 17 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER DOYMA SL PI BARCELONA PA TRAVESERA DE GARCIA, 17-21, BARCELONA, 08021, SPAIN SN 0873-2159 J9 REV PORT PNEUMOL JI Rev. Port. Pneumol. PD MAY-JUN PY 2012 VL 18 IS 3 BP 142 EP 144 DI 10.1016/j.rppneu.2012.02.005 PG 3 WC Respiratory System SC Respiratory System GA 934MT UT WOS:000303449100007 PM 22480994 ER PT J AU Maas, S AF Maas, Stefan TI Base modification RNA Editing: Information recoding on the fly SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material ID SITES C1 [Maas, Stefan] Lehigh Univ, Dept Biol Sci, Bethlehem, PA 18015 USA. RP Maas, S (reprint author), NIGMS, NIH, 45 Ctr Dr,MSC 6200, Bethesda, MD 20892 USA. EM Stefan.Maas@nih.gov NR 8 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD MAY PY 2012 VL 23 IS 3 BP 243 EP 243 DI 10.1016/j.semcdb.2011.12.002 PG 1 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 935UT UT WOS:000303547800001 PM 22193702 ER PT J AU Rider, CV Dourson, ML Hertzberg, RC Mumtaz, MM Price, PS Simmons, JE AF Rider, Cynthia V. Dourson, Michael L. Hertzberg, Richard C. Mumtaz, Moiz M. Price, Paul S. Simmons, Jane Ellen TI Incorporating Nonchemical Stressors Into Cumulative Risk Assessments SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material DE joint action; exposure; dose response; modeling ID HEALTH; PESTICIDE; FRAMEWORK; EXPOSURES; AGGREGATE AB The role of nonchemical stressors in modulating the human health risk associated with chemical exposures is an area of increasing attention. On 9 March 2011, a workshop titled "Approaches for Incorporating Nonchemical Stressors into Cumulative Risk Assessment" took place during the 50th Anniversary Annual Society of Toxicology Meeting in Washington D.C. Objectives of the workshop included describing the current state of the science from various perspectives (i.e., regulatory, exposure, modeling, and risk assessment) and presenting expert opinions on currently available methods for incorporating nonchemical stressors into cumulative risk assessments. Herein, distinct frameworks for characterizing exposure to, joint effects of, and risk associated with chemical and nonchemical stressors are discussed. C1 [Rider, Cynthia V.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Dourson, Michael L.] Toxicol Excellence Risk Assessment TERA, Cincinnati, OH 45211 USA. [Hertzberg, Richard C.] Biomath Consulting, Atlanta, GA 30322 USA. [Mumtaz, Moiz M.] Agcy Tox Subst & Dis Registry, Atlanta, GA 30333 USA. [Price, Paul S.] Dow Chem Co USA, Midland, MI 48674 USA. [Simmons, Jane Ellen] US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Rider, CV (reprint author), NIEHS, Natl Toxicol Program, 111 TW Alexander Dr,POB 12233,MD K2-12, Res Triangle Pk, NC 27709 USA. EM ridercv@niehs.nih.gov NR 20 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2012 VL 127 IS 1 BP 10 EP 17 DI 10.1093/toxsci/kfs088 PG 8 WC Toxicology SC Toxicology GA 935AT UT WOS:000303490100002 PM 22345310 ER PT J AU Ramsey, SD Zeliadt, SB Blough, DK Fedorenko, CR Fairweather, ME McDermott, CL Penson, DF Van Den Eeden, SK Hamilton, AS Arora, NK AF Ramsey, Scott D. Zeliadt, Steven B. Blough, David K. Fedorenko, Catherine R. Fairweather, Megan E. McDermott, Cara L. Penson, David F. Van Den Eeden, Stephen K. Hamilton, Ann S. Arora, Neeraj K. TI Complementary and Alternative Medicine Use, Patient-reported Outcomes, and Treatment Satisfaction Among Men With Localized Prostate Cancer SO UROLOGY LA English DT Article ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; PREVALENCE; THERAPY; CAPSURE; BOTHER AB OBJECTIVE To evaluate the association between complementary and alternative medicine (CAM) use, satisfaction with treatment, and patient-reported outcomes after treatment. METHODS The Prostate CAncer Therapy Selection Study prospectively surveyed patients newly diagnosed with localized prostate cancer about their treatment decision-making process and outcomes. The Prostate CAncer Therapy Selection Study recruited patients from 3 geographic areas through hospital-based urology clinics and community urology practices. RESULTS More than 700 patients completed the baseline and follow-up surveys. More than 50% of respondents reported using CAM; this decreased to 39% if prayer was excluded as a type of CAM. On multivariate analysis, factors related to communication with the treating physician, but not CAM use, were associated with treatment satisfaction. The likelihood of stability or improvement in urinary, bowel, and sexual function at 6 months was related to the choice of primary therapy but was unrelated to CAM use. CONCLUSION In the present prospective observational study, CAM use was highly prevalent but unrelated to treatment satisfaction or changes in functional status. The effect of CAM on these endpoints remains to be established in comparative effectiveness studies. UROLOGY 79: 1034-1041, 2012. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ramsey, Scott D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. Univ Washington, Sch Pharm, Seattle, WA 98195 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Kaiser Permanente No Calif, Div Res, Oakland, CA USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Ramsey, SD (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M3-B232, Seattle, WA 98109 USA. EM sramsey@fhcrc.org FU National Cancer Institute [HHSN261200900582P, N01-PC-35142, N01-PC-35139, N01-PC-35136]; Cancer Surveillance System of the Fred Hutchinson Cancer Research Center; Fred Hutchinson Cancer Research Center; State of Washington FX This publication was supported by the National Cancer Institute (grants HHSN261200900582P, N01-PC-35142, N01-PC-35139, and N01-PC-35136) and by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, funded by contract N01-PC-35142 from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. NR 28 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD MAY PY 2012 VL 79 IS 5 BP 1034 EP 1041 DI 10.1016/j.urology.2012.01.023 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 934TW UT WOS:000303470600022 PM 22546381 ER PT J AU Xun, P Liu, K Loria, CM Bujnowski, D Shikany, JM Schreiner, PJ Sidney, S He, K AF Xun, Pengcheng Liu, Kiang Loria, Catherine M. Bujnowski, Deborah Shikany, James M. Schreiner, Pamela J. Sidney, Stephen He, Ka TI Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEY; ARTERY RISK DEVELOPMENT; BLOOD-PRESSURE; FOLIC-ACID; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; CONTROLLED TRIAL; NATIONAL-HEALTH; CARDIA; HOMOCYSTEINE AB Background: Laboratory studies suggest that folate intake may decrease blood pressure (BP) through increasing nitric oxide synthesis in endothelial cells and/or reducing plasma homocysteine concentrations. However, human studies, particularly longitudinal data, are limited. Objective: Our objective was to investigate whether dietary folate intake is associated with the 20-y incidence of hypertension. Design: We prospectively followed 4400 men and women (African Americans and whites aged 18-30 y) without hypertension at base-line (1985) in the Coronary Artery Risk Development in Young Adults study 6 times, in 1987, 1990, 1992, 1995, 2000, and 2005. Diet was assessed by dietary-history questionnaire at baseline and in 1992 and 2005. Incident hypertension was defined as the first occurrence at any follow-up examination of systolic BP >= 140 mm Hg, diastolic BP >= 90 mm Hg, or use of antihypertensive medication. Results: A total of 989 incident cases were identified during the 20-y follow-up. After adjustment for potential confounders, participants in the highest quintile of total folate intake had a significantly lower incidence of hypertension (HR: 0.48; 95% CI: 0.38, 0.62; P-trend < 0.01) than did those in the lowest quintile. The multivariable HRs for the same comparison were 0.33 (95% Cl: 0.22, 0.51; P-trend < 0.01) in whites and 0.54 (95% CI: 0.40, 0.75; P-trend < 0.01) in African Americans (P-interaction = 0.047). The inverse associations were confirmed in a subset of the cohort (n = 1445) with serum folate measured at baseline and in 1992 and 2000. Conclusions: Higher folate intake in young adulthood was longitudinally associated with a lower incidence of hypertension later in life. This inverse association was more pronounced in whites. Additional studies are warranted to establish the causal inference. Am J Clin Nutr 2012;95:1023-30. C1 [Xun, Pengcheng; Bujnowski, Deborah; He, Ka] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Xun, Pengcheng; Bujnowski, Deborah; He, Ka] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Shikany, James M.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL USA. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Sidney, Stephen] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. RP He, K (reprint author), Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, 2221 McGavran Greenberg,Campus Box 7461, Chapel Hill, NC 27599 USA. EM kahe@unc.edu RI Xun, Pengcheng/D-3411-2013 FU National Heart, Lung, and Blood Institute [N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095]; [R01HL081572] FX Supported in part by grant R01HL081572 (PX and KH); CARDIA was supported by grants N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, and N01-HC-95095 from the National Heart, Lung, and Blood Institute. NR 35 TC 11 Z9 13 U1 1 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2012 VL 95 IS 5 BP 1023 EP 1030 DI 10.3945/ajcn.111.027250 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 930LK UT WOS:000303140700006 PM 22492371 ER PT J AU Bailey, RL Holden, J Dwyer, JT AF Bailey, Regan L. Holden, Joanne Dwyer, Johanna T. TI Intakes of copper in nutrition surveys are falsely high Reply SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 [Bailey, Regan L.; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Holden, Joanne] ARS, Nutrient Data Lab, USDA, Beltsville, MD USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2012 VL 95 IS 5 BP 1294 EP 1294 DI 10.3945/ajcn.112.035451 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 930LK UT WOS:000303140700044 ER PT J AU Pietrzak, RH Goldstein, RB Southwick, SM Grant, BF AF Pietrzak, Robert H. Goldstein, Rise B. Southwick, Steven M. Grant, Bridget F. TI Psychiatric Comorbidity of Full and Partial Posttraumatic Stress Disorder Among Older Adults in the United States: Results From Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Comorbidity; older adults; posttraumatic stress disorder ID WORLD-WAR-II; PERSONALITY-DISORDER; COMBAT VETERANS; RISK-FACTORS; PREVALENCE; TRAUMA; COMMUNITY; PTSD; IV; DISABILITY AB Objectives: To present findings on the prevalence, correlates, and psychiatric comorbidity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition posttraumatic stress disorder (PTSD) and partial PTSD in a nationally representative sample of US. older adults. Design, Setting, and Participants: Face-to-face interviews with 9,463 adults age 60 years and older in the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. Measurements: Sociodemographic correlates; worst stressful experiences; comorbid lifetime mood, anxiety, substance use, and personality disorders; psychosocial functioning; and suicide attempts. Results: Lifetime prevalences +/- standard errors of PTSD and partial PTSD were 4.5% +/- 0.25 and 5.5% +/- 0.27, respectively. Rates were higher in women (5.7% +/- 0.37 and 6.5% +/- 0.39) than in men (3.1% +/- 0.31 and 4.3% +/- 0.37). Older adults with PTSD most frequently identified unexpected death of someone close, serious illness or injury to someone close, and their own serious or life-threatening illness as their worst stressful events. Older adults exposed to trauma but without full or partial PTSD and respondents with partial PTSD most often identified unexpected death of someone close, serious illness or injury to someone close, and indirect experience of 9/11 as their worst events. PTSD was associated with elevated odds of lifetime mood, anxiety, drug use, and borderline and narcissistic personality disorders and decreased psychosocial functioning. Partial PTSD was associated with elevated odds of mood, anxiety, and narcissistic and schizotypal personality disorders and poorer psychosocial functioning relative to older adults exposed to trauma but without full or partial PTSD. Conclusions: PTSD among older adults in the United States is slightly more prevalent than previously reported and is associated with considerable psychiatric comorbidity and psychosocial dysfunction. Partial PTSD is associated with significant psychiatric comorbidity, particularly with mood and other anxiety disorders. (Am J Geriatr Psychiatry 2012; 20:380-390) C1 [Pietrzak, Robert H.; Southwick, Steven M.] Yale Univ, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst, Dept Psychiat,Sch Med, West Haven, CT 06516 USA. [Goldstein, Rise B.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Pietrzak, RH (reprint author), Yale Univ, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst, Dept Psychiat,Sch Med, 950 Campbell Ave 151-E, West Haven, CT 06516 USA. EM robert.pietrzak@yale.edu OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institutes of Health, NIAAA; National Center for Posttraumatic Stress Disorder; National Institute of Mental Health Summer Research Institute in Geriatric Mental Health; CogState, Inc. FX The National Epidemiologic Survey on Alcohol and Related Conditions is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. Preparation of this report was supported in part by the National Center for Posttraumatic Stress Disorder, the National Institute of Mental Health Summer Research Institute in Geriatric Mental Health, and a private donation.; Dr. Pietrzak receives partial salary support from CogState, Inc., for work that bears no relationship to the present study. NR 40 TC 45 Z9 47 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAY PY 2012 VL 20 IS 5 BP 380 EP 390 DI 10.1097/JGP.0b013e31820d92e7 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 932MT UT WOS:000303295900002 PM 22522959 ER PT J AU Pineda-Alvarez, DE Solomon, BD Roessler, E Balog, JZ Hadley, DW Zein, WM Brooks, BP Muenke, M AF Pineda-Alvarez, Daniel E. Solomon, Benjamin D. Roessler, Erich Balog, Joan Z. Hadley, Donald W. Zein, Wadih M. Brooks, Brian P. Muenke, Maximilian TI Patients within the broad holoprosencephaly spectrum have distinct and subtle ophthalmologic anomalies: Response to Khan SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID SONIC-HEDGEHOG; CORNEAL DIAMETER; MUTATIONS; PHENOTYPE; NANOPHTHALMOS; VALIDATION; EXPRESSION; FOREBRAIN; GENOTYPE; CHILDREN C1 [Pineda-Alvarez, Daniel E.; Solomon, Benjamin D.; Roessler, Erich; Balog, Joan Z.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Hadley, Donald W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Zein, Wadih M.; Brooks, Brian P.] NEI, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), Natl Human Genome Res, Med Genet Branch, Inst Natl Inst Hlth, 35 Convent Dr,Bldg 35 Room 1B202, Bethesda, MD 20814 USA. EM mamuenke@mail.nih.gov FU Intramural NIH HHS [ZIA HG000209-10] NR 17 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY PY 2012 VL 158A IS 5 BP 1244 EP 1245 DI 10.1002/ajmg.a.35207 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 928RH UT WOS:000303000200045 PM 22645505 ER PT J AU Romero, R Garite, TJ Kim, MH Quilligan, EJ Bump, RC Carson, SA Copeland, LJ Grobman, WA Iams, JD Jenkins, TR Kilpatrick, SJ Macones, GA Parry, S Phipps, MG AF Romero, Roberto Garite, Thomas J. Kim, Moon H. Quilligan, E. J. Bump, Richard C. Carson, Sandra A. Copeland, Larry J. Grobman, William A. Iams, Jay D. Jenkins, Todd R. Kilpatrick, Sarah J. Macones, George A. Parry, Samuel Phipps, Maureen G. TI The new American Journal of Obstetrics & Gynecology, 5 years later: looking back and moving forward SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID PELVIC-INFLAMMATORY-DISEASE; ELEVATED LIVER-ENZYMES; HEART-RATE; SEVERE PREECLAMPSIA; AMNIOTIC-FLUID; UNITED-STATES; FETAL WEIGHT; PREGNANCY; WOMEN; MANAGEMENT C1 [Romero, Roberto; Garite, Thomas J.; Kim, Moon H.; Quilligan, E. J.; Bump, Richard C.; Carson, Sandra A.; Copeland, Larry J.; Grobman, William A.; Iams, Jay D.; Jenkins, Todd R.; Kilpatrick, Sarah J.; Macones, George A.; Parry, Samuel; Phipps, Maureen G.] NICHD, Perinatol Res Branch, Program Perinatal Res & Obstet, NIH,DHHS, Bethesda, MD 20892 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, Program Perinatal Res & Obstet, NIH,DHHS, Bethesda, MD 20892 USA. NR 141 TC 4 Z9 4 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2012 VL 206 IS 5 BP 364 EP 373 DI 10.1016/j.ajog.2012.03.008 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 931JB UT WOS:000303211100008 PM 22542111 ER PT J AU Laughon, SK Branch, DW Beaver, J Zhang, J AF Laughon, S. Katherine Branch, D. Ware Beaver, Julie Zhang, Jun TI Changes in labor patterns over 50 years SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE labor; labor curve; labor duration ID GRAPHICOSTATISTICAL ANALYSIS; NULLIPAROUS WOMEN; ARREST AB OBJECTIVE: The objective of the study was to examine differences in labor patterns in a modern cohort compared with the 1960s in the United States. STUDY DESIGN: Data from pregnancies at term, in spontaneous labor, with cephalic, singleton fetuses were compared between the Collaborative Perinatal Project (CPP, n = 39,491 delivering 1959-1966) and the Consortium on Safe Labor (CSL; n = 98,359 delivering 2002-2008). RESULTS: Compared with the CPP, women in the CSL were older (26.8 +/- 6.0 vs 24.1 +/- 6.0 years), heavier (body mass index 29.9 +/- 5.0 vs 26.3 +/- 4.1 kg/m(2)), had higher epidural (55% vs 4%) and oxytocin use (31% vs 12%), and cesarean delivery (12% vs 3%). First stage of labor in the CSL was longer by a median of 2.6 hours in nulliparas and 2.0 hours in multiparas, even after adjusting for maternal and pregnancy characteristics, suggesting that the prolonged labor is mostly due to changes in practice patterns. CONCLUSION: Labor is longer in the modern obstetrical cohort. The benefit of extensive interventions needs further evaluation. C1 [Laughon, S. Katherine; Beaver, Julie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Branch, D. Ware] Intermt Healthcare, Salt Lake City, UT USA. [Branch, D. Ware] Univ Utah, Salt Lake City, UT USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, MOE, Shanghai 200030, Peoples R China. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Childrens Environm Hlth, Xinhua Hosp, Shanghai 200030, Peoples R China. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. OI Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this paper were partly obtained from the Consortium on Safe Labor, supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract number HHSN267200603425C). The other institutions in the Consortium on Safe Labor are listed with the Acknowledgments section. NR 15 TC 0 Z9 4 U1 3 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2012 VL 206 IS 5 AR 419.e1 DI 10.1016/j.ajog.2012.03.003 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 931JB UT WOS:000303211100019 PM 22542117 ER PT J AU Haskell, WL Troiano, RP Hammond, JA Phillips, MJ Strader, LC Marquez, DX Grant, SF Ramos, E AF Haskell, William L. Troiano, Richard P. Hammond, Jane A. Phillips, Michael J. Strader, Lisa C. Marquez, David X. Grant, Struan F. Ramos, Erin TI Physical Activity and Physical Fitness Standardizing Assessment with the PhenX Toolkit SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CARDIORESPIRATORY FITNESS; ACTIVITY QUESTIONNAIRE; OLDER-ADULTS; VALIDATION; EXERCISE; PERFORMANCE; PREDICTION; MORTALITY; GENOMICS; BEHAVIOR AB The focus of the PhenX (Phenotypes and eXposures) Toolkit is to provide researchers whose expertise lies outside a particular area with key measures identified by experts for uniform use in large-scale genetic studies and other extensive epidemiologic efforts going forward. The current paper specifically addresses the PhenX Toolkit research domain of physical activity and physical fitness (PA/PF), which are often associated with health outcomes. A Working Group (WG) of content experts completed a 6-month consensus process in which they identified a set of 14 high-priority, low-burden, and scientifically supported measures. During this process, the WG considered self-reported and objective measures that included the latest technology (e.g., accelerometers, pedometers, and heart-rate monitors). They also sought the input of measurement experts and other members of the research community during their deliberations. A majority of the measures include protocols for children (or adolescents), adults, and older adults or are applicable to all ages. Measures from the PA/PF domain and 20 other domains are publicly available and found at the PhenX Toolkit website, www.phenxtoolkit.org. The use of common measures and protocols across large studies enhances the capacity to combine or compare data across studies, benefiting both PA/PF experts and non-experts. Use of these common measures by the research community should increase statistical power and enhance the ability to answer scientific questions that previously might have gone unanswered. (Am J Prev Med 2012;42(5):486-492) (C) 2012 American Journal of Preventive Medicine C1 [Haskell, William L.] Stanford Univ, Sch Med, Prevent Res Ctr, Dept Med, Palo Alto, CA 94304 USA. [Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Ramos, Erin] NHGRI, NIH, Rockville, MD USA. [Hammond, Jane A.; Phillips, Michael J.; Strader, Lisa C.] RTI Int, Res Triangle Pk, NC USA. [Marquez, David X.] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL USA. [Grant, Struan F.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Haskell, WL (reprint author), Stanford Univ, Sch Med, Prevent Res Ctr, Dept Med, 1070 Arastradero Rd,Suite 100, Palo Alto, CA 94304 USA. EM whaskell@stanford.edu RI Strader, Lisa/H-3083-2013; OI Troiano, Richard/0000-0002-6807-989X FU NHGRI [U01 HG004597-01] FX This work was supported by NHGRI, Award No. U01 HG004597-01. NR 35 TC 3 Z9 3 U1 2 U2 11 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 MAY PY 2012 VL 42 IS 5 BP 486 EP 492 DI 10.1016/j.amepre.2011.11.017 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 928ED UT WOS:000302963300014 PM 22516489 ER PT J AU Thota, AB Sipe, TA Byard, GJ Zometa, CS Hahn, RA McKnight-Eily, LR Chapman, DP Abraido-Lanza, AF Pearson, JL Anderson, CW Gelenberg, AJ Hennessy, KD Duffy, FF Vernon-Smiley, ME Nease, DE Williams, SP AF Thota, Anilkrishna B. Sipe, Theresa Ann Byard, Guthrie J. Zometa, Carlos S. Hahn, Robert A. McKnight-Eily, Lela R. Chapman, Daniel P. Abraido-Lanza, Ana F. Pearson, Jane L. Anderson, Clinton W. Gelenberg, Alan J. Hennessy, Kevin D. Duffy, Farifteh F. Vernon-Smiley, Mary E. Nease, Donald E., Jr. Williams, Samantha P. CA Community Preventive Serv Task TI Collaborative Care to Improve the Management of Depressive Disorders A Community Guide Systematic Review and Meta-Analysis SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; OLDER MEDICAL INPATIENTS; UK PRIMARY-CARE; PREVENTIVE-SERVICES; UNITED-STATES; QUALITY IMPROVEMENT; CHRONIC ILLNESS; HEALTH-CARE; TASK-FORCE; INTERVENTION AB Context: To improve the quality of depression management, collaborative care models have been developed from the Chronic Care Model over the past 20 years. Collaborative care is a multicomponent, healthcare system-level intervention that uses case managers to link primary care providers, patients, and mental health specialists. In addition to case management support, primary care providers receive consultation and decision support from mental health specialists (i.e., psychiatrists and psychologists). This collaboration is designed to (1) improve routine screening and diagnosis of depressive disorders; (2) increase provider use of evidence-based protocols for the proactive management of diagnosed depressive disorders; and (3) improve clinical and community support for active client/patient engagement in treatment goal-setting and self-management. Evidence acquisition: A team of subject matter experts in mental health, representing various agencies and institutions, conceptualized and conducted a systematic review and meta-analysis on collaborative care for improving the management of depressive disorders. This team worked under the guidance of the Community Preventive Services Task Force, a nonfederal, independent, volunteer body of public health and prevention experts. Community Guide systematic review methods were used to identify, evaluate, and analyze available evidence. Evidence synthesis: An earlier systematic review with 37 RCTs of collaborative care studies published through 2004 found evidence of effectiveness of these models in improving depression outcomes. An additional 32 studies of collaborative care models conducted between 2004 and 2009 were found for this current review and analyzed. The results from the meta-analyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms (standardized mean difference [SMD] = 0.34); adherence to treatment (OR = 2.22); response to treatment (OR = 1.78); remission of symptoms (OR = 1.74); recovery from symptoms (OR = 1.75); quality of life/functional status (SMD = 0.12); and satisfaction with care (SMD = 0.39) for patients diagnosed with depression (all effect estimates were significant). Conclusions: Collaborative care models are effective in achieving clinically meaningful improvements in depression outcomes and public health benefits in a wide range of populations, settings, and organizations. Collaborative care interventions provide a supportive network of professionals and peers for patients with depression, especially at the primary care level. (Am J Prev Med 2012;42(5):525-538) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Thota, Anilkrishna B.; Sipe, Theresa Ann; Byard, Guthrie J.; Zometa, Carlos S.; Hahn, Robert A.] CDC, Community Guide Branch, Epidemiol & Anal Program Off, Off Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. [McKnight-Eily, Lela R.; Chapman, Daniel P.] CDC, Div Populat Hlth, Atlanta, GA 30333 USA. [Vernon-Smiley, Mary E.] CDC, Div Adolescent & Sch Hlth, Atlanta, GA 30333 USA. [Williams, Samantha P.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Williams, Samantha P.] CDC, Behav Intervent & Res Branch, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. [Abraido-Lanza, Ana F.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Pearson, Jane L.] NIMH, Bethesda, MD 20892 USA. [Hennessy, Kevin D.] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Anderson, Clinton W.] Amer Psychol Assoc, Washington, DC 20036 USA. [Gelenberg, Alan J.] Penn State Hershey Med Ctr, Dept Psychiat, Hershey, PA USA. [Duffy, Farifteh F.] Amer Psychiat Assoc, Arlington, VA USA. [Nease, Donald E., Jr.] Amer Acad Family Phys, Denver, CO USA. RP Thota, AB (reprint author), CDC, Community Guide Branch, Epidemiol & Anal Program Off, Off Surveillance Epidemiol & Lab Serv, 1600 Clifton Rd,Mailstop E69, Atlanta, GA 30333 USA. EM athota@cdc.gov RI Thota, Anilkrishna/J-1743-2012; Nease, Donald/B-6206-2013 OI Nease, Donald/0000-0001-8323-3720 FU Pfizer Pharmaceuticals FX AJG is a major stock owner of Healthcare Technology Stystems, Inc.; he consults to Dey Pharma, PGxHealth, Myriad Genetics, and Zynx Health; and is the principal investigator on an investigator-initiated grant from Pfizer Pharmaceuticals to Penn State. No other financial disclosures were reported by the authors of this paper. NR 76 TC 148 Z9 149 U1 8 U2 41 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 MAY PY 2012 VL 42 IS 5 BP 525 EP 538 DI 10.1016/j.amepre.2012.01.019 PG 14 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 928ED UT WOS:000302963300020 PM 22516495 ER PT J AU Balshaw, DM Kwok, RK AF Balshaw, David M. Kwok, Richard K. TI Innovative Methods for Improving Measures of the Personal Environment SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Balshaw, David M.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Kwok, Richard K.] NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Balshaw, DM (reprint author), NIEHS, Div Extramural Res & Training, MD K3-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM balshaw@niehs.nih.gov RI Kwok, Richard/B-6907-2017 OI Kwok, Richard/0000-0002-6794-8360 NR 10 TC 3 Z9 3 U1 0 U2 7 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 MAY PY 2012 VL 42 IS 5 BP 558 EP 559 DI 10.1016/j.amepre.2012.02.002 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 928ED UT WOS:000302963300025 PM 22516500 ER PT J AU Epperson, CN Steiner, M Hartlage, SA Eriksson, E Schmidt, PJ Jones, I Yonkers, KA AF Epperson, C. Neill Steiner, Meir Hartlage, S. Ann Eriksson, Elias Schmidt, Peter J. Jones, Ian Yonkers, Kimberly A. TI Premenstrual Dysphoric Disorder: Evidence for a New Category for DSM-5 SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID LATE LUTEAL-PHASE; POSTTRAUMATIC-STRESS-DISORDER; PLACEBO-CONTROLLED TRIAL; COMMUNITY-BASED SAMPLE; POPULATION-BASED TWIN; LONG-TERM TREATMENT; MENSTRUAL-CYCLE; SYMPTOM SEVERITY; MOOD DISORDER; ENVIRONMENTAL-FACTORS AB Premenstrual dysphoric disorder, which affects 2%-5% of premenopausal women, was included in Appendix B of DSMIV, "Criterion Sets and Axes Provided for Further Study." Since then, aided by the inclusion of specific and rigorous criteria in DSM-IV, there has been an explosion of research on the epidemiology, phenomenology, pathogenesis, and treatment of the disorder. In 2009, the Mood Disorders Work Group for DSM-5 convened a group of experts to examine the literature on premenstrual dysphoric disorder and provide recommendations regarding the appropriate criteria and placement for the disorder in DSM-5. Based on thorough review and lengthy discussion, the work group proposed that the information on the diagnosis, treatment, and validation of the disorder has matured sufficiently for it to qualify as a full category in DSM-5. A move to the position of category, rather than a criterion set in need of further study, will provide greater legitimacy for the disorder and encourage the growth of evidence-based research, ultimately leading to new treatments. C1 [Epperson, C. Neill] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Perelman Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. McMaster Univ, Dept Psychiat, Hamilton, ON, Canada. Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. Univ Gothenburg, Sahlgrenska Acad, Dept Pharmacol, Gothenburg, Sweden. Univ Gothenburg, Sahlgrenska Acad, Inst Physiol & Neurosci, Gothenburg, Sweden. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Cardiff Univ, Dept Psychol Med, Cardiff, S Glam, Wales. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. RP Epperson, CN (reprint author), Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. EM cepp@upenn.edu OI Steiner, Meir/0000-0001-7838-2246 FU Shire; Canadian Institutes of Health Research; APA; GlaxoSmithKline; Eli Lilly; NIMH; National Institute on Drug Abuse FX Dr. Epperson has received research support from Shire for an investigator-initiated study, has received donation of products for research purposes from Novartis, and holds equity in Johnson & Johnson and Merck. Dr. Steiner has served as a consultant for AstraZeneca, Azevan, Bayer Canada, and Servier, has received research grants from the Canadian Institutes of Health Research, and has received honoraria from AstraZeneca and the Society for Women's Health Research. Dr. Hartlage received funding from APA to conduct secondary analyses of data sets on premenstrual dysphoric disorder. Dr. Eriksson has served on advisory boards for Lundbeck and Schering-Bayer and has received consultancy fees and research grants from Lundbeck. Dr. Schmidt reports no financial relationships with commercial interests. Dr. Jones has received honoraria or consultancy fees from AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Sanofi-Aventis and has received research funding from GlaxoSmithKline. Dr. Yonkers has received research support from Eli Lilly, NIMH, and the National Institute on Drug Abuse, study medication from Pfizer for an NIMH-funded trial, and royalties from UpToDate; she also received funding from APA to conduct secondary analyses of data sets on premenstrual dysphoric disorder. NR 103 TC 63 Z9 66 U1 4 U2 16 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2012 VL 169 IS 5 BP 465 EP 475 DI 10.1176/appi.ajp.2012.11081302 PG 11 WC Psychiatry SC Psychiatry GA 932LJ UT WOS:000303292300009 PM 22764360 ER PT J AU Robbins, IM Moore, TM Blaisdell, CJ Abman, SH AF Robbins, Ivan M. Moore, Timothy M. Blaisdell, Carol J. Abman, Steven H. TI Improving Outcomes for Pulmonary Vascular Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE clinical trials; pediatrics; pulmonary hypertension; pulmonary vascular changes ID ARTERIAL-HYPERTENSION; SURVIVAL; CHILDREN; FRANCE AB Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would he expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trial.; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs. C1 [Moore, Timothy M.] NHLBI, Div Lung Dis, Nihon Univ, Rockledge Ctr 2, Bethesda, MD 20892 USA. [Robbins, Ivan M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Abman, Steven H.] Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. [Abman, Steven H.] Childrens Hosp, Denver, CO 80218 USA. RP Moore, TM (reprint author), NHLBI, Div Lung Dis, Nihon Univ, Rockledge Ctr 2, Suite 10042,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM tim.moore@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health FX This Workshop was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 11 TC 9 Z9 9 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 1 PY 2012 VL 185 IS 9 BP 1015 EP 1020 DI 10.1164/rccm.201201-0049WS PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 930ZE UT WOS:000303182700017 PM 22335936 ER PT J AU Yao, L Gai, N AF Yao, Lawrence Gai, Neville TI Fat-Corrected T2 Measurement as a Marker of Active Muscle Disease in Inflammatory Myopathy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE MRI; muscle; myopathy; myositis; T2 ID JUVENILE DERMATOMYOSITIS; ARTICULAR-CARTILAGE; MATHEMATICAL-THEORY; RELAXATION-TIMES; SPIN-ECHO; WATER; QUANTIFICATION; IDEAL; T-2; QUANTITATION AB OBJECTIVE. We sought to improve the utility of T2 measurement as a marker of active muscle disease in patients with idiopathic inflammatory myopathy by correcting for T2 prolongations caused by fatty replacement of muscle that accompnaies chronic muscle damage. SUBJECTS AND METHODS. Twenty-one patients with idiopathic inflammatory myopathy underwent a standardized MRI evaluation of the thighs. Fat fraction maps were calculated from dual-echo gradient-echo images. Fat-corrected T2 maps were generated from multiecho spin-echo images on the basis of a biexponential model that incorporated voxelwise fat fraction estimates. Semiautomated summaries of conventional and fat-corrected muscle T2 values were compared with one another and with standardized visual scores of muscle disease based on T1-weighted spin-echo and STIR images. RESULTS. Fat-corrected muscle T2 maps showed lower mean values and greater histogram entropy than conventional T2 maps, as analyzed over a standardized portion of the thigh muscles. Conventional and fat-corrected T2 values correlated with visual scores of active muscle disease on STIR images and with the varying intensity of disease depicted with STIR in focal muscle regions. CONCLUSION. MRI T2 maps of muscle can be corrected for varying fat content by combining the information from chemical shift-sensitive gradient-echo and multiecho spinecho images. Use of this strategy may prove useful in the study of idiopathic inflammatory myopathy and other diseases characterized by both muscle inflammation and atrophy. C1 [Yao, Lawrence; Gai, Neville] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Yao, L (reprint author), NIH, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lyao@cc.nih.gov FU Clinical Center, National Institutes of Health FX Supported in part by the Intramural Research Program at the Clinical Center, National Institutes of Health. NR 24 TC 14 Z9 14 U1 2 U2 6 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2012 VL 198 IS 5 BP W475 EP W481 DI 10.2214/AJR.11.7113 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 930TG UT WOS:000303162800010 PM 22528929 ER PT J AU Sheehan, FT Sipprell, WH Boden, BP AF Sheehan, Frances T. Sipprell, William H., III Boden, Barry P. TI Dynamic Sagittal Plane Trunk Control During Anterior Cruciate Ligament Injury SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE ACL injury; injury prevention; gender differences ID QUADRICEPS FEMORIS MUSCLE; NEUROMUSCULAR CONTROL; COMPUTER-SIMULATION; VIDEO ANALYSIS; KNEE INJURY; FOLLOW-UP; RISK; JOINT; MECHANISMS; KINEMATICS AB Background: Recent studies have demonstrated that trunk control likely plays a role in anterior cruciate ligament (ACL) injury. Yet, the majority of ACL research remains focused on the lower limb, with limited information on the trunk position at the time of injury. Hypotheses: Athletes experiencing a noncontact ACL injury after a 1-legged landing position their center of mass (COM) more posterior from the base of support (BOS) at initial ground contact in comparison with uninjured athletes. The distance from the COM to the BOS (COM_BOS) is larger in female, as compared with male, athletes during 1-legged landing. Study Design: Case control study; Level of evidence, 3. Methods: Movie captures of 20 athletes performing a 1-legged landing maneuver resulting in a torn ACL were compared with matched (for gender, sport, and activity just before landing) movie captures of 20 athletes performing a similar maneuver that did not result in an ACL disruption (controls). The COM_BOS, trunk(G) angle, and limbG angle (both relative to the gravity vector) were measured in the sagittal plane at initial ground-foot contact. A 2-way ANOVA (injury status x gender) was used to examine the hypotheses. Results: There was a significant difference in all 3 measures based on injury status but not on gender. The COM_BOS, normalized by femur length, and limbG angle were greater (Delta = 0.9, P < .001 and Delta = 16 degrees, P = .004, respectively), and the trunkG angle was smaller (Delta = 12 degrees, P = .016) in the participants who sustained an ACL injury as compared with controls. The average COM was calculated as 38 cm more posterior relative to the BOS in the participants who sustained an ACL injury as compared with controls. Conclusion: Landing with the COM far posterior to the BOS may be a risk factor for noncontact ACL injury and potentially can be addressed in prevention programs. C1 [Sheehan, Frances T.; Sipprell, William H., III; Boden, Barry P.] NIH, Funct & Appl Biomech Sect Rehabil Med, Bethesda, MD 20892 USA. RP Boden, BP (reprint author), Orthopaed Ctr, 9420 Key W Ave,Suite 300, Rockville, MD 20850 USA. EM bboden@starpower.net RI sheehan, frances/B-6962-2009 FU National Institutes of Health (NIH); Clinical Center at the NIH FX One or more of the authors has declared the following potential conflict of interest or source of funding: This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the Clinical Center at the NIH. NR 32 TC 23 Z9 23 U1 1 U2 23 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 J9 AM J SPORT MED JI Am. J. Sports Med. PD MAY PY 2012 VL 40 IS 5 BP 1068 EP 1074 DI 10.1177/0363546512437850 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 932XN UT WOS:000303323900016 PM 22383659 ER PT J AU Danziger-Isakov, L Mohanakumar, T Heeger, P Steward, N Worley, S Conrad, C Faro, A Goldfarb, S Hayes, D Schecter, M Spencer, H Visner, G Williams, N Ikle, D Sweet, SC AF Danziger-Isakov, L. Mohanakumar, T. Heeger, P. Steward, N. Worley, S. Conrad, C. Faro, A. Goldfarb, S. Hayes, D., Jr. Schecter, M. Spencer, H. Visner, G. Williams, N. Ikle, D. Sweet, S. C. TI Antibodies to Self Antigens (Collagen V & K-alpha 1tubulin) in Pediatric Lung Transplant SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Danziger-Isakov, L.; Worley, S.] Cleveland Clin, Cleveland, OH USA. [Mohanakumar, T.; Steward, N.; Faro, A.; Sweet, S. C.] Washington Univ, St Louis, MO 63130 USA. [Heeger, P.] Mt Sinai Med Ctr, New York, NY USA. [Conrad, C.] Stanford Univ, Stanford, CA 94305 USA. [Goldfarb, S.] Childrens Philadelphia, Philadelphia, PA USA. [Visner, G.] Boston Childrens, Boston, MA USA. [Williams, N.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 71 BP 48 EP 48 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235500072 ER PT J AU Chakkera, HA Ayub, A Gonwa, T Knowler, WC AF Chakkera, H. A. Ayub, A. Gonwa, T. Knowler, W. C. TI Validation of a Pretransplant Risk Score for New Onset Diabetes Mellitus after Kidney Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Ayub, A.; Gonwa, T.] Mayo Clin, Jacksonville, FL USA. [Knowler, W. C.] NIDDK, NIH, Phoenix, AZ USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 153 BP 71 EP 71 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235500154 ER PT J AU Terrault, NA Stravitz, RT Lok, AS Everson, GT Brown, RS Kulik, LB Olthoff, KM Saab, S Rubinas, T Argo, CK Everhart, JE Rodrigo, DR AF Terrault, N. A. Stravitz, R. T. Lok, A. S. Everson, G. T. Brown, R. S., Jr. Kulik, L. B. Olthoff, K. M. Saab, S. Rubinas, T. Argo, C. K. Everhart, J. E. Rodrigo, D. R. TI Long-Term Hepatitis C (HCV) Graft Loss and Fibrosis Severity Is Unrelated to Donor Type: Results from the Adult to Adult Living Donor Liver Transplantation (A2ALL) Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Terrault, N. A.] UCSF, San Francisco, CA USA. [Lok, A. S.; Rodrigo, D. R.] Univ Michigan, Ann Arbor, MI 48109 USA. [Everson, G. T.] Univ Colorado, Boulder, CO 80309 USA. [Brown, R. S., Jr.] Columbia Univ, New York, NY 10027 USA. [Olthoff, K. M.] Univ Penn, Philadelphia, PA 19104 USA. [Saab, S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Everhart, J. E.] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 270 BP 107 EP 107 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235500271 ER PT J AU Hall, E Pfeiffer, R Engels, E Segev, D AF Hall, E. Pfeiffer, R. Engels, E. Segev, D. TI Association of Induction Therapy with Cancer after Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Hall, E.; Segev, D.] Johns Hopkins, Baltimore, MD USA. [Pfeiffer, R.; Engels, E.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 528 BP 186 EP 186 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235501152 ER PT J AU Hall, E Pfeiffer, R Segev, D Engels, E AF Hall, E. Pfeiffer, R. Segev, D. Engels, E. TI Cumulative Incidence of Cancer after Solid Organ Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Hall, E.; Pfeiffer, R.; Engels, E.] NCI, Rockville, MD USA. [Hall, E.; Segev, D.] Johns Hopkins, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 532 BP 187 EP 188 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235501156 ER PT J AU Burckart, GJ Figg, WD Brooks, MM Green, D Girnita, DM Troutman, S Chinnock, R Canter, C Addonizio, L Bernstein, D Kirklin, JK Naftel, D Price, DK Zeevi, A Webber, SA AF Burckart, G. J. Figg, W. D., II Brooks, M. M. Green, D. Girnita, D. M. Troutman, S. Chinnock, R. Canter, C. Addonizio, L. Bernstein, D. Kirklin, J. K. Naftel, D. Price, D. K. Zeevi, A. Webber, S. A. TI A Multi-Institutional Study of Outcomes after Pediatric Heart Transplantation: Effect of ABCC2 Polymorphisms SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Burckart, G. J.; Green, D.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Figg, W. D., II; Troutman, S.; Price, D. K.] NCI, NIH, Bethesda, MD 20892 USA. [Brooks, M. M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Girnita, D. M.; Zeevi, A.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. Loma Linda Univ, Dept Pediat, Loma Linda, CA 92350 USA. [Chinnock, R.] Washington Univ, Sch Med, Dept Pediat Cardiol, St Louis, MO USA. [Canter, C.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Addonizio, L.] Stanford Univ, Div Pediat Cardiol, Palo Alto, CA 94304 USA. [Bernstein, D.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Kirklin, J. K.; Naftel, D.] Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 820 BP 270 EP 270 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235502041 ER PT J AU Danziger-Isakov, L Storch, G Buller, R Mason, S Worley, S Conrad, C Faro, A Goldfarb, S Hayes, D Schecter, M Spencer, H Visner, G Williams, N Ikle, D Sweet, SC AF Danziger-Isakov, L. Storch, G. Buller, R. Mason, S. Worley, S. Conrad, C. Faro, A. Goldfarb, S. Hayes, D., Jr. Schecter, M. Spencer, H. Visner, G. Williams, N. Ikle, D. Sweet, S. C. TI Prospective Viral Recovery and Concordance between Nasopharyngeal & Bronchoalveolar Lavage Specimens in Pediatric Lung Transplant SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Danziger-Isakov, L.; Worley, S.] Cleveland Clin, Cleveland, OH USA. [Storch, G.; Buller, R.; Mason, S.; Faro, A.; Sweet, S. C.] Washington Univ, St Louis, MO 63130 USA. [Conrad, C.] Lucile Packard Childrens, Palo Alto, CA USA. [Goldfarb, S.] Childrens Philadelphia, Philadelphia, PA USA. [Hayes, D., Jr.] Nationwide Childrens, Columbus, OH USA. [Schecter, M.] Texas Childrens, Houston, TX USA. [Visner, G.] Childrens Boston, Boston, MA USA. [Williams, N.] NIH, Bethesda, MD USA. [Ikle, D.] RHO Inc, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 964 BP 309 EP 309 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235502185 ER PT J AU Ota, Y Hisada, M Cameron, AM Zhang, X Gao, B Montgomery, RA Williams, GM Sun, Z AF Ota, Y. Hisada, M. Cameron, A. M. Zhang, X. Gao, B. Montgomery, R. A. Williams, G. M. Sun, Z. TI Successful Transplantation of Reduced Sized Rat Alcoholic Fatty Livers Made Possible by Mobilization of Host Stem Cells SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Ota, Y.; Hisada, M.; Cameron, A. M.; Zhang, X.; Montgomery, R. A.; Williams, G. M.; Sun, Z.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Gao, B.] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 1264 BP 399 EP 399 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235503167 ER PT J AU Singh, AA Seavey, CN Corcoran, PC Hoyt, RF Lewis, BGT Thomas, ML Ayares, D Horvath, KA Mohiuddin, MM AF Singh, A. A. Seavey, C. N. Corcoran, P. C. Hoyt, R. F. Lewis, B. G. T. Thomas, M. L. Ayares, D. Horvath, K. A. Mohiuddin, M. M. TI Increased Number of CD4+CD25 HIFOXP3+T Regulatory Cells in Recipient Baboons Is Associated with Long-Term Pig Cardiac Xenograft Survival. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Singh, A. A.; Seavey, C. N.; Corcoran, P. C.; Horvath, K. A.; Mohiuddin, M. M.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F.] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Lewis, B. G. T.; Thomas, M. L.] NIH, DVR, ORS, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 1434 BP 448 EP 448 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235504009 ER PT J AU Mohiuddin, MM Singh, AK Corcoran, PC Thomas, ML Lewis, B Hoyt, RF Ayares, D Reimann, KA Horvath, KA AF Mohiuddin, M. M. Singh, A. K. Corcoran, P. C. Thomas, M. L. Lewis, B. Hoyt, R. F. Ayares, D. Reimann, K. A. Horvath, K. A. TI Co-Stimulation Blockade by Anti CD40 (Clone 2C10) Extends Graft Survival Significantly and Has Multiple Advantages over Anti CD154 (5C8) and Anti CD40 (3A8) Use in a Heterotopic Cardiac Xenotransplantation Model SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY, 2012 CL Boston, MA C1 [Mohiuddin, M. M.; Singh, A. K.; Corcoran, P. C.; Horvath, K. A.] NHLBI, NIH, Cardiothorac Surg Res Program, Bethesda, MD 20892 USA. [Thomas, M. L.; Lewis, B.] NIH, ORS, DVR, Bethesda, MD 20892 USA. [Hoyt, R. F.] NHLBI, NIH, LAMS, Bethesda, MD 20892 USA. [Reimann, K. A.] Beth Israel Deaconess Med Ctr, Boston, MA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 SU 3 SI SI MA 1719 BP 530 EP 531 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QX UT WOS:000303235504309 ER PT J AU Engels, EA Preiksaitis, J Zingone, A Landgren, O AF Engels, E. A. Preiksaitis, J. Zingone, A. Landgren, O. TI Circulating Antibody Free Light Chains and Risk of Posttransplant Lymphoproliferative Disorder SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Epstein-Barr virus; immunology; lymphocyte activation; monoclonal gammopathy of undertermined significance; posttransplant lymphoproliferative disorder; tumor markers ID EPSTEIN-BARR-VIRUS; ORGAN TRANSPLANT RECIPIENTS; MONOCLONAL GAMMOPATHY; RHEUMATOID-ARTHRITIS; SERUM; EBV; LYMPHOMA; DISEASE; IMMUNOGLOBULINS; INFLAMMATION AB Posttransplant lymphoproliferative disorder (PTLD) is a major complication of solid-organ transplantation. With human immunodeficiency virus infection (an analogous immunosuppressive state), elevated kappa and lambda immunoglobulin free light chains (FLCs) in peripheral blood are associated with increased risk of lymphoma. To assess the role of B-cell dysfunction in PTLD, we measured circulating FLCs among Canadian transplant recipients, including 29 individuals with PTLD and 57 matched transplant recipients who were PTLD-free. Compared with controls, PTLD cases had higher kappa FLCs (median 1.53 vs. 1.07 times upper limit of normal) and lambda FLCs (1.03 vs. 0.68). Using samples obtained on average 3.5 months before PTLD diagnosis, cases were more likely to have polyclonal FLC elevations (i.e. elevated kappa and/or lambda with normal kappa/lambda ratio: odds ratio [OR] 4.2, 95%CI 1.115) or monoclonal elevations (elevated kappa and/or lambda with abnormal ratio: OR 3.0, 95%CI 0.518). Strong FLC-PTLD associations were also observed at diagnosis/selection. Among recipients with EpsteinBarr virus (EBV) DNA measured in blood, EBV DNAemia was associated with FLC abnormalities (ORs 6.2 and 3.2 for monoclonal and polyclonal elevations). FLC elevations are common in transplant recipients and associated with heightened PTLD risk. FLCs likely reflect B-cell dysfunction, perhaps related to EBV-driven lymphoproliferation. C1 [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Preiksaitis, J.] Univ Alberta, Dept Med, Div Infect Dis, Edmonton, AB, Canada. [Zingone, A.; Landgren, O.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM engelse@exchange.nih.gov FU National Cancer Institute FX This study was funded by the intramural program of the National Cancer Institute. NR 32 TC 10 Z9 10 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 IS 5 BP 1268 EP 1274 DI 10.1111/j.1600-6143.2011.03954.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QT UT WOS:000303235100025 PM 22300426 ER PT J AU Koulmanda, M Qipo, A Fan, Z Smith, N Auchincloss, H Zheng, XX Strom, TB AF Koulmanda, M. Qipo, A. Fan, Z. Smith, N. Auchincloss, H. Zheng, X. X. Strom, T. B. TI Prolonged Survival of Allogeneic Islets in Cynomolgus Monkeys After Short-Term Triple Therapy SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Islet allograft; nonhuman primate; transplantation; triple therapy ID REGULATORY T-CELLS; ALLOGRAFT; TRANSPLANTATION; STREPTOZOTOCIN; LYMPHOCYTES; TOLERANCE; PHENOTYPE; RESISTANT; REJECTION; BLOCKADE AB Preclinical studies in nonhuman primates (NHP) are particularly useful to evaluate the safety and efficacy of new therapeutic proteins developed for use in clinical transplantation. We hypothesized that a treatment that selectively destroys activated cytopathic donor reactive T cells while sparing resting and immunoregulatory T cells in a mouse model might also produce long-term drug-free engraftment and tolerance without the hazards of lymphopenia in the challenging nonhuman primate islet allograft model. Short-term treatment with a regimen consisting of rapamycin, and IL-2.Ig plus mutant antagonist-type IL-15.Ig cytolytic fusion proteins (triple therapy) posttransplantation results in prolonged, drug-free engraftment of cynomolgus islet allografts. Moreover slow progressive loss of islet function in some recipients was not associated with obvious pathologic evidence of rejection. C1 [Koulmanda, M.; Qipo, A.; Fan, Z.; Zheng, X. X.; Strom, T. B.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Koulmanda, M.; Qipo, A.; Fan, Z.; Zheng, X. X.; Strom, T. B.] Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Dept Med, Transplant Inst, Boston, MA 02114 USA. [Smith, N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Auchincloss, H.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Auchincloss, H.] NIAID, Bethesda, MD 20892 USA. [Zheng, X. X.] Univ Pittsburgh, Thomas Starzl Transplant Inst, Pittsburgh, PA USA. RP Koulmanda, M (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM mkoulman@bidmc.harvard.edu FU NIH [PO1 DK53087]; Juvenile Diabetes Research Foundation Center for Islet Transplantation at Harvard Medical School FX We thank Vaja Tchipashivili from the Joslin Diabetes Center for providing monkey islets and Luba Zachachin for expert assistance with tissue processing. This work was funded in part by the NIH PO1 DK53087 and the Juvenile Diabetes Research Foundation Center for Islet Transplantation at Harvard Medical School. NR 21 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2012 VL 12 IS 5 BP 1296 EP 1302 DI 10.1111/j.1600-6143.2012.03973.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 931QT UT WOS:000303235100028 PM 22390179 ER PT J AU Sharma, V Wikstrom, M Kaila, VRI AF Sharma, Vivek Wikstrom, Marten Kaila, Ville R. I. TI Dynamic water networks in cytochrome cbb(3) oxidase SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article DE Proton channel; Proton pumping; cbb(3)-type cytochrome c oxidase; Continuum electrostatics; Density functional theory (DFT); Molecular dynamics (MD) simulation ID COPPER OXYGEN REDUCTASES; SITE-DIRECTED MUTAGENESIS; C-OXIDASE; RHODOBACTER-SPHAEROIDES; MOLECULAR-DYNAMICS; ACTIVE-SITE; PROTON PUMP; ELECTROSTATIC CALCULATIONS; BRADYRHIZOBIUM-JAPONICUM; THERMUS-THERMOPHILUS AB Heme-copper oxidases (HCOs) are terminal electron acceptors in aerobic respiration. They catalyze the reduction of molecular oxygen to water with concurrent pumping of protons across the mitochondrial and bacterial membranes. Protons required for oxygen reduction chemistry and pumping are transferred through proton uptake channels. Recently, the crystal structure of the first C-type member of the HCO superfamily was resolved [Buschmann et al. Science 329 (2010) 327-330], but crystallographic water molecules could not be identified. Here we have used molecular dynamics (MD) simulations, continuum electrostatic approaches, and quantum chemical cluster calculations to identify proton transfer pathways in cytochrome cbb(3). In MD simulations we observe formation of stable water chains that connect the highly conserved Glu323 residue on the proximal side of heme b(3) both with the N- and the P-sides of the membrane. We propose that such pathways could be utilized for redox-coupled proton pumping in the C-type oxidases. Electrostatics and quantum chemical calculations suggest an increased proton affinity of Glu323 upon reduction of high-spin heme b(3). Protonation of Glu323 provides a mechanism to tune the redox potential of heme b(3) with possible implications for proton pumping. (C) 2011 Published by Elsevier B.V. C1 [Sharma, Vivek; Wikstrom, Marten] Univ Helsinki, Inst Biotechnol, Helsinki Bioenerget Grp, Programme Struct Biol & Biophys, FIN-00014 Helsinki, Finland. [Kaila, Ville R. I.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Sharma, V (reprint author), Univ Helsinki, Inst Biotechnol, Helsinki Bioenerget Grp, Programme Struct Biol & Biophys, PB 65,Viikinkaari 1, FIN-00014 Helsinki, Finland. EM vivek.sharma@helsinki.fi; marten.wikstrom@helsinki.fi; ville.kaila@nih.gov RI Sharma, Vivek/G-7383-2012; OI Sharma, Vivek/0000-0002-8838-3151 FU Sigrid Juselius Foundation; Viikki Graduate School in Molecular Biosciences; European Molecular Biology Organization (EMBO); National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Biocentrum Helsinki; Academy of Finland FX V.S. is supported from Sigrid Juselius Foundation and Viikki Graduate School in Molecular Biosciences. V.R.I.K. acknowledges the European Molecular Biology Organization (EMBO) for a Long-Term Fellowship and the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases for support. The research was supported by the Sigrid Juselius Foundation, Biocentrum Helsinki and the Academy of Finland. The Center for Scientific Computing (CSC), Finland, and the Biowulf cluster at NIH are acknowledged for computing time. NR 86 TC 8 Z9 8 U1 1 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD MAY PY 2012 VL 1817 IS 5 BP 726 EP 734 DI 10.1016/j.bbabio.2011.09.010 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 930YV UT WOS:000303181800006 PM 21963365 ER PT J AU Haraldson, K Kashuba, VI Dmitriev, AA Senchenko, VN Kudryavtseva, AV Pavlova, TV Braga, EA Pronina, IV Kondratov, AG Rynditch, AV Lerman, MI Zabarovsky, ER AF Haraldson, Klas Kashuba, Vladimir I. Dmitriev, Alexey A. Senchenko, Vera N. Kudryavtseva, Anna V. Pavlova, Tatiana V. Braga, Eleonora A. Pronina, Irina V. Kondratov, Alexandr G. Rynditch, Alla V. Lerman, Michael I. Zabarovsky, Eugene R. TI LRRC3B gene is frequently epigenetically inactivated in several epithelial malignancies and inhibits cell growth and replication SO BIOCHIMIE LA English DT Article DE Cancer; Tumor suppressor gene; NotI microarrays; Methylation; RT-qPCR ID TUMOR-SUPPRESSOR GENE; DNA METHYLATION; LUNG-CANCER; PROMOTER METHYLATION; HYPERMETHYLATION; MICROARRAYS; EXPRESSION; CARCINOMA; DELETIONS; LEUKEMIA AB Chromosome 3 specific NotI microarrays containing 180 NotI linking clones associated with 188 genes were hybridized to NotI representation probes prepared using matched tumor/normal samples from major epithelial cancers: breast (47 pairs), lung (40 pairs) cervical (43 pairs), kidney (34 pairs of clear cell renal cell carcinoma), colon (24 pairs), ovarian (25 pairs) and prostate (18 pairs). In all tested primary tumors (compared to normal controls) methylation and/or deletions was found. For the first time we showed that the gene LRRC3B was frequently methylated and/or deleted in breast carcinoma - 32% of samples, cervical - 35%, lung - 40%, renal - 35%, ovarian - 28%, colon - 33% and prostate cancer - 44%. To check these results bisulfite sequencing using cloned PCR products with representative two breast, one cervical, two renal, two ovarian and two colon cancer samples was performed. In all cases methylation was confirmed. Expression analysis using RT-qPCR showed that LRRC3B is strongly down-regulated at the latest stages of RCC and ovarian cancers. In addition we showed that LRRC3B exhibit strong cell growth inhibiting activity (more than 95%) in colony formation experiments in vitro in KRC/Y renal cell carcinoma line. All these data suggest that LRRC3B gene could be involved in the process of carcinogenesis as a tumor suppressor gene. (C) 2012 Elsevier Masson SAS. All rights reserved. C1 [Haraldson, Klas; Kashuba, Vladimir I.; Dmitriev, Alexey A.; Senchenko, Vera N.; Pavlova, Tatiana V.; Zabarovsky, Eugene R.] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Kashuba, Vladimir I.; Kondratov, Alexandr G.; Rynditch, Alla V.] Ukrainian Acad Sci, Inst Mol Biol & Genet, UA-252627 Kiev, Ukraine. [Dmitriev, Alexey A.; Senchenko, Vera N.; Kudryavtseva, Anna V.; Zabarovsky, Eugene R.] RAS, VA Engelhardt Mol Biol Inst, Moscow 117901, Russia. [Braga, Eleonora A.; Pronina, Irina V.] Russian State Genet Ctr, Moscow, Russia. [Lerman, Michael I.] NIH, NHLBI, Hematol Branch, Bethesda, MD USA. [Zabarovsky, Eugene R.] Linkoping Univ, Inst Klin & Expt Med, S-58183 Linkoping, Sweden. RP Zabarovsky, ER (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. EM eugzab@ki.se RI Dmitriev, Alexey/D-6109-2011; Senchenko, Vera/C-8992-2014; Kudryavtseva, Anna/C-9032-2014; Braga, Eleonora/P-5574-2016 OI Dmitriev, Alexey/0000-0002-6827-9584; Senchenko, Vera/0000-0002-3119-515X; Kudryavtseva, Anna/0000-0002-3722-8207; FU Swedish Cancer Society; Swedish Institute; Swedish Research Council; Karolinska Institute, State [02.740.11.5227, 16.552.11.7034]; Russian Ministry of Education and Science; Russian Foundation for Basic Research [10-04-01213-a, 11-04-00269] FX This work was supported by research grants from the Swedish Cancer Society, the Swedish Institute, the Swedish Research Council and Karolinska Institute, State Contracts 02.740.11.5227 and 16.552.11.7034 with the Russian Ministry of Education and Science and by grants 10-04-01213-a and 11-04-00269 from the Russian Foundation for Basic Research. NR 33 TC 11 Z9 13 U1 0 U2 3 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD MAY PY 2012 VL 94 IS 5 BP 1151 EP 1157 DI 10.1016/j.biochi.2012.01.019 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 932LI UT WOS:000303292200010 PM 22321817 ER PT J AU Oskvig, DB Elkahloun, AG Johnson, KR Phillips, TM Herkenham, M AF Oskvig, Devon B. Elkahloun, Abdel G. Johnson, Kory R. Phillips, Terry M. Herkenham, Miles TI Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Maternal immune activation; Inflammation; Cytokine; Lipopolysaccharide; Schizophrenia; Autism; Microarray; Bioinformatics; Cortical interneurons; GABA ID AUTISM SPECTRUM DISORDERS; AUTOPHAGIC CELL-DEATH; LIPID-BINDING PROTEIN; CORTICAL INTERNEURONS; BRAIN-DEVELOPMENT; TRANSCRIPTIONAL REGULATION; INFLAMMATORY RESPONSE; HIPPOCAMPAL-NEURONS; PRENATAL INFECTION; ALPHA-HEMOGLOBIN AB Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism. Published by Elsevier Inc. C1 [Oskvig, Devon B.; Herkenham, Miles] NIMH, Funct Neuroanat Sect, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NIH, Div Intramural Res Programs, Microarray Core Facil, Bethesda, MD 20892 USA. [Johnson, Kory R.] Natl Inst Neurol Disorders & Stroke, Bioinformat Sect, NIH, Bethesda, MD 20892 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Section, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), Bldg 35,Rm 1C913, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238 FU National Institute of Mental Health, NIH FX The research was supported by the Intramural Research Program, National Institute of Mental Health, NIH. NR 115 TC 44 Z9 46 U1 3 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAY PY 2012 VL 26 IS 4 BP 623 EP 634 DI 10.1016/j.bbi.2012.01.015 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 929PV UT WOS:000303078800016 PM 22310921 ER PT J AU Johannesdottir, F Aspelund, T Siggeirsdottir, K Jonsson, BY Mogensen, B Sigurdsson, S Harris, TB Gudnason, VG Lang, TF Sigurdsson, G AF Johannesdottir, Fjola Aspelund, Thor Siggeirsdottir, Kristin Jonsson, Brynjolfur Y. Mogensen, Brynjolfur Sigurdsson, Sigurdur Harris, Tamara B. Gudnason, Vilmundur G. Lang, Thomas F. Sigurdsson, Gunnar TI Mid-Thigh Cortical Bone Structural Parameters, Muscle Mass and Strength, and Association with Lower Limb Fractures in Older Men and Women (AGES-Reykjavik Study) SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Mid-thigh; Muscle-bone relationship; Aging; Fracture risk; CT ID MINERAL DENSITY; TRABECULAR BONE; ELDERLY-MEN; POSTMENOPAUSAL WOMEN; WHOLE-BODY; LOWER LEG; HIP; ADULTS; EXERCISE; HEALTH AB In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained < 10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns. C1 [Mogensen, Brynjolfur; Sigurdsson, Gunnar] Landspitali Univ Hosp, IS-108 Reykjavik, Iceland. [Aspelund, Thor; Siggeirsdottir, Kristin; Sigurdsson, Sigurdur; Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsson, Brynjolfur Y.] Malmo Univ Hosp, Malmo, Sweden. [Johannesdottir, Fjola; Aspelund, Thor; Mogensen, Brynjolfur; Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.] Natl Inst Aging, Bethesda, MD USA. [Lang, Thomas F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Sigurdsson, G (reprint author), Landspitali Univ Hosp, IS-108 Reykjavik, Iceland. EM gunnars@landspitali.is RI Lang, Thomas/B-2685-2012; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Lang, Thomas/0000-0002-3720-8038; Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-1-2100]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson; University of Iceland FX This study was funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), and the memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson. G.S. acknowledges support from the University of Iceland Research Fund. The study was approved by the Icelandic National Bioethics Committee (VSN 00-063). The researchers are indebted to the participants for their willingness to participate in the study. NR 45 TC 15 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD MAY PY 2012 VL 90 IS 5 BP 354 EP 364 DI 10.1007/s00223-012-9585-6 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 928VX UT WOS:000303017300002 PM 22451219 ER PT J AU Eheman, C Henley, SJ Ballard-Barbash, R Jacobs, EJ Schymura, MJ Noone, AM Pan, LP Anderson, RN Fulton, JE Kohler, BA Jemal, A Ward, E Plescia, M Ries, LAG Edwards, BK AF Eheman, Christie Henley, S. Jane Ballard-Barbash, Rachel Jacobs, Eric J. Schymura, Maria J. Noone, Anne-Michelle Pan, Liping Anderson, Robert N. Fulton, Janet E. Kohler, Betsy A. Jemal, Ahmedin Ward, Elizabeth Plescia, Marcus Ries, Lynn A. G. Edwards, Brenda K. TI Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity SO CANCER LA English DT Editorial Material DE cancer; incidence; mortality; Surveillance; Epidemiology; and End Results; the North American Association of Central Cancer Registries; National Program of Cancer Registries; United States; obesity; physical inactivity ID BODY-MASS INDEX; UNITED-STATES; COLORECTAL-CANCER; BREAST-CANCER; CHILDHOOD OBESITY; INCIDENCE RATES; COLON-CANCER; RISK-FACTORS; LUNG-CANCER; EPIDEMIOLOGIC EVIDENCE AB BACKGROUND: Annual updates on cancer occurrence and trends in the United States are provided through collaboration between the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This year's report highlights the increased cancer risk associated with excess weight (overweight or obesity) and lack of sufficient physical activity (<150 minutes of physical activity per week). METHODS: Data on cancer incidence were obtained from the CDC, NCI, and NAACCR; data on cancer deaths were obtained from the CDC's National Center for Health Statistics. Annual percent changes in incidence and death rates (age-standardized to the 2000 US population) for all cancers combined and for the leading cancers among men and among women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2008 and mortality for 1975-2008) and short-term trends (1999-2008). Information was obtained from national surveys about the proportion of US children, adolescents, and adults who are overweight, obese, insufficiently physically active, or physically inactive. RESULTS: Death rates from all cancers combined decreased from 1999 to 2008, continuing a decline that began in the early 1990s, among men and among women in most racial and ethnic groups. Death rates decreased from 1999 to 2008 for most cancer sites, including the 4 most common cancers (lung, colorectum, breast, and prostate). The incidence of prostate and colorectal cancers also decreased from 1999 to 2008. Lung cancer incidence declined from 1999 to 2008 among men and from 2004 to 2008 among women. Breast cancer incidence decreased from 1999 to 2004 but was stable from 2004 to 2008. Incidence increased for several cancers, including pancreas, kidney, and adenocarcinoma of the esophagus, which are associated with excess weight. CONCLUSIONS: Although improvements are reported in the US cancer burden, excess weight and lack of sufficient physical activity contribute to the increased incidence of many cancers, adversely affect quality of life for cancer survivors, and may worsen prognosis for several cancers. The current report highlights the importance of efforts to promote healthy weight and sufficient physical activity in reducing the cancer burden in the United States.* Cancer 2012; 118: 2338-66. (C) 2012 American Cancer Society. C1 [Eheman, Christie; Henley, S. Jane; Plescia, Marcus] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Ballard-Barbash, Rachel; Noone, Anne-Michelle; Ries, Lynn A. G.; Edwards, Brenda K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Schymura, Maria J.; Kohler, Betsy A.] N Amer Assoc Cent Canc Registries, Springfield, IL USA. [Schymura, Maria J.] New York State Canc Registry, Albany, NY USA. [Pan, Liping; Fulton, Janet E.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Anderson, Robert N.] Ctr Dis Control & Prevent, Div Vital Stat, Natl Ctr Hlth Stat, Atlanta, GA 30341 USA. [Jemal, Ahmedin; Ward, Elizabeth] Amer Canc Soc, Surveillance & Hlth Policy Res Dept, Atlanta, GA 30329 USA. RP Eheman, C (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE,Mailstop F-69, Atlanta, GA 30341 USA. EM cre1@cdc.gov OI Henley, S Jane/0000-0002-2420-306X FU Intramural CDC HHS [CC999999] NR 134 TC 212 Z9 223 U1 11 U2 57 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 MAY 1 PY 2012 VL 118 IS 9 BP 2338 EP 2366 DI 10.1002/cncr.27514 PG 29 WC Oncology SC Oncology GA 929ES UT WOS:000303044600003 PM 22460733 ER PT J AU Suh, KS Malik, M Shukla, A Ryscavage, A Wright, L Jividen, K Crutchley, JM Dumont, RA Fernandez-Salas, E Webster, JD Simpson, RM Yuspa, SH AF Suh, K. Stephen Malik, Mariam Shukla, Anjali Ryscavage, Andrew Wright, Lisa Jividen, Kasey Crutchley, John M. Dumont, Rebecca A. Fernandez-Salas, Ester Webster, Joshua D. Simpson, R. Mark Yuspa, Stuart H. TI CLIC4 is a tumor suppressor for cutaneous squamous cell cancer SO CARCINOGENESIS LA English DT Article ID CHLORIDE CHANNEL PROTEIN; ION-CHANNEL; NUCLEAR TRANSLOCATION; PROTEOMIC ANALYSIS; INDUCED APOPTOSIS; CRYSTAL-STRUCTURE; REDOX REGULATION; GENE-EXPRESSION; STEM-CELLS; DIFFERENTIATION AB Chloride intracellular channel (CLIC) 4 is a member of a redox-regulated, metamorphic multifunctional protein family, first characterized as intracellular chloride channels. Current knowledge indicates that CLICs participate in signaling, cytoskeleton integrity and differentiation functions of multiple tissues. In metabolically stressed skin keratinocytes, cytoplasmic CLIC4 is S-nitrosylated and translocates to the nucleus where it enhances transforming growth factor-beta (TGF-beta) signaling by protecting phospho-Smad 2 and 3 from dephosphorylation. CLIC4 expression is diminished in multiple human epithelial cancers, and the protein is excluded from the nucleus. We now show that CLIC4 expression is reduced in chemically induced mouse skin papillomas, mouse and human squamous carcinomas and squamous cancer cell lines, and the protein is excluded from the nucleus. The extent of reduction in CLIC4 coincides with progression of squamous tumors from benign to malignant. Inhibiting antioxidant defense in tumor cells increases S-nitrosylation and nuclear translocation of CLIC4. Adenoviral-mediated reconstitution of nuclear CLIC4 in squamous cancer cells enhances TGF-beta-dependent transcriptional activity and inhibits growth. Adenoviral targeting of CLIC4 to the nucleus of tumor cells in orthografts inhibits tumor growth, whereas elevation of CLIC4 in transgenic epidermis reduces de novo chemically induced skin tumor formation. In parallel, overexpression of exogenous CLIC4 in squamous tumor orthografts suppresses tumor growth and enhances TGF-beta signaling. These results indicate that CLIC4 suppresses the growth of squamous cancers, that reduced CLIC4 expression and nuclear residence detected in cancer cells is associated with the altered redox state of tumor cells and the absence of detectable nuclear CLIC4 in cancers contributes to TGF-beta resistance and enhances tumor development. C1 [Suh, K. Stephen; Malik, Mariam; Shukla, Anjali; Ryscavage, Andrew; Wright, Lisa; Jividen, Kasey; Crutchley, John M.; Dumont, Rebecca A.; Fernandez-Salas, Ester; Webster, Joshua D.; Simpson, R. Mark; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov RI Shukla, Anjali/G-4046-2014; OI Jividen, Kasey/0000-0003-1022-5038 FU Center for Cancer Research, National Cancer Institute, USA FX This work was supported by the Intramural research program of the Center for Cancer Research, National Cancer Institute, USA. NR 50 TC 10 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2012 VL 33 IS 5 BP 986 EP 995 DI 10.1093/carcin/bgs115 PG 10 WC Oncology SC Oncology GA 933DE UT WOS:000303338800006 PM 22387366 ER PT J AU Barnes, KA Nelson, SM Cohen, AL Power, JD Coalson, RS Miezin, FM Vogel, AC Dubis, JW Church, JA Petersen, SE Schlaggar, BL AF Barnes, Kelly Anne Nelson, Steven M. Cohen, Alexander L. Power, Jonathan D. Coalson, Rebecca S. Miezin, Francis M. Vogel, Alecia C. Dubis, Joseph W. Church, Jessica A. Petersen, Steven E. Schlaggar, Bradley L. TI Parcellation in Left Lateral Parietal Cortex Is Similar in Adults and Children SO CEREBRAL CORTEX LA English DT Article DE brain development; functional areas; functional connectivity; parietal lobe ID HUMAN CEREBRAL-CORTEX; BRAIN-DEVELOPMENT; WORKING-MEMORY; VISUAL-CORTEX; STRUCTURAL CONNECTIVITY; DEVELOPMENTAL-CHANGES; ADOLESCENT BRAIN; CORTICAL AREAS; DEFAULT MODE; NETWORKS AB A key question in developmental neuroscience involves understanding how and when the cerebral cortex is partitioned into distinct functional areas. The present study used functional connectivity MRI mapping and graph theory to identify putative cortical areas and generate a parcellation scheme of left lateral parietal cortex (LLPC) in 7 to 10-year-old children and adults. Results indicated that a majority of putative LLPC areas could be matched across groups (mean distance between matched areas across age: 3.15 mm). Furthermore, the boundaries of children's putative LLPC areas respected the boundaries generated from the adults' parcellation scheme for a majority of children's areas (13/15). Consistent with prior research, matched LLPC areas showed age-related differences in functional connectivity strength with other brain regions. These results suggest that LLPC cortical parcellation and functional connectivity mature along different developmental trajectories, with adult-like boundaries between LLPC areas established in school-age children prior to adult-like functional connectivity. C1 [Barnes, Kelly Anne; Cohen, Alexander L.; Power, Jonathan D.; Coalson, Rebecca S.; Miezin, Francis M.; Vogel, Alecia C.; Dubis, Joseph W.; Church, Jessica A.; Petersen, Steven E.; Schlaggar, Bradley L.] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Nelson, Steven M.; Petersen, Steven E.] Washington Univ, Dept Psychol, St Louis, MO 63110 USA. [Coalson, Rebecca S.; Miezin, Francis M.; Petersen, Steven E.; Schlaggar, Bradley L.] Washington Univ, Dept Radiol, St Louis, MO 63110 USA. [Petersen, Steven E.; Schlaggar, Bradley L.] Washington Univ, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Schlaggar, Bradley L.] Washington Univ, Dept Pediat, St Louis, MO 63110 USA. RP Barnes, KA (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C-104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA. EM kelly.barnes@nih.gov RI Cohen, Alexander/A-6865-2009; Church, Jessica/L-2659-2016 OI Cohen, Alexander/0000-0001-6557-5866; Church, Jessica/0000-0003-1369-9116 FU National Institutes of Health [NS007205-28, NS062489, NS053425, HD057076, MH091512, NS06114, NS046424]; Simons Foundation Autism Research Initiative FX National Institutes of Health (grants NS007205-28 to K. A. B., NS062489 to A. L. C., NS053425, HD057076, and MH091512 to B. L. S., and NS06114 and NS046424 to S. E. P.); Simons Foundation Autism Research Initiative. NR 67 TC 18 Z9 18 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD MAY PY 2012 VL 22 IS 5 BP 1148 EP 1158 DI 10.1093/cercor/bhr189 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 930SX UT WOS:000303161400017 PM 21810781 ER PT J AU Mugnaini, C Nocerino, S Pedani, V Pasquini, S Tafi, A De Chiaro, M Bellucci, L Valoti, M Guida, F Luongo, L Dragoni, S Ligresti, A Rosenberg, A Bolognini, D Cascio, MG Pertwee, RG Moaddel, R Maione, S Di Marzo, V Corelli, F AF Mugnaini, Claudia Nocerino, Stefania Pedani, Valentina Pasquini, Serena Tafi, Andrea De Chiaro, Maria Bellucci, Luca Valoti, Massimo Guida, Francesca Luongo, Livio Dragoni, Stefania Ligresti, Alessia Rosenberg, Avraham Bolognini, Daniele Cascio, Maria Grazia Pertwee, Roger G. Moaddel, Ruin Maione, Sabatino Di Marzo, Vincenzo Corelli, Federico TI Investigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach SO CHEMMEDCHEM LA English DT Article DE bioisosteres; cannabinoids; quinolones; receptors; structure-activity relationships ID PHARMACOLOGICALLY ACTIVE METABOLITES; ENERGY DECOMPOSITION; DRUG DISCOVERY; CB2 RECEPTORS; IN-VIVO; MOLECULAR-INTERACTIONS; MICROWAVE IRRADIATION; ANTICANCER AGENTS; NEUROPATHIC PAIN; FORMALIN TEST AB Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound. C1 [Mugnaini, Claudia; Nocerino, Stefania; Pedani, Valentina; Pasquini, Serena; Tafi, Andrea; Bellucci, Luca; Corelli, Federico] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy. [Valoti, Massimo; Dragoni, Stefania] Univ Siena, Dipartimento Neurosci, Sez Farmacol, I-53100 Siena, Italy. [Ligresti, Alessia; Di Marzo, Vincenzo] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, I-80078 Naples, Italy. [De Chiaro, Maria; Guida, Francesca; Luongo, Livio; Maione, Sabatino] Univ Naples 2, Dipartimento Med Sperimentale, I-80138 Naples, Italy. [Rosenberg, Avraham; Moaddel, Ruin] NIA, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Bolognini, Daniele; Cascio, Maria Grazia; Pertwee, Roger G.] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. RP Mugnaini, C (reprint author), Univ Siena, Dipartimento Farmaco Chim Tecnol, Via De Gasperi 2, I-53100 Siena, Italy. EM claudia.mugnaini@unisi.it; federico.corelli@unisi.it RI Ligresti, Alessia/B-7564-2015; OI Luongo, Livio/0000-0002-1949-2039; Pertwee, Roger/0000-0003-3227-2783 FU US National Institute on Aging; US National Institutes of Health (NIH) [DA-03672] FX A.L. and V.D.M. thank Mr. Marco Allara (CNR, Pozzuoli, Italy) for technical assistance. R.M. and A.R. thank the Intramural Research Program of the US National Institute on Aging for financial support. D.B., M.G.C. and R.G.P. thank the US National Institutes of Health (NIH) for funding (grant no.: DA-03672). NR 73 TC 11 Z9 11 U1 1 U2 16 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD MAY PY 2012 VL 7 IS 5 BP 920 EP 934 DI 10.1002/cmdc.201100573 PG 15 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 931CP UT WOS:000303192300018 PM 22383251 ER PT J AU Jia, LB AF Jia, Libin TI Cancer Complementary and Alternative Medicine Research at the US National Cancer Institute SO CHINESE JOURNAL OF INTEGRATIVE MEDICINE LA English DT Editorial Material DE complementary and alternative medicine; Chinese medicine; cancer research ID PANCREATIC-CANCER; STEM-CELLS; EXPRESSION; CARCINOMA; 6-SHOGAOL; PHY906; MICE AB The United States National Cancer Institute (NCI) supports complementary and alternative medicine (CAM) research which includes different methods and practices (such as nutrition therapies) and other medical systems (such as Chinese medicine). In recent years, NCI has spent around $120 million each year on various CAM-related research projects on cancer prevention, treatment, symptom/side effect management and epidemiology. The categories of CAM research involved include nutritional therapeutics, pharmacological and biological treatments, mind-body interventions, manipulative and body based methods, alternative medical systems, exercise therapies, spiritual therapies and energy therapies on a range of types of cancer. The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) supports various intramural and extramural cancer CAM research projects. Examples of these cancer CAM projects are presented and discussed. In addition, OCCAM also supports international research projects. C1 NCI, Off Canc Complementary & Alternat Med, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Jia, LB (reprint author), NCI, Off Canc Complementary & Alternat Med, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM libinj@mail.nih.gov NR 20 TC 13 Z9 13 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1672-0415 J9 CHIN J INTEGR MED JI Chin. J. Integr. Med. PD MAY PY 2012 VL 18 IS 5 BP 325 EP 332 DI 10.1007/s11655-011-0950-5 PG 8 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 933LD UT WOS:000303362100002 PM 22241505 ER PT J AU Fan, XY Upadhyaya, B Wu, LM Koh, C Santin-Duran, M Pittaluga, S Uzel, G Kleiner, D Williams, E Ma, CA Bodansky, A Oliveira, JB Edmonds, P Hornung, R Wong, DW Fayer, R Fleisher, T Heller, T Prussin, C Jain, A AF Fan, Xiying Upadhyaya, Bhaskar Wu, Liming Koh, Christopher Santin-Duran, Monica Pittaluga, Stefania Uzel, Gulbu Kleiner, David Williams, Ester Ma, Chi A. Bodansky, Aaron Oliveira, Joao B. Edmonds, Pamela Hornung, Ronald Wong, Duane W. Fayer, Ronald Fleisher, Tom Heller, Theo Prussin, Calman Jain, Ashish TI CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome SO CLINICAL IMMUNOLOGY LA English DT Article DE X-linked hyper-IgM syndrome; CD40 ligand; CP-870,893; CD40-R internalization ID DENDRITIC CELLS; CD40-CD40L INTERACTIONS; IMMUNOLOGICAL FEATURES; T-CELLS; PHASE-I; LIGAND; MICE; ACTIVATION; IMMUNODEFICIENCY; DEFICIENCY AB X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted. Published by Elsevier Inc. C1 [Fan, Xiying; Wu, Liming; Ma, Chi A.; Bodansky, Aaron; Edmonds, Pamela; Jain, Ashish] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Upadhyaya, Bhaskar; Prussin, Calman] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Williams, Ester; Oliveira, Joao B.; Fleisher, Tom] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Kleiner, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wong, Duane W.] Arizona Allergy Associates, Phoenix, AZ USA. [Hornung, Ronald] NCI, SAIC Frederick Inc, Clin Serv Program, Frederick, MD 21701 USA. [Santin-Duran, Monica; Fayer, Ronald] USDA, Environm Microbial & Food Safety Lab, Beltsville, MD 20705 USA. RP Jain, A (reprint author), NIAID, Lab Host Def, NIH, 10 Ctr Dr,Rm 5W 3950, Bethesda, MD 20892 USA. EM ajain@nih.gov OI Oliveira, Joao/0000-0001-9388-8173; Prussin, Calman/0000-0002-3917-3326; Fan, Xiying/0000-0003-3090-381X; Kleiner, David/0000-0003-3442-4453 FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; NIAID/NIH 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 N01-CO-12400, and supported by the intramural program of NIAID/NIH. NR 38 TC 8 Z9 9 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2012 VL 143 IS 2 BP 152 EP 161 DI 10.1016/j.clim.2012.01.014 PG 10 WC Immunology SC Immunology GA 932KV UT WOS:000303290900006 PM 22459705 ER PT J AU Berger, VW AF Berger, Vance W. TI Conservative handling of missing data SO CONTEMPORARY CLINICAL TRIALS LA English DT Letter DE Incentives; ITT; LOCF; Missing at random; Worst rank analysis ID CLINICAL-TRIALS C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 3 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAY PY 2012 VL 33 IS 3 BP 460 EP 460 DI 10.1016/j.cct.2012.02.008 PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 930XM UT WOS:000303178100002 PM 22366777 ER PT J AU Legro, RS Kunselman, AR Brzyski, RG Casson, PR Diamond, MP Schlaff, WD Christman, GM Coutifaris, C Taylor, HS Eisenberg, E Santoro, N Zhang, HP AF Legro, Richard S. Kunselman, Allen R. Brzyski, Robert G. Casson, Peter R. Diamond, Michael P. Schlaff, William D. Christman, Gregory M. Coutifaris, Christos Taylor, Hugh S. Eisenberg, Esther Santoro, Nanette Zhang, Heping CA NICHD Reprod Med Network TI The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: Rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Polycystic Ovary Syndrome; Infertility; Ovulation induction; Hyperandrogenism; Clomiphene citrate; Letrozole ID QUALITY-OF-LIFE; GENERAL PSYCHOMETRIC PROPERTIES; ADAPALENE GEL 0.3-PERCENT; FERTIQOL TOOL DEVELOPMENT; IN-VITRO FERTILIZATION; SURROGATE END-POINTS; ACNE-VULGARIS; OVULATION INDUCTION; AROMATASE INHIBITOR; INSULIN-RESISTANCE AB Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50 mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5 mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (x5 days) or 7.5 mg of letrozole a day (x5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms. (C) 2012 Elsevier Inc. All rights reserved. C1 [Legro, Richard S.] Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Penn State Coll Med, Hershey, PA 17033 USA. [Kunselman, Allen R.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Casson, Peter R.] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Diamond, Michael P.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Schlaff, William D.; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Christman, Gregory M.] Univ Michigan, Dept Obstet, Ann Arbor, MI 48109 USA. [Christman, Gregory M.] Univ Michigan, Dept Gynecol, Ann Arbor, MI 48109 USA. [Coutifaris, Christos] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Taylor, Hugh S.] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. [Eisenberg, Esther] Eunice Kennedy Shriver NICHD, Reprod Sci Branch, Rockville, MD USA. [Zhang, Heping] Yale Univ, Sch Med, Dept Biostat, New Haven, CT USA. RP Legro, RS (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Penn State Coll Med, 500 Univ Dr,H103, Hershey, PA 17033 USA. EM rsl1@psu.edu OI Diamond, Michael/0000-0001-6353-4489 FU National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, U54-HD29834]; National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), General Clinical Research Center [MO1RR10732, C06 RR016499] FX This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049 (to C.C.); U10 HD38992 (to R.S.L.); U10HD055925 (to H.Z.); U10 HD39005 (to M.P.D.); U10 HD33172 (to M.P.S.); U10 HD38998 (to W.D.S); U10 HD055936 (to G.M.C.); U10 HD055942 (to R.G.B.); and U10 HD055944 (to P.R.C.); U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research); General Clinical Research Center Grants MO1RR10732 and construction grant C06 RR016499 (to Pennsylvania State University). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or NIH. NR 48 TC 24 Z9 26 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAY PY 2012 VL 33 IS 3 BP 470 EP 481 DI 10.1016/j.cct.2011.12.005 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 930XM UT WOS:000303178100004 PM 22265923 ER PT J AU Brache, V Sitruk-Ware, R Williams, A Blithe, D Croxatto, H Kumar, N Kumar, S Tsong, YY Sivin, I Nath, A Sussman, H Cochon, L Miranda, MJ Reyes, V Faundes, A Mishell, D AF Brache, Vivian Sitruk-Ware, Regine Williams, Alistair Blithe, Diana Croxatto, Horacio Kumar, Narender Kumar, Sushma Tsong, Yun-Yen Sivin, Irving Nath, Anita Sussman, Heather Cochon, Leila Jose Miranda, Maria Reyes, Veronica Faundes, Anibal Mishell, Daniel, Jr. TI Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women SO CONTRACEPTION LA English DT Article DE Progesterone receptor modulators; Ulipristal acetate; Contraceptive vaginal ring; Ovulation inhibition; Follicular development; PRM-associated endometrial changes ID RANDOMIZED CONTROLLED-TRIAL; LOW-DOSE MIFEPRISTONE; ULIPRISTAL ACETATE; EMERGENCY CONTRACEPTION; DOUBLE-BLIND; CDB-2914; ANTIPROGESTINS; ANTAGONISTS; LEVONORGESTREL; ESTRADIOL AB Background: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. Study Design: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. Results: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of ill "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). Conclusion: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects. (C) 2012 Elsevier Inc. All rights reserved. C1 [Brache, Vivian] Profamilia, Biomed Res Dept, Santo Domingo 10401, Dominican Rep. [Sitruk-Ware, Regine; Kumar, Narender; Kumar, Sushma; Tsong, Yun-Yen; Sivin, Irving; Nath, Anita; Sussman, Heather] Populat Council, Ctr Biomed Res, New York, NY 10017 USA. [Williams, Alistair] Univ Edinburgh, Dept Pathol, Edinburgh EH16 4SA, Midlothian, Scotland. [Blithe, Diana] Natl Inst Child Hlth & Human Dev NICHD, NIH, Bethesda, MD 20892 USA. [Croxatto, Horacio] Univ Santiago Chile, Santiago 32349, Chile. [Jose Miranda, Maria; Reyes, Veronica] Inst Chileno Med Reprod ICMER, Santiago 8320165, Chile. [Mishell, Daniel, Jr.] Univ So Calif, Keck Sch Med, Dept Ob Gyn, Los Angeles, CA 90033 USA. RP Brache, V (reprint author), Profamilia, Biomed Res Dept, POB 1053, Santo Domingo 10401, Dominican Rep. EM vbrache@gmail.com OI Williams, Alistair/0000-0002-7085-4525 FU National Institute of Child Health and Human Development of the National Institutes of Health [U54 HD 29990] FX This study was supported by a grant from the National Institute of Child Health and Human Development of the National Institutes of Health (grant number U54 HD 29990). The authors would like to thank HRA Pharma, Paris, France, for supplying ulipristal acetate for the study. NR 35 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD MAY PY 2012 VL 85 IS 5 BP 480 EP 488 DI 10.1016/j.contraception.2011.10.003 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 931AX UT WOS:000303187500010 PM 22176795 ER PT J AU Rice, TW Rubinson, L Uyeki, TM Vaughn, FL John, BB Miller, RR Higgs, E Randolph, AG Smoot, BE Thompson, BT AF Rice, Todd W. Rubinson, Lewis Uyeki, Timothy M. Vaughn, Frances L. John, Benjamin B. Miller, Russell R., II Higgs, Elizabeth Randolph, Adrienne G. Smoot, B. Elizabeth Thompson, B. Taylor CA NHLBI ARDS Network TI Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States SO CRITICAL CARE MEDICINE LA English DT Article DE bacterial coinfection; critical illness; mortality; pandemic H1N1 influenza ID ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; END-EXPIRATORY PRESSURE; H1N1 VIRUS; A(H1N1) INFECTION; ILL PATIENTS; VENTILATION; PNEUMONIA; FAILURE; MEXICO AB Objectives: The contribution of bacterial coinfection to critical illness associated with 2009 influenza A virus infection remains uncertain. The objective of this study was to determine whether bacterial coinfection increased the morbidity and mortality of 2009 influenza A. Design: Retrospective and prospective cohort study. Setting: Thirty-five adult U. S. intensive care units over the course of 1 yr. Patients: Six hundred eighty-three critically ill adults with confirmed or probable 2009 influenza A. Interventions: None. Measurements and Main Results: A confirmed or probable case was defined as a positive 2009 influenza A test result or positive test for influenza A that was otherwise not subtyped. Bacterial coinfection was defined as documented bacteremia or any presumed bacterial pneumonia with or without positive respiratory tract culture within 72 hrs of intensive care unit admission. The mean age was 45 +/- 16 yrs, mean body mass index was 32.5 +/- 11.1 kg/m(2), and mean Acute Physiology and Chronic Health Examination II score was 21 +/- 9, with 76% having at least one comorbidity. Of 207 (30.3%) patients with bacterial coinfection on intensive care unit admission, 154 had positive cultures with Staphylococcus aureus (n = 57) and Streptococcus pneumoniae (n = 19), the most commonly identified pathogens. Bacterial coinfected patients were more likely to present with shock (21% vs. 10%; p = .0001), require mechanical ventilation at the time of intensive care unit admission (63% vs. 52%; p = .005), and have longer duration of intensive care unit care (median, 7 vs. 6 days; p = .05). Hospital mortality was 23%; 31% in bacterial coinfected patients and 21% in patients without coinfection (p = .002). Immunosuppression (relative risk 1.57; 95% confidence interval 1.20-2.06; p = .0009) and Staphylococcus aureus at admission (relative risk 2.82; 95% confidence interval 1.76-4.51; p < .0001) were independently associated with increased mortality. Conclusions: Among intensive care unit patients with 2009 influenza A, bacterial coinfection diagnosed within 72 hrs of admission, especially with Staphylococcus aureus, was associated with significantly higher morbidity and mortality. (Crit Care Med 2012; 40: 1487-1498) C1 [Rice, Todd W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Rubinson, Lewis] HHS ASPR OPEO, Natl Disaster Med Syst, Salt Lake City, UT USA. [Uyeki, Timothy M.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Salt Lake City, UT USA. [Vaughn, Frances L.; John, Benjamin B.] HHS ASPR OPEO, Emergency Care Coordinat Ctr, Salt Lake City, UT USA. [Miller, Russell R., II] Intermt Med Ctr, Salt Lake City, UT USA. [Miller, Russell R., II] Univ Utah, Sch Med, Salt Lake City, UT USA. [Higgs, Elizabeth] NIAID, Div Clin Res, NIH, Boston, MA USA. [Randolph, Adrienne G.] Childrens Hosp, Boston, MA 02115 USA. [Smoot, B. Elizabeth] Harvard Univ, Sch Med, Boston, MA USA. [Thompson, B. Taylor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Rice, TW (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. EM todd.rice@vanderbilt.edu OI Randolph, Adrienne/0000-0002-3084-3071 FU NHLBI [N01-HR-56179] FX Supported, in part, by NHLBI N01-HR-56179. NR 35 TC 66 Z9 72 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2012 VL 40 IS 5 BP 1487 EP 1498 DI 10.1097/CCM.0b013e3182416f23 PG 12 WC Critical Care Medicine SC General & Internal Medicine GA 930AE UT WOS:000303106900012 PM 22511131 ER PT J AU Chertow, DS AF Chertow, Daniel S. TI Contribution of bacterial coinfection to severe influenza infection SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE bacteria; coinfection; critical illness; influenza; pathogenesis ID PANDEMIC INFLUENZA; PNEUMONIA; VIRUS; ILLNESS C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Chertow, DS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NR 16 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2012 VL 40 IS 5 BP 1664 EP 1665 DI 10.1097/CCM.0b013e3182451fd8 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 930AE UT WOS:000303106900042 PM 22511151 ER PT J AU Singer, EA Kaushal, A Turkbey, B Couvillon, A Pinto, PA Parnes, HL AF Singer, Eric A. Kaushal, Aradhana Turkbey, Baris Couvillon, Anna Pinto, Peter A. Parnes, Howard L. TI Active surveillance for prostate cancer: past, present and future SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE active surveillance; focal ablation; multiparametric MRI; prostate cancer; prostate-specific antigen; screening; watchful waiting ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; FOLLOW-UP; INITIAL TREATMENT; SCREENING TRIAL; BIOPSY; MEN; MORTALITY; ANTIGEN AB Purpose of review This article reviews recent developments in the use of active surveillance for localized prostate cancer. Recent findings The treatment of localized prostate cancer continues to be a major challenge for urologic oncologists. Screening with prostate-specific antigen has resulted in increased numbers of low-risk prostate cancers being detected. Aggressive whole-gland therapy with surgery, or radiation therapy is associated with potentially life-altering treatment-related side effects such as urinary incontinence, bowel toxicity and erectile dysfunction. The goal of active surveillance is to avoid or delay the adverse events associated with prostate cancer therapy while still allowing for curative intervention in the future, if needed. Summary Active surveillance is a reasonable treatment option for many men with low-risk, and some men with intermediate-risk, prostate cancer. Additional research is needed to determine the optimal active surveillance inclusion criteria, monitoring schedule, and treatment triggers. It is hoped that advances in prostate imaging, biomarkers, and focal therapy will foster greater use of active surveillance in appropriately selected men to optimize quality-of-life without compromising cancer outcomes. C1 [Parnes, Howard L.] NCI, Res Grp, Canc Prevent Div, Natl Canc Ctr, Bethesda, MD 20892 USA. [Singer, Eric A.; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Kaushal, Aradhana] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Turkbey, Baris] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Couvillon, Anna] NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Parnes, HL (reprint author), NCI, Res Grp, Canc Prevent Div, Natl Canc Ctr, Bethesda, MD 20892 USA. EM parnesh@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD FX This research was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD. NR 68 TC 19 Z9 19 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2012 VL 24 IS 3 BP 243 EP 250 DI 10.1097/CCO.0b013e3283527f99 PG 8 WC Oncology SC Oncology GA 931LC UT WOS:000303220400008 PM 22450149 ER PT J AU Singer, EA Gupta, GN Srinivasan, R AF Singer, Eric A. Gupta, Gopal N. Srinivasan, Ramaprasad TI Targeted therapeutic strategies for the management of renal cell carcinoma SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE chromophobe; clear cell; hereditary leiomyomatosis and renal cell carcinoma; hereditary papillary renal cancer; mammalian target of rapamycin; papillary; renal cell carcinoma; targeted therapy; vascular endothelial growth factor; von Hippel-Lindau ID HOGG-DUBE-SYNDROME; PHASE-III TRIAL; TUBEROUS SCLEROSIS; FUMARATE-HYDRATASE; INTERFERON-ALPHA; KIDNEY CANCER; PROGNOSTIC-FACTORS; GENE FUSION; TRANSLOCATION; MUTATIONS AB Purpose of review This article reviews recent developments in the use of systemic targeted therapies for the treatment of advanced clear and nonclear cell renal cell carcinoma (RCC). The genetic/molecular basis of each form of RCC is discussed and current treatments and clinical trials are described. Recent findings The treatment of advanced RCC continues to be a major challenge for uro-oncologists. The rapid growth in therapeutic options has brought much needed improvements in overall and progression-free survival, although durable complete responses remain elusive. The recent identification of mutations in genes involved in chromatin remodeling will likely lead to the investigation of whether components of this critical process can also be valid therapeutic targets in clear cell RCC. Similarly, efforts to decipher the molecular mechanisms underlying nonclear cell variants of RCC are beginning to engender novel therapeutic strategies directed against these rarer forms of kidney cancer. Despite the availability of multiple treatment options, several challenges remain: selecting the best first-line or subsequent therapy for a given patient, the optimal sequencing of the various agents available, designing trials with appropriate comparison arms and endpoints, and identifying well tolerated and effective drug combinations. Summary Agents targeting the vascular endothelial growth factor and mammalian target of rapamycin pathways remain the mainstay in the management of metastatic RCC. Ongoing and future studies are expected to facilitate the development of therapeutic regimens that incorporate agents with improved tolerability and enhanced efficacy by continuing to capitalize on the strides made by basic and translational scientists in uncovering the mechanisms underlying the various forms of RCC. C1 [Singer, Eric A.; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gupta, Gopal N.] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. RP Srinivasan, R (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM ramasrin@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA FX This research was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA. NR 59 TC 30 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2012 VL 24 IS 3 BP 284 EP 290 DI 10.1097/CCO.0b013e328351c646 PG 7 WC Oncology SC Oncology GA 931LC UT WOS:000303220400014 PM 22343386 ER PT J AU Helfinstein, SM Fox, NA Pine, DS AF Helfinstein, Sarah M. Fox, Nathan A. Pine, Daniel S. TI Approach-Withdrawal and the Role of the Striatum in the Temperament of Behavioral Inhibition SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE temperament; striatum; approach-withdrawal; anxiety; reinforcement learning ID MULTIPLE MEMORY-SYSTEMS; TEMPORAL DIFFERENCE MODELS; CAUDATE-NUCLEUS LESIONS; DOPAMINE NEURONS; DECISION-MAKING; POSTNATAL-DEVELOPMENT; REWARD PREDICTION; DORSAL STRIATUM; AMYGDALA MODULATION; SOCIAL WITHDRAWAL AB Behavioral inhibition is a temperament characterized in infancy and early childhood by a tendency to withdraw from novel or unfamiliar stimuli. Children exhibiting this disposition, relative to children with other dispositions, are more socially reticent, less likely to initiate interaction with peers, and more likely to develop anxiety over time. Until recently, a dominant model attributed this disposition to reductions in the threshold for engaging the circuitry supporting fear learning, particularly the amygdala. Recent work, however, also has implicated striatal circuitry and other regions that constitute components of a presumed reward system. A series of studies found that behaviorally inhibited adolescents display heightened activation of striatal structures to cues indicating an opportunity to receive reward. This article reviews evidence implicating dual roles for fear and reward circuitry in the expression of behavioral inhibition. C1 [Fox, Nathan A.] Univ Maryland, Dept Human Dev, Inst Child Study, 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, Inst Child Study, 3304 Benjamin Bldg 143, College Pk, MD 20742 USA. EM fox@umd.edu NR 114 TC 17 Z9 17 U1 4 U2 24 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD MAY PY 2012 VL 48 IS 3 BP 815 EP 826 DI 10.1037/a0026402 PG 12 WC Psychology, Developmental SC Psychology GA 932JK UT WOS:000303287200021 PM 22148946 ER PT J AU Scott, RA Chu, AY Grarup, N Manning, AK Hivert, MF Shungin, D Tonjes, A Yesupriya, A Barnes, D Bouatia-Naji, N Glazer, NL Jackson, AU Kutalik, Z Lagou, V Marek, D Rasmussen-Torvik, LJ Stringham, HM Tanaka, T Aadahl, M Arking, DE Bergmann, S Boerwinkle, E Bonnycastle, LL Bornstein, SR Brunner, E Bumpstead, SJ Brage, S Carlson, OD Chen, H Chen, YDI Chines, PS Collins, FS Couper, DJ Dennison, EM Dowling, NF Egan, JS Ekelund, U Erdos, MR Forouhi, NG Fox, CS Goodarzi, MO Grassler, J Gustafsson, S Hallmans, G Hansen, T Hingorani, A Holloway, JW Hu, FB Isomaa, B Jameson, KA Johansson, I Jonsson, A Jorgensen, T Kivimaki, M Kovacs, P Kumari, M Kuusisto, J Laakso, M Lecoeur, C Levy-Marchal, C Li, G Loos, RJF Lyssenko, V Marmot, M Marques-Vidal, P Morken, MA Muller, G North, KE Pankow, JS Payne, F Prokopenko, I Psaty, BM Renstrom, F Rice, K Rotter, JI Rybin, D Sandholt, CH Sayer, AA Shrader, P Schwarz, PEH Siscovick, DS Stancakova, A Stumvoll, M Teslovich, TM Waeber, G Williams, GH Witte, DR Wood, AR Xie, WJ Boehnke, M Cooper, C Ferrucci, L Froguel, P Groop, L Kao, WHL Vollenweider, P Walker, M Watanabe, RM Pedersen, O Meigs, JB Ingelsson, E Barroso, I Florez, JC Franks, PW Dupuis, J Wareham, NJ Langenberg, C AF Scott, Robert A. Chu, Audrey Y. Grarup, Niels Manning, Alisa K. Hivert, Marie-France Shungin, Dmitry Toenjes, Anke Yesupriya, Ajay Barnes, Daniel Bouatia-Naji, Nabila Glazer, Nicole L. Jackson, Anne U. Kutalik, Zoltan Lagou, Vasiliki Marek, Diana Rasmussen-Torvik, Laura J. Stringham, Heather M. Tanaka, Toshiko Aadahl, Mette Arking, Dan E. Bergmann, Sven Boerwinkle, Eric Bonnycastle, Lori L. Bornstein, Stefan R. Brunner, Eric Bumpstead, Suzannah J. Brage, Soren Carlson, Olga D. Chen, Han Chen, Yii-Der Ida Chines, Peter S. Collins, Francis S. Couper, David J. Dennison, Elaine M. Dowling, Nicole F. Egan, Josephine S. Ekelund, Ulf Erdos, Michael R. Forouhi, Nita G. Fox, Caroline S. Goodarzi, Mark O. Graessler, Juergen Gustafsson, Stefan Hallmans, Goeran Hansen, Torben Hingorani, Aroon Holloway, John W. Hu, Frank B. Isomaa, Bo Jameson, Karen A. Johansson, Ingegerd Jonsson, Anna Jorgensen, Torben Kivimaki, Mika Kovacs, Peter Kumari, Meena Kuusisto, Johanna Laakso, Markku Lecoeur, Cecile Levy-Marchal, Claire Li, Guo Loos, Ruth J. F. Lyssenko, Valeri Marmot, Michael Marques-Vidal, Pedro Morken, Mario A. Mueller, Gabriele North, Kari E. Pankow, James S. Payne, Felicity Prokopenko, Inga Psaty, Bruce M. Renstrom, Frida Rice, Ken Rotter, Jerome I. Rybin, Denis Sandholt, Camilla H. Sayer, Avan A. Shrader, Peter Schwarz, Peter E. H. Siscovick, David S. Stancakova, Alena Stumvoll, Michael Teslovich, Tanya M. Waeber, Gerard Williams, Gordon H. Witte, Daniel R. Wood, Andrew R. Xie, Weijia Boehnke, Michael Cooper, Cyrus Ferrucci, Luigi Froguel, Philippe Groop, Leif Kao, W. H. Linda Vollenweider, Peter Walker, Mark Watanabe, Richard M. Pedersen, Oluf Meigs, James B. Ingelsson, Erik Barroso, Ines Florez, Jose C. Franks, Paul W. Dupuis, Josee Wareham, Nicholas J. Langenberg, Claudia TI No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels SO DIABETES LA English DT Article ID DIABETES PREVENTION PROGRAM; LIFE-STYLE INTERVENTION; COMMON VARIANTS; TYPE-2; RISK; MELLITUS; ENVIRONMENT; TRAITS; POLYMORPHISMS; PROGRESSION AB Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) X BMI and SNP x physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (beta = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 X 10(-6)). All SNPs were associated with 2-h glucose (beta = 0.06-0.12 mmol/allele, P <= 1.53 X 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P >= 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions. Diabetes 61:1291-1296, 2012 C1 [Scott, Robert A.; Barnes, Daniel; Brage, Soren; Ekelund, Ulf; Forouhi, Nita G.; Loos, Ruth J. F.; Wareham, Nicholas J.; Langenberg, Claudia] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Chu, Audrey Y.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chu, Audrey Y.; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Grarup, Niels; Hansen, Torben; Sandholt, Camilla H.; Pedersen, Oluf] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Fac Hlth Sci, Copenhagen, Denmark. [Manning, Alisa K.; Chen, Han; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Grarup, Niels; Hansen, Torben; Sandholt, Camilla H.; Pedersen, Oluf] Hagedorn Res Inst, Gentofte, Denmark. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden. [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, Umea, Sweden. [Shungin, Dmitry; Johansson, Ingegerd] Umea Univ, Dept Odontol, Umea, Sweden. [Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, Leipzig, Germany. [Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Integriertes Forsch & Behandlungszentrum IFB Adip, Leipzig, Germany. [Yesupriya, Ajay; Dowling, Nicole F.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Bouatia-Naji, Nabila; Lecoeur, Cecile; Froguel, Philippe] Inst Pasteur, CNRS, UMR 8199, F-59019 Lille, France. [Bouatia-Naji, Nabila; Lecoeur, Cecile; Levy-Marchal, Claire; Froguel, Philippe] Univ Lille Nord France, Lille, France. [Glazer, Nicole L.] Boston Univ, Dept Med Prevent Med & Epidemiol, Boston, MA 02215 USA. [Jackson, Anne U.; Stringham, Heather M.; Teslovich, Tanya M.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kutalik, Zoltan; Marek, Diana; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kutalik, Zoltan; Marek, Diana; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Lagou, Vasiliki; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lagou, Vasiliki; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Aadahl, Mette; Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Arking, Dan E.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Arking, Dan E.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Bonnycastle, Lori L.; Chines, Peter S.; Collins, Francis S.; Erdos, Michael R.; Morken, Mario A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Bornstein, Stefan R.; Graessler, Juergen; Schwarz, Peter E. H.] Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany. [Brunner, Eric; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Marmot, Michael] UCL, Dept Epidemiol & Publ Hlth, London, England. [Bumpstead, Suzannah J.] Wellcome Trust Sanger Inst, Cambridge, England. [Carlson, Olga D.; Egan, Josephine S.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Chen, Yii-Der Ida; Goodarzi, Mark O.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Dennison, Elaine M.; Jameson, Karen A.; Sayer, Avan A.; Cooper, Cyrus] Univ Southampton, MRC, Lifecourse Epidemiol Unit, Southampton, Hants, England. [Fox, Caroline S.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Gustafsson, Stefan; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hallmans, Goeran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Hu, Frank B.; Renstrom, Frida; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Isomaa, Bo] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Jonsson, Anna; Lyssenko, Valeri; Groop, Leif] Lund Univ, Diabet & Endocrinol Unit, Dept Clin Sci, Malmo, Sweden. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kuusisto, Johanna; Laakso, Markku; Stancakova, Alena] Univ Eastern Finland, Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku; Stancakova, Alena] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Levy-Marchal, Claire] Hop Robert Debre, INSERM, CIC EC 05, F-75019 Paris, France. [Li, Guo] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Li, Guo] Univ Washington, Dept Med, Seattle, WA USA. [Marques-Vidal, Pedro] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1011 Lausanne, Switzerland. [Mueller, Gabriele] Univ Dresden, Inst Med Informat & Biometry, Med Fac Carl Gustav Carus, Dresden, Germany. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Payne, Felicity; Barroso, Ines] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rybin, Denis] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Shrader, Peter; Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shrader, Peter; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Waeber, Gerard; Vollenweider, Peter] CHUV, Dept Internal Med, Lausanne, Switzerland. [Witte, Daniel R.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Wood, Andrew R.; Xie, Weijia] Peninsula Coll Med & Dent, Exeter, Devon, England. [Cooper, Cyrus] Univ Oxford, Botnar Res Ctr, Oxford, England. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Pedersen, Oluf] Univ Copenhagen, Fac Hlth Sci, Inst Biomed Sci, Copenhagen, Denmark. [Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Cambridge, England. [Barroso, Ines] Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Scott, RA (reprint author), Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. EM robert.scott@mrc-epid.cam.ac.uk RI Marques-Vidal, Pedro/C-9449-2009; Li, Guo/E-5613-2012; Schwarz, Peter/B-5127-2013; Holloway, John/B-5424-2009; Rice, Kenneth/A-4150-2013; Brage, Soren/C-6415-2013; Colaus, PsyColaus/K-6607-2013; Lagou, Vasiliki/N-8451-2013; Witte, Daniel/C-1722-2008; Prokopenko, Inga/H-3241-2014; Grarup, Niels/K-2807-2015; BOUATIA-NAJI, NABILA/D-5863-2013 OI Forouhi, Nita/0000-0002-5041-248X; Chen, Han/0000-0002-9510-4923; Jorgensen, Torben/0000-0001-9453-2830; Marmot, Michael/0000-0002-2431-6419; Payne, Felicity/0000-0003-4228-581X; Pankow, James/0000-0001-7076-483X; Bergmann, Sven/0000-0002-6785-9034; Rybin, Denis/0000-0002-3657-4829; Barnes, Daniel/0000-0002-3781-7570; Marques-Vidal, Pedro/0000-0002-4548-8500; Kivimaki, Mika/0000-0002-4699-5627; Aihie Sayer, Avan/0000-0003-1283-6457; Dupuis, Josee/0000-0003-2871-3603; Kumari, Meena/0000-0001-9716-1035; Schwarz, Peter/0000-0001-6317-7880; Shungin, Dmitry/0000-0001-7900-5856; Holloway, John/0000-0001-9998-0464; Rice, Kenneth/0000-0001-5779-4495; Bouatia-Naji, Nabila/0000-0001-5424-2134; Brage, Soren/0000-0002-1265-7355; Witte, Daniel/0000-0002-0769-2922; Prokopenko, Inga/0000-0003-1624-7457; Grarup, Niels/0000-0001-5526-1070; FU British Heart Foundation [RG/07/008/23674]; Medical Research Council [G0100222, G0701863, G0902037, G1002084, G19/35, G8802774, MC_U106179471, MC_U106179473, MC_UP_A100_1003, MC_UP_A620_1014, MC_UP_A620_1015]; NCATS NIH HHS [UL1 TR000124]; NCRR NIH HHS [UL1 RR024148, UL1 RR025741]; NHLBI NIH HHS [T32 HL007575]; NIDDK NIH HHS [K24 DK080140, P30 DK020572, P30 DK063491, R01 DK072041] NR 28 TC 5 Z9 5 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2012 VL 61 IS 5 BP 1291 EP 1296 DI 10.2337/db11-0973 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 930XW UT WOS:000303179100042 PM 22415877 ER PT J AU Brown, RJ Walter, M Rother, KI AF Brown, Rebecca J. Walter, Mary Rother, Kristina I. TI Effects of Diet Soda on Gut Hormones in Youths With Diabetes SO DIABETES CARE LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; SWEET TASTE RECEPTORS; HEALTHY-SUBJECTS; ARTIFICIAL SWEETENER; GLUCOSE-ABSORPTION; BODY-WEIGHT; FOOD-INTAKE; HUMANS; EXPRESSION; SECRETION AB OBJECTIVE-In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes. RESEARCH DESIGN AND METHODS-Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (11 = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1., glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 mm. Glucose and GLP-1 have previously been reported for the healthy control subjects. RESULTS-GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group. CONCLUSIONS-Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined. C1 [Brown, Rebecca J.; Walter, Mary; Rother, Kristina I.] NIDDK, Bethesda, MD USA. RP Brown, RJ (reprint author), NIDDK, Bethesda, MD USA. EM brownrebecca@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 28 TC 27 Z9 27 U1 5 U2 36 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2012 VL 35 IS 5 BP 959 EP 964 DI 10.2337/dc11-2424 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 931KN UT WOS:000303218900006 PM 22410815 ER PT J AU Mychaleckyj, JC Craven, T Nayak, U Buse, J Crouse, JR Elam, M Kirchner, K Lorber, D Marcovina, S Sivitz, W Sperl-Hillen, J Bonds, DE Ginsberg, HN AF Mychaleckyj, Josyf C. Craven, Timothy Nayak, Uma Buse, John Crouse, John R. Elam, Marshall Kirchner, Kent Lorber, Daniel Marcovina, Santica Sivitz, William Sperl-Hillen, JoAnn Bonds, Denise E. Ginsberg, Henry N. TI Reversibility of Fenofibrate Therapy-Induced Renal Function Impairment in ACCORD Type 2 Diabetic Participants SO DIABETES CARE LA English DT Article ID GLOMERULAR-FILTRATION-RATE; INCREASES CREATININEMIA; PLASMA HOMOCYSTEINE; SERUM CREATININE; MELLITUS; GEMFIBROZIL; COMBINATION; PROGRESSION; EQUATION; PEOPLE AB OBJECTIVE-To assess the reversibility of the elevation of serum creatinine levels in patients with diabetes after 5 years of continuous on-trial fenofibrate therapy. RESEARCH DESIGN AND METHODS-An on-drug/off-drug ancillary study to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial to investigate post-trial changes in serum creatinine and cystatin C. Eligible participants were recruited into a prospective, nested, three-group study based on retrospective on-trial serum creatinine levels: fenofibrate case subjects (n = 321, >= 20% increase after 3 months of therapy); fenofibrate control subjects (n = 175, <= 2% increase); and placebo control subjects (n = 565). Serum creatinine and cystatin C were measured at trial end and 6-8 weeks after discontinuation of trial therapy. RESULTS-At trial end, case subjects had the highest adjusted serum creatinine (+/- SE) mg/dL (1.11 +/- 0.02) and the lowest adjusted estimated glomerular filtration rate (eGFR) (+/- SE) ml/min/1.73 m(2) (68.4 +/- 1.0) versus control subjects (1.01 +/- 0.02; 74.8 +/- 1.3) and placebo subjects (0.98 +/- 0.01; 77.8 +/- 0.7). After 51 days off-drug, serum creatinine in case subjects was still higher (0.97 +/- 0.02) and eGFR still lower (77.8 +/- 1.0) than control subjects (0.90 +/- 0.02; 81.8 +/- 1.3) but not different from placebo subjects (0.99 +/- 0.01; 76.6 +/- 0.7). Changes in serum cystatin C recapitulated the serum creatinine changes. CONCLUSIONS-Participants with significant initial on-trial increases in serum creatinine (>= 20%) returned to the same level of renal function as participants receiving placebo while participants who had <= 2% increase in serum creatinine had net preservation of renal function compared with the same unselected placebo reference group. The fenofibrate-associated on-trial increases in serum creatinine were reversible, and the reversal was complete after 51 days off-drug. The similarity of the cystatin C results suggests that the mechanism of this change is not specific for serum creatinine. C1 [Mychaleckyj, Josyf C.; Nayak, Uma] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Craven, Timothy] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Buse, John] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Crouse, John R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Winston Salem, NC 27103 USA. [Elam, Marshall] Memphis VA Med Ctr, Memphis, TN USA. [Kirchner, Kent] GV Sonny Montgomery VA Med Ctr, Jackson, MS USA. [Lorber, Daniel] New York Hosp, Lang Ctr Res & Educ, Div Endocrinol, Flushing, NY USA. [Marcovina, Santica] Univ Washington, NW Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Sivitz, William] Univ Iowa Diabet Clin Res, Iowa City, IA USA. [Sperl-Hillen, JoAnn] Hlth Partners Res Fdn, Minneapolis, MN USA. [Bonds, Denise E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ginsberg, Henry N.] Columbia Univ, Dept Med, New York, NY USA. RP Mychaleckyj, JC (reprint author), Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. EM jcm6t@virginia.edu FU Abbott Laboratories; National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers; Novo Nordisk; Merck; Eli Lilly; GSK; Johnson Johnson; MannKind FX This investigator-initiated study was supported by a research grant from Abbott Laboratories (J.C.M. and T.C.). The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; the National Eye Institute; the Centers for Disease Control and Prevention; and by the General Clinical Research Centers. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis U.S., and Takeda Pharmaceuticals provided study medications, equipment, or supplies.; J.B. is an investigator (I), consultant (C) or both (I/C) without any direct financial benefit to him under contracts between his employer and the following companies: Amylin Pharmaceutical, Inc. (I/C); Andromeda (I); AstraZeneca (C); Bayhill Therapeutics (C); Biodel (C); Boehringer Ingelheim (I/C); Bristol-Myers Squibb (I/C); Catabasis (C); Diartis (C); Elcelyx (C); Eli Lilly and Co. (I/C); Exsulin (C); GI Dynamics (C); Halozyme, Inc. (I); Hoffman-LaRoche Inc. (I/C); Johnson & Johnson (I); Lexicon (I); LipoScience (C); Medtronic Mini-Med, Inc. (I); Merck (C); Metabolon (C); Novan (C); Novo Nordisk Pharmaceuticals, Inc. (I/C); Osiris Therapeutics, Inc. (C); Orexigen (C); Pfizer, Inc. (I); Sanofi (I); Tolerex (I); Transition Therapeutics (I); and TransPharma (C). M.E. is a speaker and consultant for Abbott, Merck, and Schering Plough. D.L. has received honoraria, consulting fees, and research support from Novo Nordisk; consulting fees and research support from Merck; research support from Eli Lilly, GSK, Johnson & Johnson, and MannKind; owns stock in Merck and Biodel; and is a member of the board of directors of Biodel. H.N.G. consults for Merck and Abbott, is a speaker for Merck, and has research grant funding from Merck. NR 19 TC 36 Z9 36 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2012 VL 35 IS 5 BP 1008 EP 1014 DI 10.2337/dc11-1811 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 931KN UT WOS:000303218900014 PM 22432114 ER PT J AU Stefanovski, D Youn, JH Rees, M Watanabe, RM Ader, M Ionut, V Jackson, AU Boehnke, M Collins, FS Bergman, RN AF Stefanovski, Dark Youn, Jang H. Rees, Matthew Watanabe, Richard M. Ader, Marilyn Ionut, Viorica Jackson, Anne U. Boehnke, Michael Collins, Francis S. Bergman, Richard N. TI Estimating Hepatic Glucokinase Activity Using a Simple Model of Lactate Kinetics SO DIABETES CARE LA English DT Article ID INSULIN SENSITIVITY; INTRAVENOUS GLUCOSE; GLYCOGEN-SYNTHESIS; DIABETES-MELLITUS; LIVER-GLYCOGEN; METABOLISM; RESISTANCE; ASSOCIATION; POPULATION; GLYCOLYSIS AB OBJECTIVE-Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic beta-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a "gatekeeper", determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism. RESEARCH DESIGN AND METHODS-Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (K-GK), glycolysis (K-12), and whole body fractional lactate clearance (K-01). RESULTS-To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland United States Investigation of NIDDM Genetics study cohort. Parameters KGK, K12, and K01 were precisely estimated. Median model parameter estimates were consistent with previously published values. CONCLUSIONS-This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate. C1 [Stefanovski, Dark; Youn, Jang H.; Watanabe, Richard M.; Ader, Marilyn; Ionut, Viorica; Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Rees, Matthew; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Bergman, RN (reprint author), Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. EM richard.bergman@csmc.edu FU National Institutes of Health [DK027619, DK029867, DK062370] FX This work was supported by research grants from the National Institutes of Health (DK027619, DK029867, and DK062370). NR 37 TC 10 Z9 10 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2012 VL 35 IS 5 BP 1015 EP 1020 DI 10.2337/dc11-1540 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 931KN UT WOS:000303218900015 PM 22456868 ER PT J AU Chen, LW Hu, FB Yeung, E Tobias, DK Willett, WC Zhang, CL AF Chen, Liwei Hu, Frank B. Yeung, Edwina Tobias, Deirdre K. Willett, Walter C. Zhang, Cuilin TI Prepregnancy Consumption of Fruits and Fruit Juices and the Risk of Gestational Diabetes Mellitus A prospective cohort study SO DIABETES CARE LA English DT Article ID WOMEN; METAANALYSIS; VEGETABLES AB OBJECTIVE-Examine the association of prepregnancy habitual consumption of fruits and fruit juices and gestational diabetes mellitus (GDM) risk. RESEARCH DESIGN AND METHODS-A prospective study among women with at least one singleton pregnancy in the Nurses' Health Study II from 1991 to 2001. RESULTS-Among 13,475 women, 860 reported a first diagnosis of GDM. The adjusted relative risks (RRs) for GDM from the lowest to highest quintile of whole fruit consumption were 1.00 (referent), 0.80 (95% Cl 0.65-0.98), 0.90 (0.73-1.10), 0.80 (0.64-1.00), and 0.93 (0.76-1.16), respectively. The corresponding RRs for fruit juice were 1.00, 0.82 (0.66-1.01), 0.78 (0.63-0.96), 0.84 (0.68-1.04), and 1.00 (0.81-1.23). CONCLUSIONS-These data suggest that prepregnancy higher consumption of whole fruits is not associated with an increased GDM risk. The association between fruit juices and GDM risk appears to be nonlinear. C1 [Yeung, Edwina; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Chen, Liwei] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Program Epidemiol, New Orleans, LA USA. [Hu, Frank B.; Tobias, Deirdre K.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.; Willett, Walter C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hu, Frank B.; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. EM zhangcu@mail.nih.gov RI Yeung, Edwina/F-5992-2015 OI Yeung, Edwina/0000-0002-3851-2613 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [CA-50385, DK-58845]; School of Public Health, Louisiana State University Health Science Center FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health (to L.C., E.Y., and C.Z.), and the School of Public Health, Louisiana State University Health Science Center. The Nurses' Health Study II was funded by research grants CA-50385 and DK-58845 from the National Institutes of Health. NR 12 TC 6 Z9 6 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2012 VL 35 IS 5 BP 1079 EP 1082 DI 10.2337/dc11-2105 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 931KN UT WOS:000303218900026 PM 22446174 ER PT J AU Dunn, JP Kessler, RM Feurer, ID Volkow, ND Patterson, BW Ansari, MS Li, R Marks-Shulman, P Abumrad, NN AF Dunn, Julia P. Kessler, Robert M. Feurer, Irene D. Volkow, Nora D. Patterson, Bruce W. Ansari, Mohammad S. Li, Rui Marks-Shulman, Pamela Abumrad, Naji N. TI Relationship of Dopamine Type 2 Receptor Binding Potential With Fasting Neuroendocrine Hormones and Insulin Sensitivity in Human Obesity SO DIABETES CARE LA English DT Article ID NUCLEUS-ACCUMBENS; BRAIN ACTIVITY; FOOD-INTAKE; IN-VIVO; GHRELIN; LEPTIN; REWARD; INCREASES; RESPONSES; STRIATUM AB OBJECTIVE-Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity. RESEARCH DESIGN AND METHODS-We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S-I) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [F-18] fallypride (radic ligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S-I was determined by modified oral glucose tolerance test. RESULTS-Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S-I was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BM I, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand. CONCLUSIONS-Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females. C1 [Dunn, Julia P.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Kessler, Robert M.; Ansari, Mohammad S.; Li, Rui] Vanderbilt Univ, Sch Med, Dept Radiol, Nashville, TN 37212 USA. [Feurer, Irene D.; Marks-Shulman, Pamela; Abumrad, Naji N.] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. [Feurer, Irene D.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. [Patterson, Bruce W.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. RP Dunn, JP (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. EM julia.dunn@va.gov FU National Institutes of Health from National Center for Research Resources [UL1-RR-024975]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-20593]; NIDDK (Vanderbilt Digestive Disease Research Center) [DK-058404]; Washington University Nutrition and Obesity Research Center [P30-DK-56341]; National Institute of Environmental Health Sciences [K12-ES-015855]; NIDDK [DK-70860] FX This study was supported by National Institutes of Health Grants UL1-RR-024975 from the National Center for Research Resources (Vanderbilt Clinical and Translational Science Award), DK-20593 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; Vanderbilt Diabetes Research and Training Award), DK-058404 from the NIDDK (Vanderbilt Digestive Disease Research Center), P30-DK-56341 from the Washington University Nutrition and Obesity Research Center, K12-ES-015855 from the National Institute of Environmental Health Sciences (Vanderbilt Environmental Health Science Scholars Program) to J.P.D., and DK-70860 from the NIDDK to N.N.A. NR 40 TC 49 Z9 50 U1 2 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2012 VL 35 IS 5 BP 1105 EP 1111 DI 10.2337/dc11-2250 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 931KN UT WOS:000303218900031 PM 22432117 ER PT J AU Soerensen, M Dato, S Tan, QH Thinggaard, M Kleindorp, R Beekman, M Jacobsen, R Suchiman, HED de Craen, AJM Westendorp, RGJ Schreiber, S Stevnsner, T Bohr, VA Slagboom, PE Nebel, A Vaupel, JW Christensen, K McGue, M Christiansen, L AF Soerensen, Mette Dato, Serena Tan, Qihua Thinggaard, Mikael Kleindorp, Rabea Beekman, Marian Jacobsen, Rune Suchiman, H. Eka D. de Craen, Anton J. M. Westendorp, Rudi G. J. Schreiber, Stefan Stevnsner, Tinna Bohr, Vilhelm A. Slagboom, P. Eline Nebel, Almut Vaupel, James W. Christensen, Kaare McGue, Matt Christiansen, Lene TI Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: Cross sectional and longitudinal studies SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Human longevity; Association study; Case-control data; Longitudinal data; Candidate study ID GENOME-WIDE ASSOCIATION; LIFE-SPAN; GHRELIN GENE; MUTANT MICE; KLOTHO GENE; SURVIVAL; POLYMORPHISMS; CANCER; FOXO3A; AGE AB Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing. When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age. No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive nonsignificant tendency (OR=1.162, 95% CI = 0.927-1.457). The same was true for rs10047589 (TNXRD1) (HR=0.758, 95% CI=0.543-1.058) when examining the 6 SNPs from the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563). In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms. (C) 2012 Elsevier Inc. All rights reserved. C1 [Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Jacobsen, Rune; Vaupel, James W.; Christensen, Kaare; McGue, Matt; Christiansen, Lene] Univ So Denmark, Inst Publ Hlth, Danish Aging Res Ctr, DK-5000 Odense C, Denmark. [Soerensen, Mette; Tan, Qihua; Christensen, Kaare; Christiansen, Lene] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark. [Soerensen, Mette; Tan, Qihua; Christensen, Kaare; Christiansen, Lene] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark. [Dato, Serena] Univ Calabria, Dept Cell Biol, I-87036 Arcavacata Di Rende, CS, Italy. [Kleindorp, Rabea; Schreiber, Stefan; Nebel, Almut] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Kleindorp, Rabea; Schreiber, Stefan; Nebel, Almut] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany. [Beekman, Marian; Suchiman, H. Eka D.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands. [Beekman, Marian; Suchiman, H. Eka D.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Netherlands Consortium Hlth Aging, NL-2300 RC Leiden, Netherlands. [de Craen, Anton J. M.; Westendorp, Rudi G. J.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [Stevnsner, Tinna; Bohr, Vilhelm A.] Aarhus Univ, Dept Mol Biol & Genet, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Vaupel, James W.] Max Planck Inst Demog Res, D-18057 Rostock, Germany. [McGue, Matt] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Christiansen, L (reprint author), Univ So Denmark, Inst Publ Hlth, Danish Aging Res Ctr, JB Winsloews Vej 9B, DK-5000 Odense C, Denmark. EM lchristiansen@health.sdu.dk RI Christensen, Kaare/C-2360-2009; Nebel, Almut/E-4196-2010; Lindahl-Jacobsen, Rune/J-2985-2012; Schreiber, Stefan/B-6748-2008; Soerensen, Mette/O-1817-2015; Slagboom, P. Eline/R-4790-2016; Suchiman, H. Eka D./F-5024-2017; OI Christensen, Kaare/0000-0002-5429-5292; Lindahl-Jacobsen, Rune/0000-0002-4622-9826; Schreiber, Stefan/0000-0003-2254-7771; Slagboom, P. Eline/0000-0002-2875-4723; Suchiman, H. Eka D./0000-0002-7168-5516; Soerensen, Mette/0000-0001-5268-3366; Beekman, Marian/0000-0003-0585-6206; dato, serena/0000-0003-2589-7929 FU Max-Planck Institute for Demographic Research (Rostock, Germany); INTERREG; European Regional Development Fund; National Institute on Aging [P01 AG08761]; Netherlands Consortium for Healthy Aging of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) [050-060-810]; European Union [259679]; Novo Nordisk Foundation; Aase and Ejnar Danielsen Foundation; Augustinus Foundation; Brodrene Hartmann Foundation; King Christian the 10th Foundation; Einer Willumsens Mindelegat Foundation; VELUX Foundation FX This study was supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), a Dutch grant from the Netherlands Consortium for Healthy Aging (Grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no 259679, the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Brodrene Hartmann Foundation, the King Christian the 10th Foundation and the Einer Willumsens Mindelegat Foundation. The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sorensen and Lene Elnegaard are thanked for excellent technical work. NR 62 TC 31 Z9 31 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD MAY PY 2012 VL 47 IS 5 BP 379 EP 387 DI 10.1016/j.exger.2012.02.010 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 929ZR UT WOS:000303105200005 PM 22406557 ER PT J AU Liu, J Zhou, L Xiong, KM Godlewski, G Mukhopadhyay, B Tam, J Yin, S Gao, P Shan, X Pickel, J Bataller, R O'Hare, J Scherer, T Buettner, C Kunos, G AF Liu, Jie Zhou, Liang Xiong, Keming Godlewski, Grzegorz Mukhopadhyay, Bani Tam, Joseph Yin, Shi Gao, Peter Shan, Xin Pickel, James Bataller, Ramon O'Hare, James Scherer, Thomas Buettner, Christoph Kunos, George TI Hepatic Cannabinoid Receptor-1 Mediates Diet-Induced Insulin Resistance via Inhibition of Insulin Signaling and Clearance in Mice SO GASTROENTEROLOGY LA English DT Article DE NASH; Signal Transduction; Mouse Model; Liver Disease ID ENDOPLASMIC-RETICULUM STRESS; INDUCED OBESE MICE; RANDOMIZED CONTROLLED-TRIAL; BOUND TRANSCRIPTION FACTOR; CB1 RECEPTOR; ER STRESS; CARDIOMETABOLIC RISK; DEGRADING ENZYME; ADIPOSE-TISSUE; GLUCOSE AB BACKGROUND & AIMS: Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB1) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB1 in insulin resistance and inhibition of insulin signaling pathways. METHODS: Wild-type mice and mice with disruption of CB1 (CB1-/- mice) or with hepatocyte-specific deletion or transgenic overexpression of CB1 were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB1 in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression. RESULTS: The HFD induced hepatic insulin resistance in wild-type mice, but not in CB1-/-mice or mice with hepatocyte-specific deletion of CB1. CB1-/-mice that overexpressed CB1 specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB1, the HFD or CB1 activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2 alpha protein translation pathway. In hepatocytes isolated from human or mouse liver, CB1 activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB1 was up-regulated in samples from patients with nonalcoholic fatty liver disease. CONCLUSIONS: Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB1-mediated inhibition of insulin signaling and clearance. C1 [Liu, Jie; Zhou, Liang; Xiong, Keming; Godlewski, Grzegorz; Mukhopadhyay, Bani; Tam, Joseph; Yin, Shi; Gao, Peter; Shan, Xin; Kunos, George] NIAAA, Lab Physiol Studies, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. [Bataller, Ramon] Inst Invest Biomed August Pi & Sunyer, Liver Unit, Barcelona, Spain. [O'Hare, James; Scherer, Thomas; Buettner, Christoph] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Liu, J (reprint author), NIAAA, Lab Physiol Studies, 5625 Fishers Lane,MSC-9413, Bethesda, MD 20892 USA. EM jiel@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX Supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism. NR 56 TC 56 Z9 56 U1 3 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2012 VL 142 IS 5 BP 1218 EP + DI 10.1053/j.gastro.2012.01.032 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 930CK UT WOS:000303113600040 PM 22307032 ER PT J AU Kim, SM Leem, SH Chu, IS Park, YY Kim, SC Kim, SB Park, ES Lim, JY Heo, J Kim, YJ Kim, DG Kaseb, A Park, YN Wang, XW Thorgeirsson, SS Lee, JS AF Kim, Soo Mi Leem, Sun-Hee Chu, In-Sun Park, Yun-Yong Kim, Sang Cheol Kim, Sang-Bae Park, Eun Sung Lim, Jae Yun Heo, Jeonghoon Kim, Yoon Jun Kim, Dae-Ghon Kaseb, Ahmed Park, Young Nyun Wang, Xin Wei Thorgeirsson, Snorri S. Lee, Ju-Seog TI Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID HEPATITIS-B-VIRUS; THERAPEUTIC TARGETS; STAGING-SYSTEM; RECURRENCE; EXPRESSION; CANCER; PROGNOSIS; LIMITATIONS; SIGNATURE; PATTERNS AB Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 x 10(-5), n = 100) and the second test cohort (P = 5.0 x 10(-5), n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS). Conclusion: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets. (HEPATOLOGY 2011) C1 [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Div Canc Med, Houston, TX 77054 USA. [Kim, Soo Mi] Chonbuk Natl Univ, Dept Physiol, Med Sch & Hosp, Jeonju, South Korea. [Leem, Sun-Hee] Dong A Univ, Dept Biol Sci, Pusan, South Korea. [Chu, In-Sun; Kim, Sang Cheol] Korea Res Inst Biosci & Biotechnol, Korean Bioinformat Ctr, Taejon, South Korea. [Park, Eun Sung] Yonsei Univ, Coll Med, Inst Med Convergence, Seoul, South Korea. [Lim, Jae Yun] Yonsei Univ, Coll Med, Dept Internal Med, Seoul, South Korea. [Heo, Jeonghoon] Kosin Univ, Coll Med, Pusan, South Korea. [Kim, Yoon Jun] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. [Kim, Yoon Jun] Seoul Natl Univ, Coll Med, Liver Res Inst, Seoul, South Korea. [Kim, Dae-Ghon] Chonbuk Natl Univ, Dept Internal Med, Div Gastroenterol & Hepatol, Med Sch & Hosp, Jeonju, South Korea. [Kaseb, Ahmed] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Div Canc Med, Houston, TX 77030 USA. [Park, Young Nyun] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Div Canc Med, Unit 950,1515 Holcombe Blvd, Houston, TX 77054 USA. EM jlee@mdanderson.org RI Kim, Yoon Jun/J-2746-2012; Wang, Xin/B-6162-2009 FU University of Texas MD Anderson Cancer Center; NCI CCSG [CA106672] FX Funded by the intramural faculty fund of the University of Texas MD Anderson Cancer Center to J-S Lee; MD Anderson Cancer Center is partially funded by NCI CCSG Core Grant CA106672. Microarray data: GSE1898, GSE4024, GSE9843, GSE14520, GSE16757, and E-TABM-36. NR 36 TC 27 Z9 27 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2012 VL 55 IS 5 BP 1443 EP 1452 DI 10.1002/hep.24813 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 929GN UT WOS:000303049400015 PM 22105560 ER PT J AU Voltaggio, L Murray, R Lasota, J Miettinen, M AF Voltaggio, Lysandra Murray, Rebecca Lasota, Jerzy Miettinen, Markku TI Gastric schwannoma: a clinicopathologic study of 51 cases and critical review of the literature SO HUMAN PATHOLOGY LA English DT Review DE Schwannoma; Stomach; Nerve sheath tumor; S100 protein; GFAP; Prognosis; Chromosome 22; Polyploidy ID GASTROINTESTINAL STROMAL TUMORS; NERVE SHEATH TUMORS; MALIGNANT SCHWANNOMA; MELANOTIC SCHWANNOMA; BENIGN SCHWANNOMA; PDGFRA MUTATIONS; DIGESTIVE-TRACT; STOMACH; FEATURES; PATIENT AB Schwannoma is a rare gastrointestinal mesenchymal tumor, as the vast majority of gastric mesenchymal tumors are gastrointestinal stromal tumors. In this study, we analyzed clinicopathologically 51 gastric schwannomas. These tumors predominantly occurred in older adults with a marked female predominance (40 women and 11 men; median and mean ages, 60 and 58 years). They variably presented with gastric discomfort, bleeding, or rarely gastric outlet obstruction; and many were incidental findings during other medical procedures. The tumors ranged from 1 to 10.5 cm (median, 4.5 cm). The typical histologic features included spindle cells usually with microtrabecular architecture and focal nuclear atypia, and peritumoral lymphoid cuff, whereas features of soft tissue schwannomas, such as encapsulation, nuclear palisading, vascular hyalinization, and dilatation, were absent or infrequent. Median mitotic count was 2/50 high-power fields, with the highest count being 13/50 high-power fields. No malignant variants were recognized, and long-term follow-up did not reveal recurrences or metastases. Immunohistochemically, all examined tumors were S100 protein positive and most were also GFAP positive, whereas CD34 and NF68 were encountered rarely and all tumors were negative for HMB45, KIT, DOG1/Ano 1, smooth muscle actin, desmin, and synaptophysin. None of the 9 tumors studied contained gastrointestinal stromal tumor specific KIT or PDGFRA mutations. Fluorescence in situ hybridization studies revealed multiple signals with BCR probe (chromosome 22) and centromeric probes for chromosomes 2 and 18 suggesting polyploidy. These findings indicate that gastric schwannoma is a distinctive form of peripheral nerve sheath tumor that in many ways differs from soft tissue schwannoma. It should be distinguished from gastrointestinal stromal tumor and other mesenchymal tumors of the gastrointestinal tract, such as the S100 protein positive gastrointestinal clear cell sarcoma and metastatic melanoma. Published by Elsevier Inc. C1 [Lasota, Jerzy; Miettinen, Markku] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Voltaggio, Lysandra; Murray, Rebecca] George Washington Univ Hosp, Dept Pathol, Washington, DC 20037 USA. [Miettinen, Markku] Armed Forces Inst Pathol, Silver Spring, MD 20306 USA. RP Miettinen, M (reprint author), NCI, Lab Surg Pathol, Bethesda, MD 20892 USA. EM Markku.Miettinen@nih.gov FU National Institutes of Health; National Cancer Institute FX This research was supported in part by the intramural research program of the National Institutes of Health and the National Cancer Institute. NR 42 TC 36 Z9 43 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD MAY PY 2012 VL 43 IS 5 BP 650 EP 659 DI 10.1016/j.humpath.2011.07.006 PG 10 WC Pathology SC Pathology GA 932JY UT WOS:000303288600005 PM 22137423 ER PT J AU Davidson, B Stavnes, HT Risberg, B Nesland, JM Wohlschlaeger, J Yang, YQ Shih, IM Wang, TL AF Davidson, Ben Stavnes, Helene Tuft Risberg, Bjorn Nesland, Jahn M. Wohlschlaeger, Jeremias Yang, Yanqin Shih, Ie-Ming Wang, Tian-Li TI Gene expression signatures differentiate adenocarcinoma of lung and breast origin in effusions SO HUMAN PATHOLOGY LA English DT Article DE Gene expression array; Breast adenocarcinoma; Lung adenocarcinoma; Serous effusions; Differential diagnosis ID CARBONIC-ANHYDRASE-XII; MATRIX METALLOPROTEINASE-7; PLEURAL EFFUSION; CANCER PATIENTS; POOR-PROGNOSIS; MESSENGER-RNA; ANTIGEN EVA; CARCINOMA; NONSMALL; PROTEIN AB Lung and breast adenocarcinoma at advanced stages commonly involve the serosal cavities, giving rise to malignant effusions. The aim of the present study was to compare the global gene expression patterns of metastases from these 2 malignancies, to expand and improve the diagnostic panel of biomarkers currently available for their differential diagnosis, as well as to define type-specific biological targets. Gene expression profiles of 7 breast and 4 lung adenocarcinoma effusions were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated lung from breast adenocarcinoma samples. We identified 289 unique probes that were significantly differentially expressed in the 2 cancers by greater than 2-fold using moderated t statistics, of which 65 and 224 were overexpressed in breast and lung adenocarcinoma, respectively. Genes overexpressed in breast adenocarcinoma included TFF1, TFF3, FOXA1, CA12, PITX1, RARRES1, CITED4, MYC, TFAP2A, EFHD1, TOB1, SPDEF, FASN, and TH. Genes overexpressed in lung adenocarcinoma included TITF1, SFTPG, MMP7, EVA1, GPR116, HOP, SCGB3A2, and MET. The differential expression of 15 genes was validated by quantitative real-time PCR, and differences in 8 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes breast adenocarcinoma from lung adenocarcinoma and identifies genes that are differentially expressed in these 2 tumor types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery. (C) 2012 Elsevier Inc. All rights reserved. C1 [Davidson, Ben] Norwegian Radium Hosp, Oslo Univ Hosp, Dept Pathol, Div Pathol, N-0310 Oslo, Norway. [Davidson, Ben; Nesland, Jahn M.] Univ Oslo, Fac Med, N-0316 Oslo, Norway. [Wohlschlaeger, Jeremias] Univ Hosp Essen, Dept Pathol & Neuropathol, Essen, Germany. [Yang, Yanqin] NHLBI, Gene Express Core Facil, NIH, Bethesda, MD 20892 USA. [Shih, Ie-Ming] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Shih, Ie-Ming; Wang, Tian-Li] Johns Hopkins Med Inst, Dept Gynecol Obstet & Oncol, Baltimore, MD 21205 USA. RP Davidson, B (reprint author), Norwegian Radium Hosp, Oslo Univ Hosp, Dept Pathol, Div Pathol, N-0310 Oslo, Norway. EM bend@medisin.uio.no; tlw@welch.jhu.edu FU Norwegian Cancer Society; Research Foundation at the Norwegian Radium Hospital; NIH [R01 CA103937] FX This work was supported by grants from the Norwegian Cancer Society and the Research Foundation at the Norwegian Radium Hospital as well as NIH grant R01 CA103937. NR 57 TC 5 Z9 5 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD MAY PY 2012 VL 43 IS 5 BP 684 EP 694 DI 10.1016/j.humpath.2011.06.015 PG 11 WC Pathology SC Pathology GA 932JY UT WOS:000303288600009 PM 21937081 ER PT J AU Margalit, M Yogev, L Yavetz, H Lehavi, O Hauser, R Botchan, A Barda, S Levitin, F Weiss, M Pastan, I Wreschner, DH Paz, G Kleiman, SE AF Margalit, M. Yogev, L. Yavetz, H. Lehavi, O. Hauser, R. Botchan, A. Barda, S. Levitin, F. Weiss, M. Pastan, I. Wreschner, D. H. Paz, G. Kleiman, S. E. TI Involvement of the prostate and testis expression (PATE)-like proteins in spermoocyte interaction SO HUMAN REPRODUCTION LA English DT Article DE human sperm; PATE genes; human spermatogenesis; TFP; Ly-6; uPAR proteins; oolemma penetration ID SPERM-EGG FUSION; ACROSOME REACTION; PLASMA-MEMBRANE; HUMAN-SPERMATOZOA; FERTILIZING ABILITY; PHOSPHOLIPASE A(2); AZOOSPERMIC MEN; IN-VITRO; PLASMINOGEN-ACTIVATOR; EQUATORIAL SEGMENT AB The prostate and testis expression (PATE)-like family of proteins are expressed mainly in the male genital tract. They are localized in the sperm head and are homologous to SP-10, the acrosomal vesicle protein also named ACRV1. Our aim was to characterize the expression and functional role of three PATE-like proteins in the testis and ejaculated sperm. The expression and localization of PATE-like proteins in human testis biopsies (n 95) and sperm cells were assessed by RTPCR, immunohistochemistry and immunofluorescence staining (at least 600 sperm cells per specimen). The function of the PATE protein was tested by the hemizona assay and hamster egg penetration test (HEPT). PATE and PATE-M genes and proteins were present almost exclusively in germ cells in the testis: immunoflourescence showed that the percentage of germ cells positive for PATE, PATE-M and PATE-B was 85, 50 and 2, respectively. PATE and PATE-M proteins were localized in the equatorial segment of the sperm head, while PATE-B protein was localized in the post-acrosomal region. A polyclonal antibody (Ab, at 1:50 and 1:200 dilutions) against the PATE protein did not inhibit spermzona binding in the hemizona assay (hemizona index of 89.6 10 and 87 36, respectively). However, there was inhibition of spermoolemma fusion and penetration in the HEPT (penetration index: without Ab 7 3.9; Ab dilution of 1:100, 4 3.5; Ab dilution of 1:20, 0.6 1.2, P 0.001). Our data suggest that PATE protein is involved in spermoolemma fusion and penetration but not spermzona binding. C1 [Margalit, M.; Yogev, L.; Yavetz, H.; Lehavi, O.; Hauser, R.; Botchan, A.; Barda, S.; Paz, G.; Kleiman, S. E.] Tel Aviv Univ, Sackler Fac Med, Tel Aviv Sourasky Med Ctr, Inst Study Fertil,Lis Matern Hosp, IL-69978 Tel Aviv, Israel. [Levitin, F.; Wreschner, D. H.] Tel Aviv Univ, Dept Cell Res & Immunol, Ramat Aviv, Israel. [Weiss, M.] Assaf Harofe Med Ctr, Dept Endocrinol, Zerifin, Israel. [Pastan, I.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kleiman, SE (reprint author), Tel Aviv Univ, Sackler Fac Med, Tel Aviv Sourasky Med Ctr, Inst Study Fertil,Lis Matern Hosp, IL-69978 Tel Aviv, Israel. EM ser@tasmc.health.gov.il OI Barda, Shimi/0000-0001-6553-0350 FU Alan and Ada Selwyn Chair in Clinical Infertility Research and Molecular Medicine (Melbourne, Australia); NIH, National Cancer Institute, Center for Cancer Research FX The research was carried out under the auspices of the Alan and Ada Selwyn Chair in Clinical Infertility Research and Molecular Medicine (Melbourne, Australia) granted to one of the authors (G.P.). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD MAY PY 2012 VL 27 IS 5 BP 1238 EP 1248 DI 10.1093/humrep/des064 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 930TB UT WOS:000303161900002 PM 22402205 ER PT J AU Kwon, S Park, HS Stanley, CJ Kim, J Kim, J Damiano, DL AF Kwon, Suncheol Park, Hyung-Soon Stanley, Christopher J. Kim, Jung Kim, Jonghyun Damiano, Diane L. TI A Practical Strategy for sEMG-Based Knee Joint Moment Estimation During Gait and Its Validation in Individuals With Cerebral Palsy SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Cerebral palsy (CP); estimation of knee internal moment; muscular cocontraction; sEMG-moment relationship ID SINGLE-LIMB STANCE; FORCE MODEL; CROUCH GAIT; EMG; MUSCLES; PREVALENCE; EXTENSION; CHILDREN; HIP; ELECTROMYOGRAPHY AB Individuals with cerebral palsy have neurological deficits that may interfere with motor function and lead to abnormal walking patterns. It is important to know the joint moment generated by the patient's muscles during walking in order to assist the suboptimal gait patterns. In this paper, we describe a practical strategy for estimating the internal moment of a knee joint from surface electromyography (sEMG) and knee joint angle measurements. This strategy requires only isokinetic knee flexion and extension tests to obtain a relationship between the sEMG and the knee internal moment, and it does not necessitate comprehensive laboratory calibration, which typically requires a 3-D motion capture system and ground reaction force plates. Four estimation models were considered based on different assumptions about the functions of the relevant muscles during the isokinetic tests and the stance phase of walking. The performance of the four models was evaluated by comparing the estimated moments with the gold standard internal moment calculated from inverse dynamics. The results indicate that an optimal estimation model can be chosen based on the degree of cocontraction. The estimation error of the chosen model is acceptable (normalized root-mean-squared error: 0.15-0.29, R: 0.71-0.93) compared to previous studies (Doorenbosch and Harlaar, 2003; Doorenbosch and Harlaar, 2004; Doorenbosch, Joosten, and Harlaar, 2005), and this strategy provides a simple and effective solution for estimating knee joint moment from sEMG. C1 [Park, Hyung-Soon; Stanley, Christopher J.; Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Kwon, Suncheol] Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. RP Park, HS (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM sun.kwon@kaist.ac.kr; parkhs@cc.nih.gov; stanleycj@cc.nih.gov; kimj13@cc.nih.gov kimj13@cc.nih.gov; kimj13@cc.nih.gov kimj13@cc.nih.gov RI Park, Hyung-Soon/B-3334-2010; Kim, Jung/C-1636-2011; Van Mulders, Benjamin/P-1241-2014; Damiano, Diane/B-3338-2010 OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356 FU Je Won Research Foundation; National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0020934]; National Institutes of Health [10-CC-0073] FX This work was supported by the Je Won Research Foundation, the Happy Tech. Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology under Grant 2011-0020934, and the Intramural Research Program at the National Institutes of Health (Protocol #: 10-CC-0073). S. Kwon and H.-S. Park equally contributed to the work. Asterisk indicates corresponding author. NR 43 TC 8 Z9 9 U1 0 U2 18 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD MAY PY 2012 VL 59 IS 5 BP 1480 EP 1487 DI 10.1109/TBME.2012.2187651 PG 8 WC Engineering, Biomedical SC Engineering GA 931FJ UT WOS:000303201000031 PM 22410952 ER PT J AU Yahiro, K Tsutsuki, H Ogura, K Nagasawa, S Moss, J Noda, M AF Yahiro, Kinnosuke Tsutsuki, Hiroyasu Ogura, Kohei Nagasawa, Sayaka Moss, Joel Noda, Masatoshi TI Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells SO INFECTION AND IMMUNITY LA English DT Article ID TOXIGENIC ESCHERICHIA-COLI; STRESS-SIGNALING PATHWAYS; INDUCED APOPTOSIS; MAMMALIAN-CELLS; TRANSLATION; DEGRADATION; TRANSCRIPTION; SURVIVAL; FAMILY; IRE1 AB Shiga-toxigenic Escherichia coli (STEC) produces subtilase cytotoxin (SubAB), which cleaves the molecular chaperone BiP in the endoplasmic reticulum (ER), leading to an ER stress response and then activation of apoptotic signaling pathways. Here, we show that an early event in SubAB-induced apoptosis in HeLa cells is mediated by RNA-dependent protein kinase (PKR)-like ER kinase (PERK), not activating transcription factor 6 (ATF6) or inositol-requiring enzyme 1(Ire1), two other ER stress sensors. PERK knockdown suppressed SubAB-induced eIF2 alpha phosphorylation, activating transcription factor 4 (ATF4) expression, caspase activation, and cytotoxicity. Knockdown of eIF2 alpha by small interfering RNA (siRNA) or inhibition of eIF2 alpha dephosphorylation by Sal003 enhanced SubAB-induced caspase activation. Treatment with proteasome inhibitors (i.e., MG132 and lactacystin), but not a general caspase inhibitor (Z-VAD) or a lysosome inhibitor (chloroquine), suppressed SubAB-induced caspase activation and poly(ADP-ribose) polymerase (PARP) cleavage, suggesting that the ubiquitin-proteasome system controls events leading to caspase activation, i.e., Bax/Bak conformational changes, followed by cytochrome c release from mitochondria. Levels of ubiquitinated proteins in HeLa cells were significantly decreased by SubAB treatment. Further, in an early event, some antiapoptotic proteins, which normally turn over rapidly, have their synthesis inhibited, and show enhanced degradation via the proteasome, resulting in apoptosis. In PERK knockdown cells, SubAB-induced loss of ubiquitinated proteins was inhibited. Thus, SubAB-induced ER stress is caused by BiP cleavage, leading to PERK activation, not by accumulation of ubiquitinated proteins, which undergo PERK-dependent degradation via the ubiquitin-proteasome system. C1 [Yahiro, Kinnosuke; Tsutsuki, Hiroyasu; Ogura, Kohei; Nagasawa, Sayaka; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba, Japan. [Nagasawa, Sayaka] Chiba Univ, Grad Sch Med, Dept Legal Med, Chiba, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Yahiro, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba, Japan. EM yahirok@faculty.chiba-u.jp FU Ministry of Education, Science and Culture of Japan; Japan Science and Technology Agency; National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by grants in aid for Scientific Research from the Ministry of Education, Science and Culture of Japan and Improvement of Research Environment for Young Researchers from the Japan Science and Technology Agency. Joel Moss was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 55 TC 5 Z9 5 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2012 VL 80 IS 5 BP 1803 EP 1814 DI 10.1128/IAI.06164-11 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 925VX UT WOS:000302791100021 PM 22354021 ER PT J AU Marcsisin, RA Campeau, SA Lopez, JE Barbour, AG AF Marcsisin, Renee A. Campeau, Shelley A. Lopez, Job E. Barbour, Alan G. TI Alp, an Arthropod-Associated Outer Membrane Protein of Borrelia Species That Cause Relapsing Fever SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE; ANTIGENIC VARIATION; SURFACE PROTEIN; MONOCLONAL-ANTIBODY; LINEAR PLASMIDS; MOUSE MODEL; HERMSII; BURGDORFERI; SPIROCHETE; EXPRESSION AB Borrelia hermsii and other relapsing fever (RF) species are noted for their highly polymorphic surface antigens, the variable major proteins (VMP). Less is known about other surface proteins of these pathogens in either their vertebrate reservoirs or arthropod vectors. To further characterize these proteins, we elicited antibodies against VMP-less cells, noted antibody reactions against whole cells and cell components, and then subjected selected antigens to mass spectroscopy for amino acid sequencing for comparison against a B. hermsii genome database. One of the derived monoclonal antibodies, H0120, agglutinated spirochetes, and in Western blot analyses, it bound to a 14-kDa protein of whole cells and their membrane fractions but not after protease treatment. A search of open reading frames of the B. hermsii genome with extracted peptides identified the 14-kDa protein with bha128, a 453-nucleotide gene of the 175-kb linear plasmid. The bha128 gene was synthesized and expressed in Escherichia coli. The protein product was bound by antibody H0120. Genes homologous to bha128 occur in the RF species Borrelia turicatae, B. duttonii, and B. recurrentis but not in Lyme disease Borrelia species or other organisms. The following findings indicated an association of BHA128, renamed Alp, with the tick environment: (i) Alp was produced at higher levels at 23 degrees C than at 34 degrees C; (ii) almost all spirochetes in tick salivary glands were bound by the H0120 antibody, but only similar to 1% of spirochetes in the blood of infected mice were bound; and (iii) infected mice produced antibodies to several B. hermsii antigens but not detectably to native or recombinant Alp. C1 [Marcsisin, Renee A.; Campeau, Shelley A.; Barbour, Alan G.] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Marcsisin, Renee A.; Campeau, Shelley A.; Barbour, Alan G.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Marcsisin, Renee A.; Campeau, Shelley A.; Barbour, Alan G.] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92717 USA. [Lopez, Job E.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Barbour, AG (reprint author), Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. EM abarbour@uci.edu OI Barbour, Alan/0000-0002-0719-5248 FU Public Health Service from the National Institute of Allergy and Infectious Diseases [AI-24424]; patent royalties; National Institutes of Health FX This work was supported by Public Health Service grant AI-24424 from the National Institute of Allergy and Infectious Diseases (A.G.B.), patent royalties (A.G.B.), and intramural funds of the National Institutes of Health (J.E.L.). NR 57 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2012 VL 80 IS 5 BP 1881 EP 1890 DI 10.1128/IAI.06419-11 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 925VX UT WOS:000302791100029 PM 22354035 ER PT J AU Haydon, AA Herring, AH Prinstein, MJ Halpern, CT AF Haydon, Abigail A. Herring, Amy H. Prinstein, Mitchell J. Halpern, Carolyn Tucker TI Beyond Age at First Sex: Patterns of Emerging Sexual Behavior in Adolescence and Young Adulthood SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Oral sex; Anal sex; Latent class analysis; Nationally representative; Noncoital; Sexuality development; Adolescent sexual behavior; Sociodemographic differences ID ORAL SEX; INTERCOURSE; PREVALENCE; HIV; PREDICTORS; GENDER; HEALTH; RISK; PART AB Purpose: Although the emergence of sexual expression during adolescence and early adulthood is nearly universal, little is known about patterns of initiation. Methods: We used latent class analysis to group 12,194 respondents from waves I and IV of the National Longitudinal Study of Adolescent Health(Add Health) into one of five classes based on variety, timing, spacing, and sequencing of oral-genital, anal, and vaginal sex. Multinomial logistic regression models, stratified by biological sex, examined associations between sociodemographic characteristics and class membership. Results: Approximately half of respondents followed a pattern characterized predominately by initiation of vaginal sex first, average age of initiation of approximately 16 years, and spacing of >1 year between initiation of the first and second behaviors; almost one-third initiated sexual activity slightly later but reported first experiences of oral-genital and vaginal sex within the same year. Classes characterized by postponement of sexual activity, initiation of only one type of behavior, or adolescent initiation of anal sex were substantially less common. Compared with white respondents, black respondents were more likely to appear in classes characterized by initiation of vaginal sex first. Respondents from lower socioeconomic backgrounds were more likely to be in classes distinguished by early/atypical patterns of initiation. Conclusions: A small number of typical and atypical patterns capture the emergence of sexual behavior during adolescence, but these patterns reveal complex associations among different elements of emerging sexuality that should be considered in future research. (C) 2012 Society for Adolescent Health and Medicine. All rights reserved. C1 [Haydon, Abigail A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, AAAS APA Execut Branch, NIH, Bethesda, MD 20892 USA. [Halpern, Carolyn Tucker] Univ N Carolina, Dept Maternal & Child Hlth, UNC Gillings Sch Global, Chapel Hill, NC USA. [Herring, Amy H.; Halpern, Carolyn Tucker] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, UNC Gillings Sch Global, Chapel Hill, NC USA. [Prinstein, Mitchell J.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. RP Haydon, AA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, AAAS APA Execut Branch, NIH, 6100 Execut Blvd,Room 8B07J,MSC 7510, Bethesda, MD 20892 USA. EM aahaydon@gmail.com RI Prinstein, Mitchell/F-7955-2013 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01-HD31921, 5 R24 HD050924, R01HD57046] FX This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health Web site (http://www.cpc.unc.edu/addhealth). No direct support was received from grant P01-HD31921 for this analysis. This research was supported by grant 5 R24 HD050924, Carolina Population Center, awarded to the Carolina Population Center at the University of North Carolina at Chapel Hill by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Effort by A.A.H. and C.T.H. was supported by grant R01HD57046, awarded to C.T.H. of the Carolina Population Center at the University of North Carolina at Chapel Hill by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 28 TC 17 Z9 17 U1 4 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAY PY 2012 VL 50 IS 5 BP 456 EP 463 DI 10.1016/j.jadohealth.2011.09.006 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 930HP UT WOS:000303128600007 PM 22525108 ER PT J AU Agwu, AL Siberry, GK Ellen, J Fleishman, JA Rutstein, R Gaur, AH Korthuis, PT Warford, R Spector, SA Gebo, KA AF Agwu, Allison L. Siberry, George K. Ellen, Jonathan Fleishman, John A. Rutstein, Richard Gaur, Aditya H. Korthuis, P. Todd Warford, Robert Spector, Stephen A. Gebo, Kelly A. TI Predictors of Highly Active Antiretroviral Therapy Utilization for Behaviorally HIV-1-Infected Youth: Impact of Adult Versus Pediatric Clinical Care Site SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; Youth; Highly active antiretroviral therapy (HAART); Disparities; Utilization; HIV Research Network; Clinical site ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; NAIVE PATIENTS; UNITED-STATES; SPECIAL NEEDS; ADOLESCENTS; SERVICES; ADHERENCE; COHORT; EXPERIENCE AB Objectives: We evaluated highly active antiretroviral therapy (HAART) utilization in youth infected with HIV through risk behaviors who met treatment criteria for HAART. We assessed the impact of receiving care at an adult or pediatric HIV clinical site on initiation and discontinuation of the first HAART regimen in behaviorally infected youth (BIY). Methods: This was a retrospective analysis of treatment-naive BIY, aged 12-24 years, who enrolled in the HIV Research Network between 2002 and 2008 and who met criteria for HAART. The outcomes were time from meeting criteria to initiation of HAART and time to discontinuation of the first HAART regimen. Analyses were conducted using Cox proportional hazards regression. Results: Of 287 treatment-eligible youth, 198 (69%) received HAART; of these 198 youth, 58 (29.3%) subsequently discontinued HAART. In multivariable analyses, there was no significant difference in the time between meeting treatment criteria and initiating HAART for BIY followed at adult or pediatric HIV clinical sites. However, BIY followed at adult sites discontinued HAART sooner than BIY followed at pediatric HIV clinical sites (adjusted hazard ratio [AHR]: 3.19 [1.26-8.06]). Conclusions: Two-thirds of treatment-eligible BIY in the HIV Research Network cohort initiated HAART; however, one-third who initiated HAART discontinued it during the study period. Identifying factors associated with earlier HAART initiation and sustainability can inform interventions to enhance HAART utilization among treatment-eligible youth. The finding of earlier HAART discontinuation for youth at adult care sites deserves further study. (C) 2012 Society for Adolescent Health and Medicine. All rights reserved. C1 [Agwu, Allison L.] Johns Hopkins Sch Med, Div Pediat Infect Dis, Dept Pediat, Johns Hopkins Med Inst, Baltimore, MD 21287 USA. [Agwu, Allison L.; Gebo, Kelly A.] Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21287 USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Baltimore, MD 21287 USA. [Ellen, Jonathan] Johns Hopkins Sch Med, Div Adolescent Med, Baltimore, MD 21287 USA. [Fleishman, John A.] Agcy Hlth Care Res & Qual, Ctr Financing, Rockville, MD USA. [Rutstein, Richard] Childrens Hosp Philadelphia, Div Gen Pediat, Philadelphia, PA 19104 USA. [Gaur, Aditya H.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97201 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Warford, Robert] St Lukes Roosevelt Hosp, New York, NY 10032 USA. [Spector, Stephen A.] Univ Calif San Diego, Div Pediat Infect Dis, La Jolla, CA 92093 USA. [Spector, Stephen A.] Rady Childrens Hosp, Div Pediat Infect Dis, San Diego, CA USA. RP Agwu, AL (reprint author), Johns Hopkins Sch Med, Div Pediat Infect Dis, Dept Pediat, Johns Hopkins Med Inst, 200 N Wolfe St,Room 3145, Baltimore, MD 21287 USA. EM ageorg10@jhmi.edu FU Agency for Healthcare Research and Quality [290-01-0012]; National Institute on Aging, NIH [RO1 AG026250]; Johns Hopkins University; National Institutes of Allergy and Infectious Diseases [1K23AI084549-01A1]; Johns Hopkins Ross Clinician scientist Award; National Institute on Drug Abuse [K23DA019809]; Health Resources and Services Administration, Rockville, MD; Data Coordinating Center Johns Hopkins University; Tibotec FX The study was supported by the Agency for Healthcare Research and Quality (290-01-0012) and the National Institute on Aging, NIH (RO1 AG026250). K.A.G. also received support from the Johns Hopkins University Richard Ross Clinician Scientist Award.; A.L.A. is supported by the National Institutes of Allergy and Infectious Diseases (1K23AI084549-01A1) and the Johns Hopkins Ross Clinician scientist Award. P.T.K. is supported by the National Institute on Drug Abuse (K23DA019809).; Sponsoring Agencies: Agency for Healthcare Research and Quality, Rockville, MD (Fred Hellinger, Ph.D.; John Fleishman, Ph.D., Irene Fraser, Ph.D.); Health Resources and Services Administration, Rockville, MD (Robert Mills, Ph.D.); and Data Coordinating Center Johns Hopkins University (Richard Moore, M.D., Jeanne Keruly, C.R.N.P., Kelly Gebo, M.D., Cindy Voss, M.A., Bonnie Cameron, M.S.).; K.A.G. has received research funding from Tibotec. NR 36 TC 7 Z9 8 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAY PY 2012 VL 50 IS 5 BP 471 EP 477 DI 10.1016/j.jadohealth.2011.09.001 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 930HP UT WOS:000303128600009 PM 22525110 ER PT J AU Krousel-Wood, M Muntner, P Carson, A Anderson, AH Delaune, E Cushman, WC Cutler, JA Piller, LB Goforth, GA Whelton, PK AF Krousel-Wood, Marie Muntner, Paul Carson, April Anderson, Amanda H. Delaune, Erin Cushman, William C. Cutler, Jeffrey A. Piller, Linda B. Goforth, Gary A. Whelton, Paul K. TI Hypertension Control Among Newly Treated Patients Before and After Publication of the Main ALLHAT Results and JNC 7 Guidelines SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; JOINT NATIONAL COMMITTEE; HIGH BLOOD-PRESSURE; ALPHA-BLOCKER; 7TH REPORT; CHLORTHALIDONE; PREVENTION; OUTCOMES; TRENDS AB Medication prescribing practice changed following the publications of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 2002 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) in 2003. Few data are available on changes in hypertension control rates for patients initiating antihypertensive treatment before and after these publications. The authors compared systolic and diastolic blood pressure (SBP and DBP) levels and hypertension control (SBP <140 mm Hg and DBP <90 mm Hg) rates in patients initiating antihypertensive treatment in a large managed care organization during 2 time periods: July 1, 2001, to June 30, 2002 (n=322); and July 1, 2003, to June 30, 2004 (n=323). The blood pressure reduction associated with antihypertensive medication initiation was similar in 20012002 and 20032004 (-11.9 and -10.5 mm Hg, respectively, P=.251 for SBP; -6.9 and -5.9 mm Hg, respectively, P=.160 for DBP). The mean SBP and DBP prior to treatment were significantly lower in 20032004 vs 20012002 (145.4 vs 151.3 mm Hg, P<.001 for SBP; 87.6 vs 90.1 mm Hg, P<.002 for DBP). Hypertension control rates increased from 38.0% to 50.2% (P=.005) from 20012002 to 20032004. Lower pretreatment SBP and DBP explained hypertension control improvement over time. In this real-world clinic population, antihypertensive treatment was initiated at lower blood pressure levels following publication of ALLHAT and JNC 7, resulting in substantial improvements in hypertension control rates. J Clin Hypertens (Greenwich). 2012; 14:277283. (c) 2012 Wiley Periodicals, Inc. C1 [Krousel-Wood, Marie] Ochsner Clin Fdn, Ctr Hlth Res, New Orleans, LA 70121 USA. [Krousel-Wood, Marie] Tulane Univ, New Orleans, LA 70118 USA. [Muntner, Paul; Carson, April] Univ Alabama, Birmingham, AL USA. [Anderson, Amanda H.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Delaune, Erin] Louisiana Off Publ Hlth, Metairie, LA USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Cutler, Jeffrey A.] NHLBI, Bethesda, MD 20892 USA. [Piller, Linda B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Goforth, Gary A.] Montgomery Ctr Family Med, Greenwood, SC USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. RP Krousel-Wood, M (reprint author), Ochsner Clin Fdn, Ctr Hlth Res, 1514 Jefferson Highway, New Orleans, LA 70121 USA. EM mawood@ochsner.org RI Krousel-Wood, Marie Antoinette/D-4718-2011 FU National Heart, Lung, and Blood Institute [NO1-HC-35130]; Pfizer, Inc.; GlaxoSmithKline; King; Merck; Novartis FX The ALLHAT study was supported by a contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc, (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer, Inc.; William C. Cushman has consulted for Calpis, Daiichi Sankyo, Gilead Colorado, Novartis, Noven, Pharmacopeia, Sanofi Aventis, Sciele, Takeda, Theravance; has received honoraria from Bristol-Myers Squibb, Forest Pharmaceuticals, and King; and has received research support from GlaxoSmithKline, King, Merck, and Novartis. Amanda H. Anderson, April Carson, Jeffrey A. Cutler, Erin Delaune, Gary A. Goforth, Marie Krousel-Wood, Paul Muntner, Linda B. Piller, and Paul K. Whelton have no financial interests to disclose. NR 15 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD MAY PY 2012 VL 14 IS 5 BP 277 EP 283 DI 10.1111/j.1751-7176.2012.00609.x PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 931DX UT WOS:000303196500002 PM 22533653 ER PT J AU Menotti-Raymond, M David, VA Weir, BS O'Brien, SJ AF Menotti-Raymond, Marilyn David, Victor A. Weir, Bruce S. O'Brien, Stephen J. TI A Population Genetic Database of Cat Breeds Developed in Coordination with a Domestic Cat STR Multiplex SO JOURNAL OF FORENSIC SCIENCES LA English DT Article DE forensic science; domestic cat; simple tandem repeat; forensic typing system; population genetic database; cat breeds ID RADIATION HYBRID MAP; FELIS-CATUS; TRACE EVIDENCE; TYPING SYSTEM; HAIR; DOG; TYROSINASE; GENOME; CANINE; INDIVIDUALIZATION AB A simple tandem repeat (STR) PCR-based typing system developed for the genetic individualization of domestic cat samples has been used to generate a population genetic database of domestic cat breeds. A panel of 10 tetranucleotide STR loci and a gender-identifying sequence tagged site (STS) were co-amplified in genomic DNA of 1043 individuals representing 38 cat breeds. The STR panel exhibits relatively high heterozygosity in cat breeds, with an average 10-locus heterozygosity of 0.71, which represents an average of 38 breed-specific heterozygosities for the 10-member panel. When the entire set of breed individuals was analyzed as a single population, a heterozygosity of 0.87 was observed. Heterozygosities obtained for the 10 loci range from 0.72 to 0.96. The power for genetic individualization of domestic cat samples of the multiplex is high, with a probability of match (pm) of 6.2E-14, using a conservative ? = 0.05. C1 [Menotti-Raymond, Marilyn; David, Victor A.; O'Brien, Stephen J.] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Weir, Bruce S.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Menotti-Raymond, M (reprint author), NCI, Lab Genom Div, Bldg 560,Room 11-38, Frederick, MD 21702 USA. EM raymondm@mail.nih.gov RI Weir, Bruce/A-2894-2013 FU National Institute of Justice, Office of Justice Programs, US Department of Justice [1999-IJ-R-A079]; NIH [GM 75091] FX Supported by an Interagency Grant (IAA # 1999-IJ-R-A079) awarded by the National Institute of Justice, Office of Justice Programs, US Department of Justice to the National Cancer Institute's Laboratory of Genomic Diversity. BSW has been supported in part by NIH grant GM 75091. Points of view in this document are those of the authors and do not necessarily represent the official position or policies of the US Department of Justice. NR 36 TC 5 Z9 5 U1 0 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-1198 J9 J FORENSIC SCI JI J. Forensic Sci. PD MAY PY 2012 VL 57 IS 3 BP 596 EP 601 DI 10.1111/j.1556-4029.2011.02040.x PG 6 WC Medicine, Legal SC Legal Medicine GA 928QX UT WOS:000302999000004 PM 22268511 ER PT J AU Keim, SA Daniels, JL Siega-Riz, AM Dole, N Herring, AH Scheidt, PC AF Keim, Sarah A. Daniels, Julie L. Siega-Riz, Anna Maria Dole, Nancy Herring, Amy H. Scheidt, Peter C. TI Depressive Symptoms during Pregnancy and the Concentration of Fatty Acids in Breast Milk SO JOURNAL OF HUMAN LACTATION LA English DT Article DE depression; postpartum depression; fatty acids; pregnancy; breast milk; introduction ID BLOOD-CELL MEMBRANES; POSTPARTUM DEPRESSION; DOCOSAHEXAENOIC ACID; OMEGA-3-FATTY-ACIDS; SUPPLEMENTATION; CONSUMPTION; WOMEN; ESSENTIALITY; PREDICTORS; LIPIDS AB The aim of the present study was to examine the association between depressive symptoms in pregnancy and the concentration of long-chain polyunsaturated fatty acids (LCPUFAs) in breast milk. Women (n = 287) enrolled in the Pregnancy, Infection, and Nutrition Study completed the Center for Epidemiologic Studies Depression Scale in pregnancy (< 20 and 24-29 weeks) and had LCPUFAs measured in breast milk (4 months postpartum). Multiple linear regression was used to examine associations between depressive symptoms and breast milk LCPUFAs. Increasing depressive symptoms at < 20 weeks were associated with lower docosahexaenoic acid concentrations (adjusted beta = -1.15, 95% confidence interval = -2.12, -0.19). No similar associations were observed with other fatty acids nor between symptoms at 24-29 weeks and LCPUFAs. Depressive symptoms, even in the subclinical range, early in pregnancy are inversely associated with breast milk docosahexaenoic acid. This may have implications for the timing of screening and interventions for perinatal depression and the nutritional value of breast milk. C1 [Keim, Sarah A.; Daniels, Julie L.; Siega-Riz, Anna Maria; Dole, Nancy] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Keim, Sarah A.; Scheidt, Peter C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, Bethesda, MD USA. [Daniels, Julie L.] Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Siega-Riz, Anna Maria] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Siega-Riz, Anna Maria; Dole, Nancy; Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Keim, SA (reprint author), 700 Childrens Dr, Columbus, OH 43205 USA. EM keim.22@osu.edu RI Keim, Sarah/F-8929-2013; OI Keim, Sarah/0000-0003-3490-3649; Dole, Nancy/0000-0002-2113-7984 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD37584, HD39373]; National Institute of Diabetes and Digestive and Kidney Diseases [DK61981, DK56350]; National Institute of Environmental Health Sciences, National Institutes of Health [P30ES10126]; Carolina Population Center FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD37584, HD39373), the National Institute of Diabetes and Digestive and Kidney Diseases (DK61981, DK56350), and the National Institute of Environmental Health Sciences (P30ES10126) of the National Institutes of Health, the Carolina Population Center, and as part of the salary-supported activities of extramural staff of the National Institute of Child Health and Human Development. NR 33 TC 3 Z9 3 U1 2 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 J9 J HUM LACT JI J. Hum. Lact. PD MAY PY 2012 VL 28 IS 2 BP 189 EP 195 DI 10.1177/0890334411424727 PG 7 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA 930GO UT WOS:000303125900018 PM 22223516 ER PT J AU Sanai, N Polley, MY McDermott, MW Parsa, AT Berger, MS AF Sanai, Nader Polley, Mei-Yin McDermott, Michael W. Parsa, Andrew T. Berger, Mitchel S. TI Untitled RESPONSE SO JOURNAL OF NEUROSURGERY LA English DT Letter ID RESECTION; EXTENT C1 [Sanai, Nader] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Polley, Mei-Yin] NCI, Rockville, MD USA. [McDermott, Michael W.; Parsa, Andrew T.; Berger, Mitchel S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Sanai, N (reprint author), Barrow Neurol Inst, Phoenix, AZ 85013 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 MAY PY 2012 VL 116 IS 5 BP 1167 EP 1168 DI 10.3171/2011.8.JNS11637c PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 929TO UT WOS:000303088800043 ER PT J AU Eid, N Ito, Y Otsuki, Y Mehta, GU Lonser, RR Oldfield, EH AF Eid, Nabil Ito, Yuko Otsuki, Yoshinori Mehta, Gautam U. Lonser, Russell R. Oldfield, Edward H. TI Cushing disease SO JOURNAL OF NEUROSURGERY LA English DT Letter ID EGYPTIANS; HISTORY C1 [Eid, Nabil; Ito, Yuko; Otsuki, Yoshinori] Osaka Med Coll, Osaka, Japan. [Mehta, Gautam U.; Oldfield, Edward H.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Mehta, Gautam U.; Lonser, Russell R.] NINDS, Bethesda, MD 20892 USA. RP Eid, N (reprint author), Osaka Med Coll, Osaka, Japan. NR 6 TC 0 Z9 0 U1 0 U2 0 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 MAY PY 2012 VL 116 IS 5 BP 1168 EP 1168 DI 10.3171/2012.1.JNS1224 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 929TO UT WOS:000303088800044 PM 22424567 ER PT J AU Major, JM Yu, K Chung, CC Weinstein, SJ Yeager, M Wheeler, W Snyder, K Wright, ME Virtamo, J Chanock, S Albanes, D AF Major, Jacqueline M. Yu, Kai Chung, Charles C. Weinstein, Stephanie J. Yeager, Meredith Wheeler, William Snyder, Kirk Wright, Margaret E. Virtamo, Jarmo Chanock, Stephen Albanes, Demetrius TI Genome-Wide Association Study Identifies Three Common Variants Associated with Serologic Response to Vitamin E Supplementation in Men SO JOURNAL OF NUTRITION LA English DT Article ID PREVENTION TRIAL SELECT; PROSTATE-CANCER RISK; ALPHA-TOCOPHEROL; LIPID-PEROXIDATION; RECOMBINATION HOTSPOTS; LINKAGE DISEQUILIBRIUM; COLORECTAL-CANCER; BETA-CAROTENE; PLASMA; DISEASE AB Vitamin E inhibits lipid peroxidation in cell membranes, prevents oxidative damage to DNA by scavenging free radicals, and reduces carcinogen production. No study to our knowledge, however, has examined the association between genetic variants and response to long-term vitamin E supplementation. We conducted a genome-wide association study (GWAS) of common variants associated with circulating alpha-tocopherol concentrations following 3 y of controlled supplementation. The study population included 2112 middle-aged, male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort who received a trial supplementation of alpha-tocopherol (50 mg/d) and had fasting serum. alpha-tocopherol concentrations measured after 3 y. Serum concentrations were log-transformed for statistical analysis and general linear models adjusted for age, BMI, serum total cholesterol, and cancer case status. Associations with serum response to alpha-tocopherol supplementation achieved genome-wide significance for 2 single nucleotide polymorphisms (SNP): rs964184 on 11q23.3 (P = 2.6 x 10(-12)) and rs2108622 on 19pter-p13.11 (P = 2.2 X 10(-7)), and approached genome-wide significance for one SNP, rs7834588 on 8q12.3 (P = 6.2 X 10(-7)). Combined, these SNP explain 3.4% of the residual variance in serum alpha-tocopherol concentrations during controlled vitamin E supplementation. A GWAS has identified 3 genetic variants at different loci that appear associated with serum concentrations after vitamin E supplementation in men. Identifying genetic variants that influence serum nutrient biochemical status (e.g., alpha-tocopherol) under supplementation conditions improves our understanding of the biological determinants of these nutritional exposures and their associations with cancer etiology. J. Nutr. 142: 866-871, 2012. C1 [Major, Jacqueline M.; Yu, Kai; Weinstein, Stephanie J.; Chanock, Stephen; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chung, Charles C.; Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, NIH, Bethesda, MD 20892 USA. [Wheeler, William; Snyder, Kirk] Informat Management Serv Inc, Silver Spring, MD USA. [Wright, Margaret E.] Univ Illinois, Dept Pathol, Chicago, IL USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 FU NIH; National Cancer Institute; Public Health Service from National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX Supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, the research was supported by Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services. NR 46 TC 8 Z9 11 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAY PY 2012 VL 142 IS 5 BP 866 EP 871 DI 10.3945/jn.111.156349 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 929TX UT WOS:000303089700009 PM 22437554 ER PT J AU Pfeiffer, CM Hughes, JP Lacher, DA Bailey, RL Berry, RJ Zhang, M Yetley, EA Rader, JI Sempos, CT Johnson, CL AF Pfeiffer, Christine M. Hughes, Jeffery P. Lacher, David A. Bailey, Regan L. Berry, R. J. Zhang, Mindy Yetley, Elizabeth A. Rader, Jeanne I. Sempos, Christopher T. Johnson, Clifford L. TI Estimation of Trends in Serum and RBC Folate in the U.S. Population from Pre- to Postfortification Using Assay-Adjusted Data from the NHANES 1988-2010 SO JOURNAL OF NUTRITION LA English DT Article ID TOTAL HOMOCYSTEINE CONCENTRATIONS; FOLIC-ACID FORTIFICATION; BIO-RAD RADIOASSAY; UNITED-STATES; ROUND-TABLE; MICROBIOLOGIC ASSAY; VITAMIN-B-12 STATUS; NATIONAL-HEALTH; BLOOD FOLATE; LC-MS/MS AB The NHANES has monitored folate status of the U.S. population from prefortification (1988-1994) to postfortification (1999-2010) by measuring serum and RBC folate concentrations. The Bio-Rad radioassay (BR) was used from 1988 to 2006, and the microbiologic assay (MBA) was used from 2007 to 2010. The MBA produces higher concentrations than the BR and is considered to be more accurate. Thus, to bridge assay differences and to examine folate trends over time, we adjusted the BR results to be comparable to the MBA results. Postfortification, assay-adjusted serum and RBC folate concentrations were 2.5 times and 1.5 times prefortification concentrations, respectively, and showed a significant linear trend (P < 0.001) to slightly lower concentrations during 1999-2010. The postfortification prevalence of low serum (<10 nmol/L) or RBC (<340 nmol/L) folate concentrations was <= 1%, regardless of demographic subgroup, compared with 24% for serum folate and 3.5% for RBC folate prefortification, with substantial variation among demographic subgroups, The central 95% reference intervals for serum and RBC folate varied by demographic subgroup during both pre- and post-fortification periods. Age and dietary supplement use had the greatest effects on prevalence estimates of low folate concentrations during the prefortification period. In summary, the MBA-equivalent blood folate concentrations in the U.S. population showed first a sharp increase from pre- to postfortification, then showed a slight decrease (17% for serum and 12% for RBC folate) during the 12-y postfortification period. The MBA-equivalent pre- and postfortification reference concentrations will inform countries that plan folic acid fortification or that need to evaluate its impact. J. Nutr. 142: 886-893, 2012. C1 [Pfeiffer, Christine M.; Zhang, Mindy] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Hughes, Jeffery P.; Lacher, David A.; Johnson, Clifford L.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Bailey, Regan L.; Yetley, Elizabeth A.; Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Berry, R. J.] CDC, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Rader, Jeanne I.] US FDA, College Pk, MD USA. RP Pfeiffer, CM (reprint author), CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. EM cpfeiffer@cdc.gov OI Berry, Robert/0000-0002-7162-5046 FU Office of Dietary Supplements, NIH FX Supported by funding from the Office of Dietary Supplements, NIH. The findings and conclusions in this report are those of the authors and do not necessarily represent the official views or positions of the CDC and Prevention/Agency for Toxic Substances and Disease Registry, the NIH, or the Department of Health and Human Services. NR 29 TC 67 Z9 70 U1 1 U2 12 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAY PY 2012 VL 142 IS 5 BP 886 EP 893 DI 10.3945/jn.111.156919 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 929TX UT WOS:000303089700012 PM 22437563 ER PT J AU Pfeiffer, CM Hughes, JP Durazo-Arvizu, RA Lacher, DA Sempos, CT Zhang, M Yetley, EA Johnson, CL AF Pfeiffer, Christine M. Hughes, Jeffery P. Durazo-Arvizu, Ramon A. Lacher, David A. Sempos, Christopher T. Zhang, Mindy Yetley, Elizabeth A. Johnson, Clifford L. TI Changes in Measurement Procedure from a Radioassay to a Microbiologic Assay Necessitate Adjustment of Serum and RBC Folate Concentrations in the US Population from the NHANES 1988-2010 SO JOURNAL OF NUTRITION LA English DT Article ID BIO-RAD RADIOASSAY; WHOLE-BLOOD FOLATE; LC-MS/MS; INTERNATIONAL STANDARD; ROUND-TABLE; VITAMIN-B-12; BIOMARKERS; HISTORY AB The NHANES measured serum and RBC folate concentrations by using a radioassay during prefortification (1988-1994) and postfortification (1999-2006) periods followed by the use of a microbiologic assay (MBA) from 2007-2010. The MBA produces higher concentrations than does the radioassay and is considered to be more accurate. To allow for accurate long-term trending (1988-2010), we evaluated different regression models (linear, piecewise linear, and fractional polynomial) to assay-adjust the radioassay results to be comparable to the MBA results. The data used to derive the regression models originated from 2 crossover studies in which the 2 assays were applied to a set of 325 serum and 171 whole-blood samples. Fractional polynomial regression of logarithmically transformed data provided the best fit for serum folate. Linear regression of logarithmically transformed whole-blood data provided an equally good fit compared with the other models and was the simplest to apply for RBC folate. Prefortification serum and RBC folate geometric mean concentrations increased after adjustment from 13.0 to 16.7 nmol/L and from 403 to 747 nmol/L, respectively. Postfortification serum folate concentrations increased from similar to 30 to similar to 43 nmol/L, and RBC folate concentrations increased from similar to 600 to similar to 1100 nmol/L after adjustment, with some variation across survey cycles. The presented regression equations allow the estimation of more accurate prevalence estimates and long-term trends in blood folate concentrations in the U.S. population by using results that are equivalent to the MBA. This information will be useful to public health officials in the United States who are dealing with folic acid fortification issues. J. Nutr. 142: 894-900, 2012. C1 [Hughes, Jeffery P.; Lacher, David A.; Johnson, Clifford L.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Pfeiffer, Christine M.; Zhang, Mindy] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Durazo-Arvizu, Ramon A.] Loyola Univ, Dept Prevent Med & Epidemiol, Chicago, IL 60611 USA. [Sempos, Christopher T.; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Pfeiffer, CM (reprint author), CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. EM cpfeiffer@cdc.gov FU Office of Dietary Supplements, NIH FX Supported by funding from the Office of Dietary Supplements, NIH. The findings and conclusions in this report are those of the authors and do not necessarily represent the official views or positions of the CDC/Agency for Toxic Substances and Disease Registry, the NIH, or the Department of Health and Human Services. NR 24 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAY PY 2012 VL 142 IS 5 BP 894 EP 900 DI 10.3945/jn.111.156901 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 929TX UT WOS:000303089700013 PM 22437557 ER PT J AU Wang, Q McPherron, AC AF Wang, Qian McPherron, Alexandra C. TI Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SKELETAL-MUSCLE; PROLONGED ABSENCE; LATENT MYOSTATIN; ADDITION IS/IS; MYOTUBE SIZE; STEM-CELLS; MASS; GROWTH; GENE; COUNTERPOINT AB Muscle fibres are multinucleated post-mitotic cells that can change dramatically in size during adulthood. It has been debated whether muscle fibre hypertrophy requires activation and fusion of muscle stem cells, the satellite cells. Myostatin (MSTN) is a negative regulator of skeletal muscle growth during development and in the adult, and MSTN inhibition is therefore a potential therapy for muscle wasting diseases, some of which are associated with a depletion of satellite cells. Conflicting results have been obtained in previous analyses of the role of MSTN on satellite cell quiescence. Here, we inhibited MSTN in adult mice with a soluble activin receptor type IIB and analysed the incorporation of new nuclei using 5'-bromo-2'-deoxyuridine (BrdU) labelling by isolating individual myofibres. We found that satellite cells are activated by MSTN inhibition. By varying the dose and time course for MSTN inhibition, however, we found that myofibre hypertrophy precedes the incorporation of new nuclei, and that the overall number of new nuclei is relatively low compared to the number of total myonuclei. These results reconcile some of the previous work obtained by other methods. In contrast with previous reports, we also found that Mstn null mice do not have increased satellite cell numbers during adulthood and are not resistant to sarcopaenia. Our results support a previously proposed model of hypertrophy in which hypertrophy can precede satellite cell activation. Studies of the metabolic and functional effects of postnatal MSTN inhibition are needed to determine the consequences of increasing the cytoplasm/ myonuclear ratio after MSTN inhibition. C1 [Wang, Qian; McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP McPherron, AC (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Rm 8D12A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mcpherrona@niddk.nih.gov OI McPherron, Alexandra/0000-0002-5875-9154 FU NIH, NIDDK; NICHD FX This work was supported by the Intramural Research Program of the NIH, NIDDK. We thank Kathleen Savage for helpful discussions, Tingqing Guo for help purifying ACVR2B:Fc, Onur Kanisicak and Shahragim Tajbakhsh for technical advice, Bryan Millis for creating the macro for the imaging analysis, Yunping Wu for help with confocal microscopy, and Kathryn Wagner for comments on the manuscript. The Pax7 hybridoma developed by A. Kawakami was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242, USA. NR 63 TC 44 Z9 44 U1 0 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY PY 2012 VL 590 IS 9 BP 2151 EP 2165 DI 10.1113/jphysiol.2011.226001 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 931TJ UT WOS:000303241900010 PM 22393251 ER PT J AU Saha, TD Harford, T Goldstein, RB Kerridge, BT Hasin, D AF Saha, Tulshi D. Harford, Thomas Goldstein, Rise B. Kerridge, Bradley T. Hasin, Deborah TI Relationship of Substance Abuse to Dependence in the U.S. General Population SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE DISORDER; DSM-IV ALCOHOL; HEALTH INTERVIEW SURVEY; ITEM RESPONSE THEORY; DIFFERENT PSYCHOACTIVE SUBSTANCES; DRUG-DEPENDENCE; CANNABIS DEPENDENCE; CONSTRUCT-VALIDITY; SCHEDULE AUDADIS AB Objective: The diagnostic categories of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for substance abuse and dependence are commonly used in clinical work and research studies, but whether abuse and dependence represent two different syndromes has been debated. The purpose of this article is to investigate the relationship of substance abuse and dependence for cannabis, cocaine, stimulants and sedatives among lifetime users of these substances in the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative survey conducted in 2001-2002. Method: The multiple indicators multiple causes (MIMIC) model addresses three sets of relationships: those between (1) diagnostic criteria and latent factors, (2) latent factors and covariates, and (3) criteria and covariates. This approach allows for the detection of and compensation for noninvariance of the measurement of criteria across subgroups. Results: Compared with one-factor models, two-factor models (factors roughly corresponding to abuse and dependence) fit significantly better across all substances, with abuse and dependence factors highly correlated. The MIMIC model indicated that race/ethnicity, age, income, and marital status showed some differential relationships across substance groups, although most covariates showed similar associations to dependence and abuse factors. Noninvariance of criteria measurement by demographic covariates was most pronounced for cannabis abuse and dependence criteria. Conclusions: The general relationship of abuse to dependence was consistent across substances. Results were equivocal on the value of retaining separate factors; therefore, investigating the relationships of specific genetic variants and treatment outcomes to dimensional indicators of abuse, dependence, and measures combining these criteria is warranted. Measurement of cannabis abuse and dependence criteria appears most affected by demographic characteristics. (I Stud. Alcohol Drugs, 73, 368-378, 2012) C1 [Saha, Tulshi D.; Goldstein, Rise B.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Harford, Thomas] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Portsmouth, NH USA. [Kerridge, Bradley T.] Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD 20742 USA. [Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3083,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM sahatd@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism from the National Institute on Drug Abuse (NIDA); National Institutes of Health/NIDA [5F31DA025377] FX The National Institute on Alcohol Abuse and Alcoholism funded the National Epidemiologic Survey on Alcohol and Related Conditions with supplemental funding from the National Institute on Drug Abuse (NIDA). Bradley T. Kerridge was supported by National Institutes of Health/NIDA Fellowship 5F31DA025377. NR 48 TC 5 Z9 5 U1 3 U2 13 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAY PY 2012 VL 73 IS 3 BP 368 EP 378 PG 11 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 929UQ UT WOS:000303091600004 PM 22456242 ER PT J AU Frazier, JA Giuliano, AJ Johnson, JL Yakutis, L Youngstrom, EA Breiger, D Sikich, L Findling, RL McClellan, J Hamer, RM Vitiello, B Lieberman, JA Hooper, SR AF Frazier, Jean A. Giuliano, Anthony J. Johnson, Jacqueline L. Yakutis, Lauren Youngstrom, Eric A. Breiger, David Sikich, Linmarie Findling, Robert L. McClellan, Jon Hamer, Robert M. Vitiello, Benedetto Lieberman, Jeffrey A. Hooper, Stephen R. TI Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE early-onset; schizophrenia; neurocognition; outcomes; antipsychotics ID DOUBLE-BLIND; 1ST-EPISODE SCHIZOPHRENIA; ANTIPSYCHOTIC-DRUGS; FOLLOW-UP; CHILDHOOD; TEOSS; TRIAL; METAANALYSIS; ADOLESCENTS; MEDICATIONS AB Objective: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). Method: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. Results: Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. Conclusions: Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(5):496-505. Clinical trial registry information Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703. C1 [Frazier, Jean A.; Giuliano, Anthony J.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Giuliano, Anthony J.] Beth Israel Deaconess Med Ctr, Massachu setts Mental Hlth Ctr, Publ Psychiat Div, Boston, MA USA. [Johnson, Jacqueline L.; Youngstrom, Eric A.; Sikich, Linmarie; Hamer, Robert M.; Hooper, Stephen R.] Univ N Carolina, Chapel Hill, NC USA. [Breiger, David; McClellan, Jon] Univ Washington, Seattle, WA USA. [Lieberman, Jeffrey A.] Columbia Univ, Coll Physicians & Surgeons, New York, NY 10027 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Frazier, JA (reprint author), Univ Massachusetts, Sch Med, Biotech 1,Suite 100,365 Plantat St, Worcester, MA 01605 USA. EM Jean.Frazier@umassmed.edu FU National Institute of Mental Health (NIMH) [U01MH61528, U01MH61464, U01MH62726, U01MH61355]; Maternal Child Health Bureau [MCJ379154A]; Administration on Developmental Disabilities [90DD043003]; National Institute of Health (NIH) [M01-RR00037]; University of North Carolina [MH01-RR00046]; Bristol-Myers Squibb; GlaxoSmithKline; Janssen; Johnson and Johnson; Neuropharm; Otsuka American; Seaside Therapeutics; Pfizer; Abbot; Adrenex; Alexza; American Psychiatric Press; AstraZeneca; Biovail; Forest; Guilford Press; Johns Hopkins University Press; KemPharm Lilly; Lundbeck; Merck; National Institutes of Health; Novatris; Noven; Organon; Otsuka; Physicians' Post-Graduate Press; Rhodes; Roche; Sage; Sanofi-Aventis; Schering-Plough; Sepracore; Shionogi; Shire; Solvay; Stanley Medical Research Institute; Sunovion; Supernus; Transcept; Validus; WebMD; Wyeth; Acadia; Allergan; Alpharma; Cenerx; Corcept; EnabledMD; Epix; Pepper-Hamilton; Solvey; F. Hoffman-La Roche; Pepracor (Sunovion); Targacept; Allon; Eli Lilly and Co.; Intercellular Therapies FX Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) is funded by the National Institute of Mental Health (NIMH) under cooperative agreements U01MH61528 (LS), U01MH61464 (JM), U01MH62726 (JAF), and U01MH61355 (RLF), the Maternal Child Health Bureau (#MCJ379154A), and the Administration on Developmental Disabilities (#90DD043003). The research was conducted in National Institute of Health (NIH) supported Clinical Research Centers at University of Washington (M01-RR00037) and the University of North Carolina (MH01-RR00046). Study drugs for TEOSS were supplied by Janssen and Eli Lilly and Co.; Dr. Frazier has received research support from or participated in clinical trials with Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Johnson and Johnson, Neuropharm, Otsuka American, Seaside Therapeutics, and Pfizer. Dr. Findling has received research support from, served as a consultant for, received royalties from, and/or served on the speakers' bureau for Abbot, Adrenex, Alexza, American Psychiatric Press, AstraZeneca, Biovail, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson and Johnson, KemPharm Lilly, Lundbeck, Merck, National Institutes of Health, Neuropharm, Novatris, Noven, Organon, Otsuka, Pfizer, Physicians' Post-Graduate Press, Rhodes, Roche, Sage, Sanofi-Aventis, Schering-Plough, Seaside Therapeutics, Sepracore, Shionogi, Shire, Solvay, Stanley Medical Research Institute, Sunovion, Supernus, Transcept, Validus, WebMD, and Wyeth. Dr. Hamer has received research support, served as a consultant for, or served on a data safety monitoring board/independent data monitoring committee for Acadia, Allergan, Alpharma, AstraZeneca, Cenerx, Corcept, EnabledMD, Epix, Johnson and Johnson, Novartis, epper-Hamilton, Pfizer, SAS Institute, Schwartz, Solvey, Sanofi-Aventis, Takeda, Winston-Strawn (a law suit involving Forest, Lundbeck, Sun, and Caraco), and Wyeth. He and/or his spouse are stockholders in Bristol-Myers Squibb, Amgen, Eli Lilly and Co., Genentech, Proctor and Gamble, and Sepracor. Dr. Hooper has received research support from and served as a consultant for Eli Lilly and Co. Dr. Lieberman has served on the advisory boards for Bioline, Pierre Fabre, and PsychoGenics. He has received grant support from Allon, GlaxoSmithKline, Eli Lilly and Co., Intercellular Therapies, Merck, Novartis, Pfizer, F. Hoffman-La Roche, Pepracor (Sunovion), and Targacept. He holds a patent from Repligen. Dr. McClellan has received research support from Pfizer. Dr. Sikich has received research support from or participated in clinical trials with Bristol-Myers Squibb, Curemark, Pfizer, Olsuka, and Seaside Therapeutics. He has served as a consultant for Sanofi Aventis and ABT Associates. He has received software from Posit Science. Dr. Youngstrom has served on the data safety monitoring board for Eli Lilly and Co. He has served as a consultant for Otsuka. He has received travel support from Bristol-Myers Squibb. Drs. Breiger, Giuliano, Johnson, and Vitiello, and Ms. Yakutis report no biomedical financial interests or potential conflicts of interest. NR 55 TC 12 Z9 12 U1 10 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAY PY 2012 VL 51 IS 5 BP 496 EP 505 DI 10.1016/j.jaac.2012.02.001 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 932NH UT WOS:000303297300009 PM 22525956 ER PT J AU Wadiwala, MF Sonawalla, A Kamal, AK AF Wadiwala, Muhammad Faisal Sonawalla, Ambreen Kamal, Ayeesha Kamran TI What is the role of free radical scavengers in acute stroke? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Wadiwala, Muhammad Faisal; Kamal, Ayeesha Kamran] Aga Khan Univ, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr,Med Coll, Karachi, Pakistan. [Wadiwala, Muhammad Faisal] Aga Khan Univ, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Natl Inst Neurol Disorders & Stroke,Med Coll, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr,Med Coll, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2012 VL 62 IS 5 BP 512 EP 513 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 930VN UT WOS:000303170200027 PM 22755325 ER PT J AU Richardson, ET Luo, R Fink, DL Nutman, TB Geisse, JK Barry, M AF Richardson, Eugene T. Luo, Robert Fink, Doran L. Nutman, Thomas B. Geisse, John K. Barry, Michele TI Transient Facial Swellings in a Patient With a Remote African Travel History SO JOURNAL OF TRAVEL MEDICINE LA English DT Article ID LOA-LOA INFECTION; LOIASIS AB We present a case of Loa loa infection in a patient, 21 years after visiting an endemic area for only 4 days. To our knowledge, this case represents the longest time for the diagnosis of loiasis to be made post-exposure in a traveler and emphasizes that even short exposures can place travelers at risk. C1 [Richardson, Eugene T.] Stanford Univ, Med Ctr, Dept Med, Sch Med, Stanford, CA 94305 USA. [Luo, Robert] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Fink, Doran L.; Nutman, Thomas B.] NIAID, Bethesda, MD 20892 USA. [Geisse, John K.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Geisse, John K.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. RP Richardson, ET (reprint author), Stanford Univ, Med Ctr, Dept Med, Sch Med, 300 Pasteur Dr,Grant S101, Stanford, CA 94305 USA. EM etr@stanford.edu FU Intramural NIH HHS [Z01 AI000439-24] NR 9 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1195-1982 J9 J TRAVEL MED JI J. Travel Med. PD MAY-JUN PY 2012 VL 19 IS 3 BP 183 EP 185 DI 10.1111/j.1708-8305.2012.00612.x PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 931EJ UT WOS:000303197900009 PM 22530826 ER PT J AU Murabito, JM Yuan, R Lunetta, KL AF Murabito, Joanne M. Yuan, Rong Lunetta, Kathryn L. TI The Search for Longevity and Healthy Aging Genes: Insights From Epidemiological Studies and Samples of Long-Lived Individuals SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Longevity; Genetics; Epidemiological studies ID GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAIT LOCI; ONSET ALZHEIMERS-DISEASE; LOWER-EXTREMITY FUNCTION; BONE-MINERAL DENSITY; OLDER MALE TWINS; AGED 75 YEARS; NATURAL MENOPAUSE; LIFE-SPAN; ENVIRONMENTAL-INFLUENCES AB Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span. C1 [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Murabito, Joanne M.] Boston Univ, Dept Med, Gen Internal Med Sect, Sch Med, Boston, MA 02215 USA. [Yuan, Rong] Jackson Lab, Aging Ctr, Bar Harbor, ME 04609 USA. [Lunetta, Kathryn L.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM murabito@bu.edu OI Murabito, Joanne/0000-0002-0192-7516; Lunetta, Kathryn/0000-0002-9268-810X FU National Institute on Aging [R01AG29451, P30 AG038070, AG034349] FX This work was funded through grants from the National Institute on Aging (R01AG29451, Drs J.M.M. and K. L. L.; P30 AG038070, Drs J.M.M. and R.Y.; AG034349, Dr R.Y.). NR 97 TC 54 Z9 55 U1 4 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2012 VL 67 IS 5 BP 470 EP 479 DI 10.1093/gerona/gls089 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 930SC UT WOS:000303158600005 PM 22499766 ER PT J AU Pilling, LC Harries, LW Powell, J Llewellyn, DJ Ferrucci, L Melzer, D AF Pilling, L. C. Harries, L. W. Powell, J. Llewellyn, D. J. Ferrucci, L. Melzer, D. TI Genomics and Successful Aging: Grounds for Renewed Optimism? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Longevity; Genetics; Public health ID ALZHEIMERS-DISEASE; GENE-EXPRESSION; MACULAR DEGENERATION; CAENORHABDITIS-ELEGANS; ARTERY-DISEASE; MESSENGER-RNA; OLDER-PEOPLE; VARIANTS; RISK; AGE AB Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned. Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control. Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the "fine tuning" of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively. The emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades. C1 [Pilling, L. C.; Powell, J.; Llewellyn, D. J.; Melzer, D.] Univ Exeter, Epidemiol & Publ Hlth Grp, Peninsula Coll Med & Dent, Exeter EX4 4QJ, Devon, England. [Harries, L. W.] Univ Exeter, Inst Biomed & Clin Sci, Peninsula Coll Med & Dent, Exeter EX4 4QJ, Devon, England. [Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Melzer, D (reprint author), Peninsula Med Sch, Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk RI Pilling, Luke/E-4917-2013; Harries, Lorna/D-2241-2014; OI Pilling, Luke/0000-0002-3332-8454; Melzer, David/0000-0002-0170-3838 FU Dunhill Medical Trust [R69/0208]; University of Exeter; National Institute on Aging, U.S. National Institutes of Health FX Work on this review was supported by an unrestricted research grant from the Dunhill Medical Trust (Drs. M. D. and L.D.J., Grant R69/0208) and by internal University of Exeter funding. Dr. F. L. is supported by the Intramural Research Program, National Institute on Aging, U.S. National Institutes of Health. NR 77 TC 10 Z9 11 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2012 VL 67 IS 5 BP 511 EP 519 DI 10.1093/gerona/gls091 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 930SC UT WOS:000303158600010 PM 22454374 ER PT J AU Leishear, K Ferrucci, L Lauretani, F Boudreau, RM Studenski, SA Rosano, C Abbate, R Gori, AM Corsi, AM Di Iorio, A Guralnik, JM Bandinelli, S Newman, AB Strotmeyer, ES AF Leishear, Kira Ferrucci, Luigi Lauretani, Fulvio Boudreau, Robert M. Studenski, Stephanie A. Rosano, Caterina Abbate, Rosanna Gori, Anna M. Corsi, Anna M. Di Iorio, Angelo Guralnik, Jack M. Bandinelli, Stefania Newman, Anne B. Strotmeyer, Elsa S. TI Vitamin B12 and Homocysteine Levels and 6-Year Change in Peripheral Nerve Function and Neurological Signs SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Vitamin B12; Homocysteine; Peripheral nerve function; Neurological signs ID OLDER PERSONS; PHYSICAL PERFORMANCE; QUADRICEPS STRENGTH; ELDERLY POPULATION; BODY-COMPOSITION; WOMENS HEALTH; FOLIC-ACID; AGE; DYSFUNCTION; NEUROPATHY AB Low vitamin B12 and high homocysteine (Hcy) levels are common in older adults and may be associated with worse neurological function. The aim of this study is to determine whether changes in B12 or Hcy levels are associated with longitudinal changes in peripheral nerve function and clinical neurological signs and symptoms. Participants aged 60 years and older at baseline (n = 678; 72.2 +/- 6.2 years; 43.5% male) were from the InCHIANTI Study. Low B12 (< 260 pmol/L) and high Hcy (>= 13 mu mol/L) were measured at baseline and 3-year follow-up. Neurological function was assessed by peroneal nerve conduction amplitude (compound motor action potential) and velocity, neurological examination, and peripheral neuropathy symptoms at baseline, 3-year, and 6-year follow-up. At baseline, 43.8% had low B12 levels and 58.6% had high Hcy levels. Over 6 years, 12.4% declined to poor compound motor action potential (< 1 mV) and 42.1% declined to poor nerve conduction velocity (< 40 m/s). In mixed models analyses, sustained high Hcy was associated with worse compound motor action potential compared with sustained normal Hcy (p = .04), adjusting for demographics, diabetes, and folate level. Participants whose Hcy level became high at follow-up were more likely to become unable to detect monofilament at 6-year follow-up compared with those with sustained normal Hcy (odds ratio: 5.4; 95% CI: 1.5-19.0), adjusting for demographics, diabetes, body mass index, and peripheral arterial disease. There was no association with vitamin B12 level or with symptoms. High Hcy may be associated with worse sensory and motor peripheral nerve function. Because poor nerve function has been associated with lower strength and physical performance, these results have important implications for disability in older adults. C1 [Leishear, Kira; Boudreau, Robert M.; Rosano, Caterina; Newman, Anne B.; Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Studenski, Stephanie A.; Newman, Anne B.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Sch Med, Pittsburgh, PA 15213 USA. [Abbate, Rosanna] Univ Florence, Dept Med & Surg Crit Care, I-50121 Florence, Italy. [Gori, Anna M.] Thrombosis Ctr, Dept Med & Surg Crit Care, Florence, Italy. [Gori, Anna M.] Fdn Don Carlo Gnocchi Onlus IRCCS, Ctr S Maria Ulivi, Florence, Italy. [Corsi, Anna M.] Tuscany Reg Agcy Hlth, Florence, Italy. [Di Iorio, Angelo] Univ G dAnnunzio, Dept Med & Sci Aging, Chieti, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Santori Firenze, Geriatr Rehabil Unit, Florence, Italy. RP Strotmeyer, ES (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, 130 N Bellefield Ave,Room 515, Pittsburgh, PA 15213 USA. EM strotmeyere@edc.pitt.edu RI Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; Lauretani, Fulvio/K-5115-2016 OI Newman, Anne/0000-0002-0106-1150; Gori, annamaria.gori@unifi.it/0000-0001-6857-5861; Rosano, Caterina/0000-0002-0909-1506; Strotmeyer, Elsa/0000-0002-4093-6036; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187; Lauretani, Fulvio/0000-0002-5287-9972 FU National Institute on Aging (NIA) [N01-AG-919413, N01-AG-821336, R01-AG027012, R01-AG029148]; NIA, National Institutes of Health; Italian Ministry of Health [ICS-110.1/RS97.71] FX This work was supported by National Institute on Aging (NIA) and the Intramural Research Program, NIA, National Institutes of Health. The InCHIANTI study was supported as a targeted project (ICS-110.1/RS97.71) by the Italian Ministry of Health and by the NIA (contracts N01-AG-919413 and N01-AG-821336; grants R01-AG027012 and R01-AG029148). NR 40 TC 15 Z9 15 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2012 VL 67 IS 5 BP 537 EP 543 DI 10.1093/gerona/glr202 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 930SC UT WOS:000303158600013 PM 22156506 ER PT J AU Oki, Y Copeland, A Romaguera, J Fayad, L Fanale, M Faria, SD Medeiros, LJ Ivy, P Younes, A AF Oki, Yasuhiro Copeland, Amanda Romaguera, Jorge Fayad, Luis Fanale, Michelle Faria, Silvana de Castro Medeiros, L. Jeffrey Ivy, Percy Younes, Anas TI Clinical experience with the heat shock protein-90 inhibitor, tanespimycin, in patients with relapsed lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Letter ID PHASE-I TRIAL; CELL-CYCLE ARREST; ADVANCED CANCER; ALK EXPRESSION; KINASE; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; COMPLEX; AKT C1 [Oki, Yasuhiro; Copeland, Amanda; Romaguera, Jorge; Fayad, Luis; Fanale, Michelle; Younes, Anas] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Faria, Silvana de Castro] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Imaging, Houston, TX 77030 USA. [Medeiros, L. Jeffrey] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Ivy, Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD USA. RP Younes, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Unit 429,1515 Holcombe Blvd, Houston, TX 77030 USA. EM ayounes@mdanderson.org FU NCI NIH HHS [5 R21 CA117070-02] NR 14 TC 7 Z9 7 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAY PY 2012 VL 53 IS 5 BP 990 EP 992 DI 10.3109/10428194.2011.631236 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 929NA UT WOS:000303070900040 PM 21988665 ER PT J AU Sastalla, I Leppla, SH AF Sastalla, Inka Leppla, Stephen H. TI Occurrence, recognition, and reversion of spontaneous, sporulation-deficient Bacillus anthracis mutants that arise during laboratory culture SO MICROBES AND INFECTION LA English DT Review DE Bacillus anthracis; Sporulation; spo0A; Mutation; Amerithrax ID PROTECTIVE ANTIGEN; ILLEGITIMATE RECOMBINATION; EXPERIMENTAL POPULATIONS; SUBTILIS; CLONING; STRAIN; GENE; BACTERIOPHAGE; SEQUENCE; IDENTIFICATION AB Bacillus anthracis is a spore-forming, soil-dwelling bacterium. This review describes the occurrence of spontaneous mutations leading to loss of sporulation and the selective pressures that can lead to their enrichment. We also discuss recognition of the associated phenotypes on solid medium, thereby allowing researchers to employ measures that either prevent or favor selection of sporulation-deficient mutants. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Sastalla, Inka; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 33, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 42 TC 2 Z9 2 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD MAY PY 2012 VL 14 IS 5 BP 387 EP 391 DI 10.1016/j.micinf.2011.11.009 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932CS UT WOS:000303268600001 PM 22166343 ER PT J AU Moayeri, M Sastalla, I Leppla, SH AF Moayeri, Mahtab Sastalla, Inka Leppla, Stephen H. TI Anthrax and the inflammasome SO MICROBES AND INFECTION LA English DT Review DE Anthrax lethal toxin; Inflammasome; Caspase-1; Nlrp1; Nlrp1b; Bacillus anthracis ID TOXIN-INDUCED CYTOLYSIS; LETHAL FACTOR CLEAVES; END RULE PATHWAY; BACILLUS-ANTHRACIS; CELL-DEATH; CASPASE-1 ACTIVATION; MURINE MACROPHAGES; EDEMA TOXIN; PROTECTIVE ANTIGEN; KINASE-KINASE AB Anthrax lethal toxin (LT), a major virulence determinant of anthrax disease, induces vascular collapse in mice and rats. LT activates the Nlrp1 inflammasome in macrophages and dendritic cells, resulting in caspase-1 activation, IL-1 beta and IL-18 maturation and a rapid cell death (pyroptosis). This review presents the current understanding of LT-induced activation of Nlrp1 in cells and its consequences for toxin-mediated effects in rodent toxin and spore challenge models. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Moayeri, Mahtab; Sastalla, Inka; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Lab Bacterial Dis, NIH, Bldg 33,Room 1W20B, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov; sastallai@niaid.nih.gov; sleppla@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 78 TC 28 Z9 29 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD MAY PY 2012 VL 14 IS 5 BP 392 EP 400 DI 10.1016/j.micinf.2011.12.005 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932CS UT WOS:000303268600002 PM 22207185 ER PT J AU Mage, M Dolan, M Wang, R Boyd, L Revilleza, M Robinson, H Natarajan, K Myers, N Hansen, T Margulies, D AF Mage, Michael Dolan, Michael Wang, Rui Boyd, Lisa Revilleza, Maria Robinson, Howard Natarajan, Kannan Myers, Nancy Hansen, Ted Margulies, David TI The peptide-receptive transition state of MHC-I molecules: Insight from structure and molecular dynamics SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 7th Biannual Workshop on Antigen Presentation CY APR 24-27, 2012 CL Amsterdam, NETHERLANDS C1 [Mage, Michael; Wang, Rui; Boyd, Lisa; Revilleza, Maria; Natarajan, Kannan; Margulies, David] NIAID, NIH, Immunol Lab, Mol Biol Sect, Bethesda, MD USA. [Dolan, Michael] NIAID, NIH, Bioinformat & Computat Biosci Branch, Computat Biol Sect, Bethesda, MD USA. [Robinson, Howard] Brookhaven Natl Lab, Upton, NY 11973 USA. [Myers, Nancy; Hansen, Ted] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD MAY PY 2012 VL 51 IS 1 BP 24 EP 24 DI 10.1016/j.molimm.2012.02.064 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 934FT UT WOS:000303429800059 ER PT J AU Roche, P Furuta, K Ishido, S AF Roche, Paul Furuta, Kazuyuki Ishido, Satoshi TI MHC-II crosslinking promotes lipid-raft dependent MHC-II clustering, endocytosis, and degradation in dendritic cells SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 7th Biannual Workshop on Antigen Presentation CY APR 24-27, 2012 CL Amsterdam, NETHERLANDS C1 [Roche, Paul; Furuta, Kazuyuki] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD MAY PY 2012 VL 51 IS 1 BP 29 EP 29 DI 10.1016/j.molimm.2012.02.078 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 934FT UT WOS:000303429800072 ER PT J AU Yewdell, J David, A Dolan, B Lu, XJ Bennink, J AF Yewdell, Jonathan David, Alexandre Dolan, Brian Lu, Xiuju Bennink, Jack TI Will wonders never cease? Unraveling the Intricacies of the class I processing pathway SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 7th Biannual Workshop on Antigen Presentation CY APR 24-27, 2012 CL Amsterdam, NETHERLANDS C1 [Yewdell, Jonathan; David, Alexandre; Dolan, Brian; Lu, Xiuju; Bennink, Jack] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD MAY PY 2012 VL 51 IS 1 BP 37 EP 37 DI 10.1016/j.molimm.2012.02.105 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 934FT UT WOS:000303429800099 ER PT J AU Tomasi, D Volkow, ND AF Tomasi, D. Volkow, N. D. TI Aging and functional brain networks SO MOLECULAR PSYCHIATRY LA English DT Article DE aging; Alzheimer's disease; functional connectomes; connectivity ID ALZHEIMERS-DISEASE; DOPAMINE ACTIVITY; WORKING-MEMORY; CONNECTIVITY; DECLINE; AGE; IMPAIRMENT; PATTERNS; RESERVE; FMRI AB Aging is associated with changes in human brain anatomy and function and cognitive decline. Recent studies suggest the aging decline of major functional connectivity hubs in the 'default-mode' network (DMN). Aging effects on other networks, however, are largely unknown. We hypothesized that aging would be associated with a decline of short- and long-range functional connectivity density (FCD) hubs in the DMN. To test this hypothesis, we evaluated resting-state data sets corresponding to 913 healthy subjects from a public magnetic resonance imaging database using functional connectivity density mapping (FCDM), a voxelwise and data-driven approach, together with parallel computing. Aging was associated with pronounced long-range FCD decreases in DMN and dorsal attention network (DAN) and with increases in somatosensory and subcortical networks. Aging effects in these networks were stronger for long-range than for short-range FCD and were also detected at the level of the main functional hubs. Females had higher short- and long-range FCD in DMN and lower FCD in the somatosensory network than males, but the gender by age interaction effects were not significant for any of the networks or hubs. These findings suggest that long-range connections may be more vulnerable to aging effects than short-range connections and that, in addition to the DMN, the DAN is also sensitive to aging effects, which could underlie the deterioration of attention processes that occurs with aging. Molecular Psychiatry (2012) 17, 549-558; doi:10.1038/mp.2011.81; published online 5 July 2011 C1 [Tomasi, D.; Volkow, N. D.] NIAAA, Bethesda, MD USA. [Volkow, N. D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), Brookhaven Natl Lab, Lab Neuroimaging LNI NIAAA, Dept Med, Bldg 490,30 Bell Ave, Upton, NY 11973 USA. EM tomasi@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Alcohol Abuse and Alcoholism [2RO1AA09481] FX This study was supported by the National Institutes of Alcohol Abuse and Alcoholism (2RO1AA09481). NR 56 TC 133 Z9 135 U1 5 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAY PY 2012 VL 17 IS 5 BP 549 EP 558 DI 10.1038/mp.2011.81 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 930BN UT WOS:000303110800010 ER PT J AU Lorincz, O Toke, ER Somogyi, E Horkay, F Chandran, PL Douglas, JF Szebeni, J Lisziewicz, J AF Lorincz, Orsolya Toke, Eniko R. Somogyi, Eszter Horkay, Ferenc Chandran, Preethi L. Douglas, Jack F. Szebeni, Janos Lisziewicz, Julianna TI Structure and biological activity of pathogen-like synthetic nanomedicines SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Vaccine; Immunotherapy; Immunity; DermaVir ID GENE DELIVERY; COMPLEMENT ACTIVATION; POTENTIAL BARRIER; CATIONIC LIPIDS; PLASMID DNA; IN-VITRO; COMPLEXES; HYPERSENSITIVITY; POLYETHYLENIMINE; DERMAVIR AB Here we characterize the structure, stability and intracellular mode of action of DermaVir nanomedicine that is under clinical development for the treatment of HIV/AIDS. This nanomedicine comprises pathogen-like pDNA/PEIm nanoparticles (NPs) having the structure and function resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. Atomic force microscopy demonstrated spherical 100 - 200 nm NPs with a smooth polymer surface protecting the pDNA in the core. Optical absorption determined both the NP structural stability and biological activity relevant to their ability to escape from the endosome and release the pDNA at the nucleus. Salt, pH and temperature influence nanomedicine shelf-life and intracellular stability. This approach facilitates the development of diverse polyplex nanomedicines where the delivered pDNA-expressed antigens induce immune responses to kill infected cells. From the Clinical Editor: The authors investigated DermaVir nanomedicine comprised of pathogen-like pDNA/PEIm nanoparticles with structure and function resembling spherical viruses. DermaVir delivery of pDNA expresses antigens that induce immune responses to kill HIV infected cells. (C) 2012 Elsevier Inc. All rights reserved. C1 [Lorincz, Orsolya; Toke, Eniko R.; Somogyi, Eszter; Lisziewicz, Julianna] Genet Immun Kft, H-1045 Budapest, Hungary. [Horkay, Ferenc; Chandran, Preethi L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. [Douglas, Jack F.] NIST, Div Polymers, Gaithersburg, MD 20899 USA. [Szebeni, Janos] Bay Zoltan Fdn Appl Res, Nanomed Res & Educ Ctr, H-1089 Budapest, Hungary. [Szebeni, Janos] Semmelweis Univ, H-1089 Budapest, Hungary. [Lisziewicz, Julianna] Genet Immun LLC, Mclean, VA USA. RP Lisziewicz, J (reprint author), Genet Immun Kft, Berlini U 47-49, H-1045 Budapest, Hungary. EM lisziewj@geneticimmunity.com FU NICHD, NIH; NKTH [CARPA777]; [HIKC05]; [DVCLIN01] FX Dr. Julianna Lisziewicz holds shares in Genetic Immunity. This work was supported by grants: HIKC05 and DVCLIN01 announced by the National Office for Research and Technology (NKTH) in Hungary. Ferene Horkay and Preethi L. Chandran acknowledge the support of the Intramural Research Program of the NICHD, NIH. Janos Szebeni acknowledges the grant supports FP7 "Anticarb," NKTH CARPA777. NR 40 TC 15 Z9 15 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD MAY PY 2012 VL 8 IS 4 BP 497 EP 506 DI 10.1016/j.nano.2011.07.013 PG 10 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 930QI UT WOS:000303153800014 PM 21839051 ER PT J AU Eskan, MA Jotwani, R Abe, T Chmelar, J Lim, JH Liang, S Ciero, PA Krauss, JL Li, FG Rauner, M Hofbauer, LC Choi, EY Chung, KJ Hashim, A Curtis, MA Chavakis, T Hajishengallis, G AF Eskan, Mehmet A. Jotwani, Ravi Abe, Toshiharu Chmelar, Jindrich Lim, Jong-Hyung Liang, Shuang Ciero, Paul A. Krauss, Jennifer L. Li, Fenge Rauner, Martina Hofbauer, Lorenz C. Choi, Eun Young Chung, Kyoung-Jin Hashim, Ahmed Curtis, Michael A. Chavakis, Triantafyllos Hajishengallis, George TI The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss SO NATURE IMMUNOLOGY LA English DT Article ID PERIODONTAL-DISEASES; IL-17 RECEPTOR; ADHESION CASCADE; INNATE IMMUNITY; IN-VITRO; T-CELLS; NEUTROPHILS; MICE; RECRUITMENT; INTERLEUKIN-17 AB Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases. C1 [Eskan, Mehmet A.; Jotwani, Ravi; Abe, Toshiharu; Liang, Shuang; Ciero, Paul A.; Krauss, Jennifer L.; Li, Fenge; Hajishengallis, George] Univ Louisville, Sch Dent, Ctr Oral Hlth & Syst Dis, Louisville, KY 40292 USA. [Chmelar, Jindrich; Lim, Jong-Hyung; Choi, Eun Young; Chung, Kyoung-Jin; Chavakis, Triantafyllos] Tech Univ Dresden, Dept Med, Div Vasc Inflammat Diabet & Kidney, D-01062 Dresden, Germany. [Chmelar, Jindrich; Lim, Jong-Hyung; Choi, Eun Young; Chung, Kyoung-Jin; Chavakis, Triantafyllos] Tech Univ Dresden, Inst Physiol, D-01062 Dresden, Germany. [Rauner, Martina; Hofbauer, Lorenz C.] Tech Univ Dresden, Dept Med, Div Endocrinol Diabet & Bone Dis, D-01062 Dresden, Germany. [Choi, Eun Young] Univ Ulsan, Grad Sch, Dept Med, Seoul, South Korea. [Choi, Eun Young; Chavakis, Triantafyllos] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Hashim, Ahmed; Curtis, Michael A.] Queen Mary Univ London, Barts & London Sch Med & Dent, Ctr Immunol & Infect Dis, Blizard Inst, London, England. [Eskan, Mehmet A.; Hajishengallis, George] Univ Louisville, Sch Med, Dept Microbiol & Immunol, Louisville, KY 40292 USA. RP Hajishengallis, G (reprint author), Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. EM geoh@upenn.edu RI Rauner, Martina/A-1665-2015; Hofbauer, Lorenz/G-2490-2010 OI Hofbauer, Lorenz/0000-0002-8691-8423 FU US National Institutes of Health, National Cancer Institute; Deutsche Forschungsgemeinschaft [SFB655/TPB10, CH279/5-1]; Medical Faculty of the University of Dresden (MedDrive); Medical Research Council UK [G0900408]; US National Institutes of Health [DE015254, DE018292, DE021580, DE021685] FX We thank T. Quertermous and R. Kundu (Stanford University School of Medicine) for Edil3-/- mice; C. M. Ballantyne (Baylor College of Medicine) for Itgal-/- mice; Amgen for Il17ra-/- mice and mAb to IL-17 (M210); Novartis for LFA878; Valentis for Del-1; and S. Gaffen for discussions and advice. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute (T. C.), Deutsche Forschungsgemeinschaft (SFB655/TPB10 and CH279/5-1 to T. C.), the Medical Faculty of the University of Dresden (MedDrive to K.-J.C.), the Medical Research Council UK (G0900408 to M. A. C.) and the Extramural Research Program of the US National Institutes of Health (DE015254, DE018292, DE021580 and DE021685 to G.H.). NR 48 TC 123 Z9 130 U1 2 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 MAY PY 2012 VL 13 IS 5 BP 465 EP U64 DI 10.1038/ni.2260 PG 10 WC Immunology SC Immunology GA 929GD UT WOS:000303048400010 PM 22447028 ER PT J AU Dickendesher, TL Baldwin, KT Mironova, YA Koriyama, Y Raiker, SJ Askew, KL Wood, A Geoffroy, CG Zheng, BH Liepmann, CD Katagiri, Y Benowitz, LI Geller, HM Giger, RJ AF Dickendesher, Travis L. Baldwin, Katherine T. Mironova, Yevgeniya A. Koriyama, Yoshiki Raiker, Stephen J. Askew, Kim L. Wood, Andrew Geoffroy, Cedric G. Zheng, Binhai Liepmann, Claire D. Katagiri, Yasuhiro Benowitz, Larry I. Geller, Herbert M. Giger, Roman J. TI NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans SO NATURE NEUROSCIENCE LA English DT Article ID SPINAL-CORD-INJURY; TYROSINE-PHOSPHATASE-SIGMA; RETINAL GANGLION-CELLS; OLIGODENDROCYTE-MYELIN GLYCOPROTEIN; CORTICOSPINAL TRACT REGENERATION; OPTIC-NERVE REGENERATION; NOGO RECEPTOR; AXON REGENERATION; NEURITE GROWTH; FUNCTIONAL RECEPTOR AB In the adult mammalian CNS, chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs) stabilize neuronal structure and restrict compensatory sprouting following injury. The Nogo receptor family members NgR1 and NgR2 bind to MAIs and have been implicated in neuronal inhibition. We found that NgR1 and NgR3 bind with high affinity to the glycosaminoglycan moiety of proteoglycans and participate in CSPG inhibition in cultured neurons. Nogo receptor triple mutants (Ngr1(-/-); Ngr2(-/-); Ngr3(-/-); which are also known as Rtn4r, Rtn4rI2 and Rtn4rI1, respectively), but not single mutants, showed enhanced axonal regeneration following retro-orbital optic nerve crush injury. The combined loss of Ngr1 and Ngr3 (Ngr1(-/-); Ngr3(-/-)), but not Ngr1 and Ngr2 (Ngr1(-/-); Ngr2(-/-)), was sufficient to mimic the triple mutant regeneration phenotype. Regeneration in Ngr1(-/-); Ngr3(-/-) mice was further enhanced by simultaneous ablation of Rptp sigma (also known as Ptprs), a known CSPG receptor. Collectively, our results identify NgR1 and NgR3 as CSPG receptors, suggest that there is functional redundancy among CSPG receptors, and provide evidence for shared mechanisms of MAI and CSPG inhibition. C1 [Dickendesher, Travis L.; Giger, Roman J.] Univ Michigan, Sch Med, Neurosci Program, Ann Arbor, MI 48109 USA. [Dickendesher, Travis L.; Baldwin, Katherine T.; Mironova, Yevgeniya A.; Raiker, Stephen J.; Giger, Roman J.] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI USA. [Baldwin, Katherine T.; Mironova, Yevgeniya A.; Giger, Roman J.] Univ Michigan, Sch Med, Cellular & Mol Biol Program, Ann Arbor, MI USA. [Koriyama, Yoshiki; Benowitz, Larry I.] Harvard Univ, Childrens Hosp, Sch Med, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Koriyama, Yoshiki; Benowitz, Larry I.] Harvard Univ, Childrens Hosp, Sch Med, Lab Neurosci Res Neurosurg, Boston, MA 02115 USA. [Koriyama, Yoshiki; Benowitz, Larry I.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Raiker, Stephen J.] Univ Rochester, Sch Med & Dent, Dept Biomed Genet, Rochester, NY USA. [Askew, Kim L.; Wood, Andrew] Pfizer Global Res & Dev, Neurosci Res Unit, Groton, CT USA. [Geoffroy, Cedric G.; Zheng, Binhai] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA. [Liepmann, Claire D.; Katagiri, Yasuhiro; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Benowitz, Larry I.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Giger, Roman J.] Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI USA. RP Giger, RJ (reprint author), Univ Michigan, Sch Med, Neurosci Program, Ann Arbor, MI 48109 USA. EM rgiger@umich.edu OI Geller, Herbert/0000-0002-7048-6144 FU Neuroscience Training Grant [T32EY017878]; University of Michigan; Cellular and Molecular Biology Training Grant [T32GM007315]; National Research Service Award Ruth Kirschstein Fellowship [F31NS061589]; New York State Spinal Cord Injury Research Program; Dr. Miriam and Sheldon G. Adelson Medical Foundation on Neural Repair and Rehabilitation; US Department of Veterans Affairs [1I0IRX000229-01]; National Institute of Neurological Disorders and Stroke [R56NSO47333]; National Eye Institute FX We thank M. Tremblay for Rptp sigma-/- mice, M. Greenberg for Ngr3-/- mice, B. Pierchala for p75NTR-/- mice, B. Bates, D. Howland and M.L. Mercado for their assistance in the generation and initial analysis of Ngr1-/-; Ngr2-/-; Ngr3-/- mice, U. Rutishauser for Endo-N, D. Figge and Y. Yasui for assistance in ELISA binding assays, Y. Yin for training in optic nerve surgery, Y. Duan for generation of the RPTP sigma(Igl-3)-Fc construct,). Barbieri for technical assistance and M.M. Zaleska for project administration. This work was supported by Neuroscience Training Grant T32EY017878 and the University of Michigan Rackham Merit Fellowship (T.L.D.), Cellular and Molecular Biology Training Grant T32GM007315 (K.T.B. and Y.A.M.), National Research Service Award Ruth Kirschstein Fellowship F31NS061589 (S.J.R.), the New York State Spinal Cord Injury Research Program, the Dr. Miriam and Sheldon G. Adelson Medical Foundation on Neural Repair and Rehabilitation, the US Department of Veterans Affairs (1I0IRX000229-01), the National Institute of Neurological Disorders and Stroke (R56NSO47333, R.J.G.) and the National Eye Institute (L.I.B.). NR 48 TC 155 Z9 158 U1 4 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAY PY 2012 VL 15 IS 5 BP 703 EP 712 DI 10.1038/nn.3070 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 932DI UT WOS:000303270200014 PM 22406547 ER PT J AU Hanover, JA Krause, MW Love, DC AF Hanover, John A. Krause, Michael W. Love, Dona C. TI Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; LINKED GLCNAC TRANSFERASE; BETA-N-ACETYLGLUCOSAMINIDASE; THRIFTY PHENOTYPE HYPOTHESIS; POLYCOMB GROUP GENES; INSULIN-RESISTANCE; CAENORHABDITIS-ELEGANS; TETRATRICOPEPTIDE REPEATS; DROSOPHILA-MELANOGASTER; PROTEIN GLYCOSYLATION AB O-GlcNAcylation, which is a nutrient-sensitive sugar modification, participates in the epigenetic regulation of gene expression. The enzymes involved in O-linked beta-D-N-acetylglucosamine (O-GlcNAc) cycling - O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) - target key transcriptional and epigenetic regulators including RNA polymerase II, histones, histone deacetylase complexes and members of the Polycomb and Trithorax groups. Thus, O-GlcNAc cycling may serve as a homeostatic mechanism linking nutrient availability to higher-order chromatin organization. In response to nutrient availability, O-GlcNAcylation is poised to influence X chromosome inactivation and genetic imprinting, as well as embryonic development. The wide range of physiological functions regulated by O-GlcNAc cycling suggests an unexplored nexus between epigenetic regulation in disease and nutrient availability. C1 [Hanover, John A.; Love, Dona C.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD USA. RP Hanover, JA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov; michaelkr@niddk.nih.gov; donalove@mail.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU National Institutes of Diabetes and Digestive and Kidney Diseases FX The authors wish to thank P. Wang, M. Bond, T. Fukushige and K. Harwood for helpful discussions. The work was supported by National Institutes of Diabetes and Digestive and Kidney Diseases intramural funds. NR 112 TC 162 Z9 162 U1 5 U2 61 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD MAY PY 2012 VL 13 IS 5 BP 312 EP 321 DI 10.1038/nrm3334 PG 10 WC Cell Biology SC Cell Biology GA 930BW UT WOS:000303111800014 PM 22522719 ER PT J AU Becker, RE Greig, N AF Becker, Robert E. Greig, N. TI ARE WE READY WITH A NEW TRIAL DESIGN? SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy CY MAY 09-12, 2012 CL Stockholm, SWEDEN C1 [Becker, Robert E.] Aristea Translat Med Corp, S Freeport, ME USA. [Greig, N.] NIA, Baltimore, MD 21224 USA. EM rebecker2008@comcast.net NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAY PY 2012 VL 33 SU 1 MA 5 BP S3 EP S3 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 930NX UT WOS:000303147200006 ER PT J AU Yang, J Eliasson, B Smith, U Cushman, SW Sherman, AS AF Yang, Jian Eliasson, Bjorn Smith, Ulf Cushman, Samuel W. Sherman, Arthur S. TI The Size of Large Adipose Cells Is a Predictor of Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients SO OBESITY LA English DT Article ID ABDOMINAL ADIPOCYTE SIZE; FAT-CELLS; HUMAN-DISEASE; TISSUE; OBESITY; EXPRESSION; INFLAMMATION; RECRUITMENT; SECRETION; NUMBER AB Early studies reported that the size of adipose cells correlates with insulin resistance. However, a recent study comparing moderately obese, sensitive and resistant subjects, with comparable BMI (similar to 30), did not detect any significant difference in the size of the large cells, but rather a smaller proportion of large cells in the resistant subjects, suggesting impaired adipogenesis. We hypothesize that a decreased proportion, rather than the size, of large adipose cells is also associated with insulin resistance in first-degree relatives of type 2 diabetic patients. Thirty-five leaner (BMI 18-34) subjects who were relatively healthy were recruited. Insulin sensitivity was measured by the euglycemic, hyperinsulinemic clamp. Needle biopsies of abdominal subcutaneous fat were assayed for adipose cell size by fitting the cell size distribution with two exponentials and a Gaussian function. The fraction of large cells was defined as the area of the Gaussian peak and the size of the large cells was defined as its center (c(p)). Glucose infusion rate (GIR) and c were negatively correlated, but insulin sensitivity and the proportion of large cells were not correlated. BMI and c(p) were also strongly correlated, but a relationship of modest correlation between the cell size and insulin resistance was still significant after correcting for BMI. In contrast to moderately obese subjects, in the first-degree relatives of type 2 diabetic patients both BMI and the size of the large adipose cells predict the degree of insulin resistance; no correlation is found between the proportion of large adipose cells and insulin resistance. C1 [Sherman, Arthur S.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Yang, Jian; Cushman, Samuel W.] NIDDK, Diabet Branch, NIH, Bethesda, MD USA. [Yang, Jian] Univ S Alabama, Coll Med, Dept Physiol, Mobile, AL 36688 USA. [Eliasson, Bjorn; Smith, Ulf] Univ Gothenburg, Dept Mol & Clin Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden. RP Sherman, AS (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM jyang@usouthal.edu; arthur.sherman@nih.gov OI Eliasson, Bjorn/0000-0003-2569-4160 FU Swedish Research Council; Novo Nordisk Foundation; Swedish Diabetes Association; NIDDK, NIH FX B.E. and U.S. were supported by the Swedish Research Council, the Novo Nordisk Foundation, and the Swedish Diabetes Association. J. Y., S. C., and A. S. were supported by the Intramural Research Program of NIDDK, NIH. We thank Junghyo Jo and Vipul Periwal (LBM, NIDDK) for the insightful comments. We thank Tracey McLaughlin for permission to reanalyze the data from a previous study. NR 34 TC 29 Z9 29 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2012 VL 20 IS 5 BP 932 EP 938 DI 10.1038/oby.2011.371 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 932ND UT WOS:000303296900002 PM 22240722 ER PT J AU Diamond, MP Kruger, M Santoro, N Zhang, HP Casson, P Schlaff, W Coutifaris, C Brzyski, R Christman, G Carr, BR McGovern, PG Cataldo, NA Steinkampf, MP Gosman, GG Nestler, JE Carson, S Myers, EE Eisenberg, E Legro, RS AF Diamond, Michael P. Kruger, Michael Santoro, Nanette Zhang, Heping Casson, Peter Schlaff, William Coutifaris, Christos Brzyski, Robert Christman, Gregory Carr, Bruce R. McGovern, Peter G. Cataldo, Nicholas A. Steinkampf, Michael P. Gosman, Gabriella G. Nestler, John E. Carson, Sandra Myers, Evan E. Eisenberg, Esther Legro, Richard S. CA Eunice Kennedy Shriver Natl Inst C TI Endometrial Shedding Effect on Conception and Live Birth in Women With Polycystic Ovary Syndrome SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 22, 2012 CL San Diego, CA SP Soc Gynecol Invest ID HORMONE PULSE-GENERATOR; ANDROGEN RECEPTOR EXPRESSION; HOMEOSTASIS MODEL; GENE-EXPRESSION; MENSTRUAL-CYCLE; CLINICAL-TRIALS; PROGESTERONE; SENSITIVITY; INFERTILITY; INHIBITION AB OBJECTIVE: To estimate whether progestin-induced endometrial shedding, before ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS). METHODS: A secondary analysis of the data from 626 women with PCOS from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed). RESULTS: Although ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live births per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; P<.001). The difference was more marked when rate was calculated per ovulation (live births per ovulation: spontaneous menses 3.0%; anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; P<.001). CONCLUSION: Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared with anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin before ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS. C1 Wayne State Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Detroit, MI USA. Univ Colorado, Dept Obstet & Gynecol, Aurora, CO USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Univ Vermont, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Burlington, VT USA. Univ Colorado Denver, Sch Med, Dept Obstet & Gynecol, Adv Reprod Med,Sect Reprod Endocrinol & Infertil, Aurora, CO USA. Univ Penn, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Med Ctr, Philadelphia, PA 19104 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Obstet Gynecol & Womens Hlth, Newark, NJ 07103 USA. Univ Alabama, Birmingham, AL USA. Univ Pittsburgh, Pittsburgh, PA USA. Virginia Commonwealth Univ, Dept Med, Sch Med, Richmond, VA 23298 USA. Brown Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Warren Alpert Med Sch, Providence, RI 02912 USA. Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Med Network, Reprod Sci Branch, Populat Res Ctr,NIH, Bethesda, MD USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Coll Med, Hershey, PA 17033 USA. RP Diamond, MP (reprint author), 60 W Hancock, Detroit, MI 48201 USA. EM mdiamond@med.wayne.edu OI Diamond, Michael/0000-0001-6353-4489 FU NCRR NIH HHS [C06 RR016499, M01 RR000056, M01 RR010732, M01RR00056, M01RR10732]; NICHD NIH HHS [HD55925, HD055942, HD055944, HD27011, HD27049, HD33172, HD38988, HD38992, HD38997, HD38998, HD38999, HD39005, HD55936, U01 HD038997, U10 HD027011, U10 HD027049, U10 HD033172, U10 HD038988, U10 HD038992, U10 HD038998, U10 HD038999, U10 HD039005, U10 HD055925, U10 HD055936, U10 HD055942, U10 HD055944] NR 33 TC 22 Z9 25 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAY PY 2012 VL 119 IS 5 BP 902 EP 908 DI 10.1097/AOG.0b013e31824da35c PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 930OW UT WOS:000303150000004 PM 22525900 ER PT J AU Gabbe, SG Landon, MB Warren-Boulton, E Fradkin, J AF Gabbe, Steven G. Landon, Mark B. Warren-Boulton, Elizabeth Fradkin, Judith TI Promoting Health After Gestational Diabetes: A National Diabetes Education Program Call to Action Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Gabbe, Steven G.; Landon, Mark B.] Ohio State Univ, Wexner Med Ctr, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Warren-Boulton, Elizabeth] Hager Sharp Inc, Washington, DC USA. [Fradkin, Judith] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. RP Gabbe, SG (reprint author), Ohio State Univ, Wexner Med Ctr, Dept Obstet & Gynecol, Columbus, OH 43210 USA. NR 1 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAY PY 2012 VL 119 IS 5 BP 1055 EP 1055 DI 10.1097/AOG.0b013e318253aa80 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 930OW UT WOS:000303150000027 ER PT J AU Wei, H Xiang, LM Wayne, AS Chertov, O FitzGerald, DJ Bera, TK Pastan, I AF Wei, Hui Xiang, Laiman Wayne, Alan S. Chertov, Oleg FitzGerald, David J. Bera, Tapan K. Pastan, Ira TI Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA methylation; drug resistance; ADP-ribosylation; diphthamide synthesis; epigenetic regulation ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; DNA METHYLATION; MYELODYSPLASTIC SYNDROME; RECOMBINANT IMMUNOTOXIN; RFB4(DSFV)-PE38 BL22; PSEUDOMONAS EXOTOXIN; LYMPHOCYTIC-LEUKEMIA; GROUP-B; CANCER AB HA22 is a recombinant immunotoxin composed of an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A. HA22 produced a high rate of complete remissions in drug-resistant hairy cell leukemia and has a lower response rate in pediatric acute lymphoblastic leukemia (ALL). To understand why patients with ALL have poorer responses, we isolated an ALL cell line that is resistant to killing by HA22. The resistance is unstable; without HA22 the cells revert to HA22 sensitivity in 4 mo. We showed that in the resistant cell line, HA22 is unable to ADP ribosylate and inactivate elongation factor-2 (EF2), owing to a low level of DPH4 mRNA and protein, which prevents diphthamide biosynthesis and renders EF2 refractory to HA22. Analysis of the promoter region of the DPH4 gene shows that the CpG island was hypomethylated in the HA22-sensitive cells, heavily methylated in the resistant cells, and reverted to low methylation in the revertant cells. Our data show that immunotoxin resistance is associated with reversible CpG island methylation and silencing of DPH4 gene transcription. Incubation of sensitive cells with the methylation inhibitor 5-azacytidine prevented the emergence of resistant cells, suggesting that this agent in combination with HA22 may be useful in the treatment of some cases of ALL. C1 [Wei, Hui; Xiang, Laiman; Wayne, Alan S.; FitzGerald, David J.; Bera, Tapan K.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chertov, Oleg] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; [HHSN261200800001E] FX We thank Xiu-fen Liu for providing primers for DPH1 and DPH5 genes. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and was funded in part under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 45 TC 29 Z9 30 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 1 PY 2012 VL 109 IS 18 BP 6898 EP 6903 DI 10.1073/pnas.1204523109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100034 PM 22509046 ER PT J AU Devaiah, BN Lewis, BA Cherman, N Hewitt, MC Albrecht, BK Robey, PG Ozato, K Sims, RJ Singer, DS AF Devaiah, Ballachanda N. Lewis, Brian A. Cherman, Natasha Hewitt, Michael C. Albrecht, Brian K. Robey, Pamela G. Ozato, Keiko Sims, Robert J., III Singer, Dinah S. TI BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BROMODOMAIN PROTEIN BRD4; P-TEFB; TRANSCRIPTION; ELONGATION; PROGRESSION; INTERACTS; CYCLE; REPLICATION; RECRUITMENT; INHIBITION AB The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription. C1 [Devaiah, Ballachanda N.; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Lewis, Brian A.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Cherman, Natasha; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Ozato, Keiko] Natl Inst Dent & Craniofacial Res, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Hewitt, Michael C.; Albrecht, Brian K.; Sims, Robert J., III] Constellat Pharmaceut Inc, Cambridge, MA 02142 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Drs. Andrew Stern, Kent Hunter, and Lou Staudt for critical reading of the manuscript and members of the laboratory for discussions. We also thank Dr. Anne Gegonne for help with the 5-flourouridine cell staining. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 37 TC 102 Z9 104 U1 2 U2 21 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 MAY 1 PY 2012 VL 109 IS 18 BP 6927 EP 6932 DI 10.1073/pnas.1120422109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100039 PM 22509028 ER PT J AU Yang, CZ Iyer, RR Yu, ACH Yong, RL Park, DM Weil, RJ Ikejiri, B Brady, RO Lonser, RR Zhuang, ZP AF Yang, Chunzhang Iyer, Rajiv R. Yu, Albert C. H. Yong, Raymund L. Park, Deric M. Weil, Robert J. Ikejiri, Barbara Brady, Roscoe O. Lonser, Russell R. Zhuang, Zhengping TI beta-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE astrocyte activation; glioblastoma multiforme; wound healing; adherent junction ID CONTACT INHIBITION; CELL-MIGRATION; STEM-CELLS; IN-VITRO; EXPRESSION; PATHWAY; DISEASE; GROWTH; CADHERIN; PROTEIN AB Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of beta-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active-but dysregulated-in astrocytomas. Inhibition of beta-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain. C1 [Yang, Chunzhang; Iyer, Rajiv R.; Yong, Raymund L.; Ikejiri, Barbara; Brady, Roscoe O.; Lonser, Russell R.; Zhuang, Zhengping] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Yu, Albert C. H.] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci,Minist Educ,Neurosci Res Inst, Dept Neurobiol,Minist Publ Hlth,Key Lab Neurosci, Beijing 100191, Peoples R China. [Park, Deric M.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22903 USA. [Weil, Robert J.] Cleveland Clin, Neurol Inst, Rose Ella Burkhardt Brain Tumor & Neurooncol Ctr, Dept Neurosurg, Cleveland, OH 44195 USA. RP Brady, RO (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM bradyr@ninds.nih.gov; lonserr@ninds.nih.gov; zhuangp@ninds.nih.gov RI Park, Deric/C-5675-2013 FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health; Melvin Burkhardt chair in neurosurgical oncology; Karen Colina Wilson research endowment within the Brain Tumor and Neuro-Oncology Center at the Cleveland Clinic Foundation FX We thank Dr. Dragan Maric for the assistance in flowcytometry assay and data analysis. This research was supported by the intramural research program in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health; and by the Melvin Burkhardt chair in neurosurgical oncology and the Karen Colina Wilson research endowment within the Brain Tumor and Neuro-Oncology Center at the Cleveland Clinic Foundation. NR 39 TC 29 Z9 31 U1 1 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 MAY 1 PY 2012 VL 109 IS 18 BP 6963 EP 6968 DI 10.1073/pnas.1118754109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100045 PM 22505738 ER PT J AU Dolan, BP Sharma, AA Gibbs, JS Cunningham, TJ Bennink, JR Yewdell, JW AF Dolan, Brian P. Sharma, Aditi A. Gibbs, James S. Cunningham, Tshaka J. Bennink, Jack R. Yewdell, Jonathan W. TI MHC class I antigen processing distinguishes endogenous antigens based on their translation from cellular vs. viral mRNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-SYNTHESIS; CYTOSOLIC PEPTIDES; CELLS; DEGRADATION; EXPRESSION; IMMUNODOMINANCE; TRANSCRIPTION; LOCALIZATION; GENERATION; ANTIBODIES AB To better understand the generation of MHC class I-associated peptides, we used a model antigenic protein whose proteasome-mediated degradation is rapidly and reversibly controlled by Shield-1, a cell-permeant drug. When expressed from a stably transfected gene, the efficiency of antigen presentation is similar to 2%, that is, one cell-surface MHC class I-peptide complex is generated for every 50 folded source proteins degraded upon Shield-1 withdrawal. By contrast, when the same protein is expressed by vaccinia virus, its antigen presentation efficiency is reduced similar to 10-fold to values similar to those reported for other vaccinia virus-encoded model antigens. Virus infection per se does not modify the efficiency of antigen processing. Rather, the efficiency difference between cellular and virus-encoded antigens is based on whether the antigen is synthesized from transgene- vs. virus-encoded mRNA. Thus, class I antigen-processing machinery can distinguish folded proteins based on the precise details of their synthesis to modulate antigen presentation efficiency. C1 [Dolan, Brian P.; Sharma, Aditi A.; Gibbs, James S.; Cunningham, Tshaka J.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@nih.gov FU Intramural NIH HHS NR 32 TC 18 Z9 19 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 1 PY 2012 VL 109 IS 18 BP 7025 EP 7030 DI 10.1073/pnas.1112387109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100056 PM 22509014 ER PT J AU Schulze, K Vargha-Khadem, F Mishkin, M AF Schulze, Katrin Vargha-Khadem, Faraneh Mishkin, Mortimer TI Test of a motor theory of long-term auditory memory SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; mimic; arcuate fasciculus ID SUPERIOR TEMPORAL SULCUS; SPEECH-PERCEPTION; RECOGNITION MEMORY; HUMAN BRAIN; DEVELOPMENTAL AMNESIA; LANGUAGE PATHWAYS; PREMOTOR CORTEX; MIRROR NEURONS; RHESUS-MONKEY; BROCAS AREA AB Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e. g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory-suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve. C1 [Mishkin, Mortimer] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Schulze, Katrin; Vargha-Khadem, Faraneh] UCL, Inst Child Hlth, Dev Cognit Neurosci Unit, London WC1N 1EH, England. RP Mishkin, M (reprint author), NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. EM mishkinm@mail.nih.gov RI Schulze, Katrin/A-7385-2010 FU National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services; Medical Research Council [G0300117/65439]; University College London [06CN05] FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, as well as by the Medical Research Council (G0300117/65439) and University College London Pump Prime Grant 06CN05. NR 63 TC 14 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 MAY 1 PY 2012 VL 109 IS 18 BP 7121 EP 7125 DI 10.1073/pnas.1204717109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100072 PM 22511719 ER PT J AU Li, YP Ramirez, S Gottwein, JM Scheel, TKH Mikkelsen, L Purcell, RH Bukh, J AF Li, Yi-Ping Ramirez, Santseharay Gottwein, Judith M. Scheel, Troels K. H. Mikkelsen, Lotte Purcell, Robert H. Bukh, Jens TI Robust full-length hepatitis C virus genotype 2a and 2b infectious cultures using mutations identified by a systematic approach applicable to patient strains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNA; neutralization; inhibitor; interferon; antiviral ID CELL-CULTURE; IN-VITRO; GENETIC-VARIATION; HUH-7 CELLS; CDNA-CLONE; REPLICATION; RNA; INHIBITOR; PROTEIN; POTENT AB Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases worldwide, but treatment options are limited. Basic HCV research required for vaccine and drug development has been hampered by inability to culture patient isolates, and to date only the JFH1 (genotype 2a) recombinant replicates spontaneously in hepatoma cells and releases infectious virus. A JFH1 chimera with the 5' end through NS2 from another genotype 2a strain, J6, had enhanced infectivity. However, the full-length J6 clone (J6CF), which we previously found to be fully functional in vivo, was replication incompetent in vitro. Through a systematic approach of culturing J6 with minimal JFH1 sequences, we identified three mutations in NS3, NS4A, and NS5B that permitted full-length J6 propagation and adaptation with infectivity titers comparable to JFH1-based systems. The most efficient recombinant, J6cc, had six adaptive mutations and did not accumulate additional changes following viral passage. We demonstrated that HCV NS3/NS4A protease-, NS5A- and NS5B polymerase-directed drugs respectively inhibited full-length J6 infection dose dependently. Importantly, the three J6-derived mutations enabled culture adaptation of the genetically divergent isolate J8 (genotype 2b), which differed from the J6 nucleotide sequence by 24%. The most efficient recombinant, J8cc, had nine adaptive mutations and was genetically stable after viral passage. The availability of these robust JFH1-independent genotype 2a and 2b culture systems represents an important advance, and the approach used might permit culture development of other isolates, with implications for improved individualized treatments of HCV patients and for development of broadly efficient vaccines. C1 [Purcell, Robert H.; Bukh, Jens] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Li, Yi-Ping; Ramirez, Santseharay; Gottwein, Judith M.; Scheel, Troels K. H.; Mikkelsen, Lotte; Bukh, Jens] Copenhagen Univ Hosp, Copenhagen Hepatitis Program CO HEP C, Dept Infect Dis, DK-2650 Hvidovre, Denmark. [Li, Yi-Ping; Ramirez, Santseharay; Gottwein, Judith M.; Scheel, Troels K. H.; Mikkelsen, Lotte; Bukh, Jens] Copenhagen Univ Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Li, Yi-Ping; Ramirez, Santseharay; Gottwein, Judith M.; Scheel, Troels K. H.; Mikkelsen, Lotte; Bukh, Jens] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen N, Denmark. RP Purcell, RH (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM RPURCELL@niaid.nih.gov; jbukh@sund.ku.dk RI Ramirez, Santseharay/R-9257-2016; OI Ramirez, Santseharay/0000-0003-3699-1814; Scheel, Troels/0000-0003-1545-4067 FU Lundbeck Foundation; Danish Cancer Society; Novo Nordisk Foundation; A. P. Moller og Hustru Chastine Mc-Kinney Mollers Fondation; Danish Council for Independent Research - Medical Sciences; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank L. Ghanem, A. L. Sorensen, and B. Landt for technical assistance; S. B. Serre and T. Carlsen for discussions; and J. O. Nielsen and O. Andersen for providing valuable support (all from Copenhagen University Hospital). We thank S. U. Emerson (National Institutes of Health, Bethesda, MD), C. M. Rice (Rockefeller University) and T. Wakita (National Institute of Infectious Diseases, Tokyo, Japan) for providing reagents. This study was supported by research grants from Lundbeck Foundation (to J. G. M., T. H. K. S., and J. B.); The Danish Cancer Society (to J. M. G. and J. B.); The Novo Nordisk Foundation (to J. M. G. and J. B.); The A. P. Moller og Hustru Chastine Mc-Kinney Mollers Fondation (to J. B.); the Danish Council for Independent Research - Medical Sciences (to Y.-P.L., S. R., and J. B.); and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to R. H. P. and J. B.). S. R. and T. K. H. S. are the recipients of Individual Postdoctoral Stipends from the Danish Council for Independent Research - Medical Sciences. NR 67 TC 36 Z9 38 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 1 PY 2012 VL 109 IS 18 BP E1101 EP E1110 DI 10.1073/pnas.1203829109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 936PI UT WOS:000303602100011 PM 22467829 ER PT J AU Pellett, PE Ablashi, DV Ambros, PF Agut, H Caserta, MT Descamps, V Flamand, L Gautheret-Dejean, A Hall, CB Kamble, RT Kuehl, U Lassner, D Lautenschlager, I Loomis, KS Luppi, M Lusso, P Medveczky, PG Montoya, JG Mori, Y Ogata, M Pritchett, JC Rogez, S Seto, E Ward, KN Yoshikawa, T Razonable, RR AF Pellett, Philip E. Ablashi, Dharam V. Ambros, Peter F. Agut, Henri Caserta, Mary T. Descamps, Vincent Flamand, Louis Gautheret-Dejean, Agnes Hall, Caroline B. Kamble, Rammurti T. Kuehl, Uwe Lassner, Dirk Lautenschlager, Irmeli Loomis, Kristin S. Luppi, Mario Lusso, Paolo Medveczky, Peter G. Montoya, Jose G. Mori, Yasuko Ogata, Masao Pritchett, Joshua C. Rogez, Sylvie Seto, Edward Ward, Katherine N. Yoshikawa, Tetsushi Razonable, Raymund R. TI Chromosomally integrated human herpesvirus 6: questions and answers SO REVIEWS IN MEDICAL VIROLOGY LA English DT Review ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; REPLICATION IN-VITRO; MAREKS-DISEASE VIRUS; HHV-6 DNA; HUMAN-HERPESVIRUS-6 REACTIVATION; LIVER-TRANSPLANT; VIRAL LOAD; HYPERSENSITIVITY-SYNDROME AB Chromosomally integrated human herpesvirus 6 (ciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV-6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV-6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV-6 due to cell lysis and release of cellular DNA. High HHV-6 DNA loads associated with ciHHV-6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV-6 may be at increased risk for bacterial infection and graft rejection. ciHHV-6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV-6 individuals are put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV-6. Little is known about whether individuals with ciHHV-6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV-6 in disease. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Pellett, Philip E.] Wayne State Univ, Dept Immunol & Microbiol, Sch Med, Detroit, MI 48201 USA. [Ablashi, Dharam V.; Loomis, Kristin S.; Pritchett, Joshua C.] HHV 6 Fdn, Santa Barbara, CA USA. [Ambros, Peter F.] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Agut, Henri; Gautheret-Dejean, Agnes] Grp Hosp Pitie Salpetriere, Serv Virol, F-75634 Paris, France. [Caserta, Mary T.] Univ Rochester, Sch Med, Dept Pediat, Rochester, NY 14642 USA. [Descamps, Vincent] Bichat Claude Bernard Hosp, Dept Dermatol, Paris, France. [Flamand, Louis] Univ Laval, Rheumatol & Immunol Res Ctr, Quebec City, PQ, Canada. [Hall, Caroline B.] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Hall, Caroline B.] Univ Rochester, Sch Med & Dent, Dept Med, Rochester, NY 14642 USA. [Kamble, Rammurti T.] Baylor Coll Med, Houston, TX 77030 USA. [Kuehl, Uwe] Charite, Berlin, Germany. [Lassner, Dirk] Inst Cardiac Diag & Treatment, Berlin, Germany. [Lautenschlager, Irmeli] HUSLAB, Dept Virol, Helsinki, Finland. [Lautenschlager, Irmeli] Univ Helsinki, Helsinki, Finland. [Luppi, Mario] Univ Modena & Reggio Emilia, Emilia Romagna, Italy. [Lusso, Paolo] NIAID, NIH, Bethesda, MD 20892 USA. [Medveczky, Peter G.] Univ S Florida, Dept Mol Med, Tampa, FL USA. [Montoya, Jose G.] Stanford Univ, Dept Infect Dis, Stanford, CA 94305 USA. [Mori, Yasuko] Kobe Univ, Div Clin Virol, Kobe, Hyogo 657, Japan. [Ogata, Masao] Oita Univ, Ctr Blood Transfus, Oita 87011, Japan. [Rogez, Sylvie] CHRU Dupuytren, Dept Virol, Limoges, France. [Seto, Edward] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USA. [Ward, Katherine N.] UCL, Dept Infect, London, England. [Yoshikawa, Tetsushi] Fujita Hlth Univ, Dept Pediat, Toyoake, Aichi, Japan. [Razonable, Raymund R.] Mayo Clin, Div Infect Dis, Rochester, MN 55905 USA. RP Pellett, PE (reprint author), Wayne State Univ, Dept Immunol & Microbiol, Sch Med, 6225 Scott Hall,540 E Canfield Ave, Detroit, MI 48201 USA. EM ppellett@med.wayne.edu; razonable.raymund@mayo.edu RI Medveczky, Peter/A-6846-2012; Luppi, Mario/J-3668-2016; Rogez, Sylvie/O-8891-2016; OI Luppi, Mario/0000-0002-0373-1154; Rogez, Sylvie/0000-0002-4092-7164; Medveczky, Peter/0000-0002-1798-2595; Ogata, Masao/0000-0002-4896-5878; Lassner, Dirk/0000-0003-0815-7013; Ambros, Peter F./0000-0002-5507-7211 FU HHV-6 Foundation FX This project was supported by the HHV-6 Foundation. Several of the co-authors have received research grants from the HHV-6 Foundation. NR 88 TC 84 Z9 85 U1 1 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1052-9276 J9 REV MED VIROL JI Rev. Med. Virol. PD MAY PY 2012 VL 22 IS 3 BP 144 EP 155 DI 10.1002/rmv.715 PG 12 WC Virology SC Virology GA 930EH UT WOS:000303119600002 PM 22052666 ER PT J AU Kelly, DL Raley, HG Lo, S Wright, K Liu, F McMahon, RP Moolchan, ET Feldman, S Richardson, CM Wehring, HJ Heishman, SJ AF Kelly, Deanna L. Raley, Heather G. Lo, Suzanne Wright, Katherine Liu, Fang McMahon, Robert P. Moolchan, Eric T. Feldman, Stephanie Richardson, Charles M. Wehring, Heidi J. Heishman, Stephen J. TI Perception of Smoking Risks and Motivation to Quit Among Nontreatment-Seeking Smokers With and Without Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE smoking; schizophrenia; motivation; health risks ID FAGERSTROM TOLERANCE QUESTIONNAIRE; CIGARETTE-SMOKING; MONETARY REINFORCEMENT; TRANSDERMAL NICOTINE; EXTRINSIC MOTIVATION; PSYCHOTIC DISORDER; CESSATION; OUTPATIENTS; REHABILITATION; DEPENDENCE AB We examined perceived consequences/benefits of cigarette smoking and motivation for quitting in nontreatment-seeking smokers who had schizophrenia or schizoaffective disorder (N = 100) or had no Axis I psychiatric disorder (normals, N = 100). Participants completed questionnaires and provided a breath carbon monoxide (CO) sample 10-15 minutes after smoking 1 preferred-brand cigarette. Primary assessments included the Smoking Consequences Questionnaire-Adult, the Reasons for Quitting Scale, and the Stages of Change. There were no differences between the schizophrenia and control group in mean age of smoking onset (16.2 +/- 5.4 vs 15.6 +/- 5.5 y, P = .44), number of cigarettes daily (17.9 +/- 11.6 vs 17.0 +/- 7.9, P = 0.51), or in breath CO (28.0 +/- 14.5 vs 22.9 +/- 8.0 ppm, P = .61). Compared with normals, people with schizophrenia report greater stimulation/state enhancement (P < .0001) and social facilitation (P < .004) from smoking. People with schizophrenia had less appreciation of health risks associated with smoking than normal controls (P < .0001) and were less motivated to quit smoking than normal controls (P = .002), even though they were as likely to be in the preparation stage of change. Immediate reinforcement (P = .04) and health concerns (P = .002) were rated lower as motivators for considering quitting smoking in schizophrenia than normals. People with schizophrenia reported greater motivation to stop smoking due to social pressure/rewards than normals (P = .047). This study underscores the degree to which people with schizophrenia perceive the state-enhancing effects of smoking and their lower appreciation for health risks of smoking compared with normal controls. C1 [Kelly, Deanna L.; Raley, Heather G.; Wright, Katherine; Liu, Fang; McMahon, Robert P.; Feldman, Stephanie; Richardson, Charles M.; Wehring, Heidi J.] Univ Maryland, Baltimore Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Lo, Suzanne; Heishman, Stephen J.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Moolchan, Eric T.] Alkermes Inc, Cambridge, MA USA. RP Kelly, DL (reprint author), Univ Maryland, Baltimore Sch Med, Maryland Psychiat Res Ctr, Box 21247, Baltimore, MD 21228 USA. EM dkelly@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009 FU National Institutes of Health, National Institute on Drug Abuse; National Institute on Drug Abuse Residential Research Support Services [HHSN271200599091CADB, NO-1DA-5-9909] FX Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, and National Institute on Drug Abuse Residential Research Support Services Contract HHSN271200599091CADB, NO-1DA-5-9909 (PI: Deanna L. Kelly). NR 44 TC 17 Z9 17 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAY PY 2012 VL 38 IS 3 BP 543 EP 551 DI 10.1093/schbul/sbq124 PG 9 WC Psychiatry SC Psychiatry GA 930VB UT WOS:000303169000022 PM 21041835 ER PT J AU Knutson, KL Zhao, XC Mattingly, M Galli, G Cizza, G AF Knutson, Kristen L. Zhao, Xiongce Mattingly, Megan Galli, Giulia Cizza, Giovanni TI Predictors of sleep-disordered breathing in obese adults who are chronic short sleepers SO SLEEP MEDICINE LA English DT Article DE Sleep-disordered breathing; Obese; Actigraphy; Subjective sleep quality; Sleepiness; Apnea ID MIDDLE-AGED ADULTS; CARDIOVASCULAR-DISEASE; DAYTIME SLEEPINESS; HEART HEALTH; RISK-FACTOR; APNEA; PREVALENCE; INDEX; DURATION; STROKE AB Background: Sleep disordered breathing (SDB) is common in obese adults, but not all obese adults have SDB. The aim of these analyses was to determine what predicted SDB in a sample of obese adults. Methods: We conducted cross-sectional analysis of 139 obese men and women aged 18-50 years who are chronic short sleepers. Habitual sleep duration and sleep efficiency were estimated using two weeks of wrist actigraphy. Respiratory disturbance index (RDI) was assessed by a portable screening device. SDB was defined as RDI >= 15 events h (1). Subjective sleep quality, sleepiness, and sociodemographic characteristics were evaluated by questionnaires. Results: Increased sleep duration from actigraphy was associated with reduced odds of SDB (OR 0.44 per hour, p = 0.043). Neither subjective sleep quality nor sleepiness was associated with SDB. Male sex, older age, and increased waist circumference were associated with increased odds of SDB. Conclusions: In this sample of obese adults, subjective measures of sleep quality and sleepiness were not indicators of SDB. These results suggest that, in obese patients, physicians should not rely on subjective measures to determine who should be referred for a clinical sleep study. A wider use of portable apnea screening devices should be considered in nonsymptomatic, non-Hispanic white males. (C) 2012 Elsevier B. V. All rights reserved. C1 [Knutson, Kristen L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Zhao, Xiongce; Mattingly, Megan; Galli, Giulia; Cizza, Giovanni] NIDDK, Sect Neuroendocrinol Obes, Bethesda, MD USA. [Galli, Giulia] Univ Hosp Pisa, Dept Endocrinol & Kidney, Pisa, Italy. RP Knutson, KL (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave,MC6076, Chicago, IL 60637 USA. EM kknutson@medicine.bsd.uchicago.edu; Zhao.Xiongce@nih.gov; mattinglym@niddk.nih.gov; giulia.galli@nih.gov; cizzag@intra.niddk.nih.gov OI Knutson, Kristen/0000-0002-2751-6168 FU National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK); Clinical Center, National Institutes of Health (NIH) FX This study is supported by the Intramural Program of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) and the Clinical Center, National Institutes of Health (NIH). This study is conducted under the NIDDK protocol 06-DK-0036 and is listed in ClinicalTrials.gov (identifier: NCT00261898). Statistical expertise and a central sample handling and assays facility are provided by the NIDDK Intramural Obesity Initiative of the NIH Clinical Center. NR 27 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 J9 SLEEP MED JI Sleep Med. PD MAY PY 2012 VL 13 IS 5 BP 484 EP 489 DI 10.1016/j.sleep.2011.11.009 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 933FX UT WOS:000303346800006 PM 22326831 ER PT J AU Sappol, M AF Sappol, Michael TI Anatomy as Spectacle: Public Exhibitions of the Body from 1700 to the Present SO SOCIAL HISTORY OF MEDICINE LA English DT Book Review C1 [Sappol, Michael] Natl Lib Med, Bethesda, MD 20894 USA. RP Sappol, M (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM sappolm@mail.nlm.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0951-631X J9 SOC HIST MED JI Soc. Hist. Med. PD MAY PY 2012 VL 25 IS 2 BP 546 EP 548 DI 10.1093/shm/hks017 PG 3 WC History; History & Philosophy Of Science SC History; History & Philosophy of Science GA 933BK UT WOS:000303334000020 ER PT J AU Chen, XJ Summers, RM Cho, M Bagci, U Yao, JY AF Chen, Xinjian Summers, Ronald M. Cho, Monique Bagci, Ulas Yao, Jianhua TI An Automatic Method for Renal Cortex Segmentation on CT Images: Evaluation on Kidney Donors SO ACADEMIC RADIOLOGY LA English DT Article DE Kidney; renal cortex; automatic renal cortex segmentation; kidney donors ID ENHANCED MR-ANGIOGRAPHY; SEMIAUTOMATED SEGMENTATION; GRAPH-CUTS; ALGORITHMS; RENOGRAPHY; EXPERIENCE; AGREEMENT; MODELS AB Rationale and Objectives: The aims of this study were to develop and validate an automated method to segment the renal cortex on contrast-enhanced abdominal computed tomographic images from kidney donors and to track cortex volume change after donation. Materials and Methods: A three-dimensional fully automated renal cortex segmentation method was developed and validated on 37 arterial phase computed tomographic data sets (27 patients, 10 of whom underwent two computed tomographic scans before and after nephrectomy) using leave-one-out strategy. Two expert interpreters manually segmented the cortex slice by slice, and linear regression analysis and Bland-Altman plots were used to compare automated and manual segmentation. The true-positive and false-positive volume fractions were also calculated to evaluate the accuracy of the proposed method. Cortex volume changes in 10 subjects were also calculated. Results: The linear regression analysis results showed that the automated and manual segmentation methods had strong correlations, with Pearson's correlations of 0.9529, 0.9309, 0.9283, and 0.9124 between intraobserver variation, interobserver variation, automated and user 1, and automated and user 2, respectively (P < .001 for all analyses). The Bland-Altman plots for cortex segmentation also showed that the automated and manual methods had agreeable segmentation. The mean volume increase of the cortex for the 10 subjects was 35.1 +/- 13.2% (P < .01 by paired t test). The overall true-positive and false-positive volume fractions for cortex segmentation were 90.15 +/- 3.11% and 0.85 +/- 0.05%. With the proposed automated method, the time for cortex segmentation was reduced from 20 minutes for manual segmentation to 2 minutes. Conclusions: The proposed method was accurate and efficient and can replace the current subjective and time-consuming manual procedure. The computer measurement confirms the volume of renal cortex increases after kidney donation. C1 [Chen, Xinjian; Summers, Ronald M.; Bagci, Ulas; Yao, Jianhua] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. [Cho, Monique] NIDDK, Kidney Dis Branch, Bethesda, MD USA. RP Yao, JY (reprint author), NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10,Room 1C515, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov RI Bagci, Ulas/A-4225-2012; Chen, Xinjian/E-8592-2016; OI Bagci, Ulas/0000-0001-7379-6829 FU National Institutes of Health Clinical Center FX From the Radiology and Imaging Sciences Department, National Institutes of Health Clinical Center, Building 10, Room 10515, Bethesda, MD 20892-1182 (X.C., R.M.S., U.B., J.Y.); and the Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.C.). Received September 26, 2011; accepted January 9, 2012. This paper was presented at the 2010 annual meeting of the Radiological Society of North America as a scientific paper. This research was supported by the Intramural Program of the National Institutes of Health Clinical Center. Address correspondence to: J.Y. e-mail: jyao@cc.nih.gov NR 28 TC 8 Z9 9 U1 1 U2 7 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 MAY PY 2012 VL 19 IS 5 BP 562 EP 570 DI 10.1016/j.acra.2012.01.005 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 929OR UT WOS:000303075700009 PM 22341876 ER PT J AU Linguraru, MG Sandberg, JK Jones, EC Petrick, N Summers, RM AF Linguraru, Marius George Sandberg, Jesse K. Jones, Elizabeth C. Petrick, Nicholas Summers, Ronald M. TI Assessing Hepatomegaly: Automated Volumetric Analysis of the Liver SO ACADEMIC RADIOLOGY LA English DT Article DE Hepatomegaly; volumetric analysis; liver; segmentation; nomogram ID SURGICAL DECISION-MAKING; MULTIDETECTOR ROW CT; COMPUTED-TOMOGRAPHY; RIEDELS LOBE; ULTRASONIC DETERMINATION; OBSERVER VARIATION; SPLEEN VOLUME; LIVING DONOR; SPIRAL CT; SIZE AB Rationale and Objectives: The aims of this study were to define volumetric nomograms for identifying hepatomegaly and to retrospectively evaluate the performance of radiologists in assessing hepatomegaly. Materials and Methods: Livers were automatically segmented from 148 abdominal contrast-enhanced computed tomographic scans: 77 normal livers and 71 cases of hepatomegaly (diagnosed by visual inspection and/or linear liver height by radiologists). Quantified liver volumes were compared to manual measurements using volume overlap and error. Liver volumes were normalized to body surface area, from which hepatomegaly nomograms were defined (H scores) by analyzing the distribution of liver sizes in the healthy population. H scores were validated against consensus reports. The performance of radiologists in diagnosing hepatomegaly was retrospectively evaluated. Results: The automated segmentation of livers was robust, with volume overlap and error of 96.2% and 2.2%, respectively. There were no significant differences (P > .10) between manual and automated segmentation for either the normal or the hepatomegaly subgroup. The average volumes of normal and enlarged livers were 1.51 +/- 0.25 and 2.32 +/- 0.75 L, respectively. One-way analysis of variance found that body surface area (P = .004) and gender (P = .02), but not age, significantly affected normal liver volume. No significant effects were observed for two-way and three-way interactions among the three variables (P > .18). H-score cutoffs of 0.92 and 1.08 L/m(2) were used to define mild and massive hepatomegaly (95% confidence interval, +/- 0.02 L/m(2)). Using the H score as the reference standard, the sensitivity of radiologists in detecting all, mild, and massive hepatomegaly was 84.4%, 56.7%, and 100.0% at 90.1% specificity, respectively. Radiologists disagreed on 20.9% of the diagnosed cases (n = 31). The area under the receiver-operating characteristic curve of the H-score criterion for hepatomegaly detection was 0.98. Conclusions: Nomograms for the identification and grading of hepatomegaly from automatic volumetric liver assessment normalized to body surface area (H scores) are introduced. H scores match well with clinical interpretations for hepatomegaly and may improve hepatomegaly detection compared with height measurements or visual inspection, commonly used in current clinical practice. C1 [Linguraru, Marius George; Sandberg, Jesse K.; Jones, Elizabeth C.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Linguraru, Marius George] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Linguraru, MG (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM mlingura@cnmc.org FU National Institutes of Health, Clinical Center; US Food and Drug Administration FX From the Imaging Biomarkers and Computer-Aided Diagnosis Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland (M.G.L., J.K.S., E.C.J., R.M.S.); The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010 (M.G.L.); and the Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland (N.P.). Received September 26, 2011; accepted January 28, 2012. This work was supported in part by the Intramural Research Programs of the National Institutes of Health, Clinical Center, and the US Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either actual or implied endorsements of such products by the US Department of Health and Human Services. Address correspondence to: M.G.L. e-mail: mlingura@cnmc.org NR 58 TC 8 Z9 9 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 J9 ACAD RADIOL JI Acad. Radiol. PD MAY PY 2012 VL 19 IS 5 BP 588 EP 598 DI 10.1016/j.acra.2012.01.015 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 929OR UT WOS:000303075700012 PM 22361033 ER PT J AU Garces, A Mcclure, EM Hambidge, M Krebs, NF Mazariegos, M Wright, LL Moore, J Carlo, WA AF Garces, Ana Mcclure, Elizabeth M. Hambidge, Michael Krebs, Nancy F. Mazariegos, Manolo Wright, Linda L. Moore, Janet Carlo, Waldemar A. TI Training traditional birth attendants on the WHO Essential Newborn Care reduces perinatal mortality SO ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA LA English DT Article DE Developing countries; newborn care; perinatal mortality; stillbirths; traditional birth attendants ID NEONATAL DEATHS; STILLBIRTHS; COUNTRIES AB Objectives. To evaluate the impact of birth attendant training using the World Health Organization Essential Newborn Care (ENC) course among traditional birth attendants, with a particular emphasis on the effect of acquisition of skills on perinatal outcomes. Design. Population-based, prospective, interventional pre-post design study. Setting. 11 rural clusters in Chimaltenango, Guatemala. Population. Health care providers. Methods. This study analyzed the effect of training and implementation of the ENC health care provider training course between September 2005 and December 2006. Outcome measures. The primary outcome measure was the rate of death from all causes in the first seven days after birth in fetuses/infants =1500g. Secondary outcome measures were overall rate of stillbirth, rate of perinatal death, which included stillbirths plus neonatal deaths in the first seven days in fetuses/infants =1500g. Results. Perinatal mortality decreased from 39.5/1000 pre-ENC to 26.4 post-ENC (RR 0.72; 95%CI 0.540.97). This reduction was attributable almost entirely to a decrease in the stillbirth rate of 21.4/1000 pre-Essential Newborn Care to 7.9/1000 post-ENC (RR 0.40; 95%CI 0.250.64). Seven-day neonatal mortality did not decrease (18.3/1000 to 18.6/1000; RR 1.05; 95%CI 0.701.57). Conclusion. Essential Newborn Care training reduced stillbirths in a population-based controlled study with deliveries conducted almost exclusively by traditional birth attendants. Scale-up of this intervention in other settings might help assess reproducibility and sustainability. C1 [Garces, Ana; Mazariegos, Manolo] IMSALUD, Guatemala City, Guatemala. [Mcclure, Elizabeth M.; Moore, Janet] RTI, Res Triangle Pk, NC USA. [Hambidge, Michael; Krebs, Nancy F.] Univ Colorado Denver, Aurora, CO USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL USA. RP Garces, A (reprint author), IMSALUD, 3Ra Calle A 6-56,Zona 10, Guatemala City, Guatemala. EM anagarces@imsalud.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development) [NICHD U01 HD040657 UCD, U01 HD043464 UAB, U01 HD040636 RTI] FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD U01 HD040657 UCD; U01 HD043464 UAB; and U01 HD040636 RTI). NR 12 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6349 J9 ACTA OBSTET GYN SCAN JI Acta Obstet. Gynecol. Scand. PD MAY PY 2012 VL 91 IS 5 BP 593 EP 597 DI 10.1111/j.1600-0412.2012.01374.x PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 928RR UT WOS:000303001500012 PM 22324644 ER PT J AU Litten, RZ Egli, M Heilig, M Cui, CH Fertig, JB Ryan, ML Falk, DE Moss, H Huebner, R Noronha, A AF Litten, Raye Z. Egli, Mark Heilig, Markus Cui, Changhai Fertig, Joanne B. Ryan, Megan L. Falk, Daniel E. Moss, Howard Huebner, Robert Noronha, Antonio TI Medications development to treat alcohol dependence: a vision for the next decade SO ADDICTION BIOLOGY LA English DT Review DE Alcohol; alcohol dependence; alcohol use disorders; drug development; medications ID RANDOMIZED CONTROLLED-TRIAL; OPIOID RECEPTOR GENE; DOUBLE-BLIND; USE DISORDERS; ETHANOL DRINKING; DRUG-DEPENDENCE; HEAVY-DRINKING; UNITED-STATES; FUNCTIONAL POLYMORPHISM; ACHIEVING CONSILIENCE AB More than 76 million people world-wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism's (NIAAA's) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder. C1 [Litten, Raye Z.; Egli, Mark; Heilig, Markus; Cui, Changhai; Fertig, Joanne B.; Ryan, Megan L.; Falk, Daniel E.; Moss, Howard; Huebner, Robert; Noronha, Antonio] NIAAA, Bethesda, MD USA. RP Litten, RZ (reprint author), NIAA, NIH, 5635 Fishers Lane,Room 2041, Rockville, MD 20852 USA. EM rlitten@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 FU Intramural NIH HHS [Z99 AA999999] NR 115 TC 78 Z9 81 U1 4 U2 19 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAY PY 2012 VL 17 IS 3 BP 513 EP 527 DI 10.1111/j.1369-1600.2012.00454.x PG 15 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 928QR UT WOS:000302998400002 PM 22458728 ER PT J AU Schank, JR Goldstein, AL Rowe, KE King, CE Marusich, JA Wiley, JL Carroll, FI Thorsell, A Heilig, M AF Schank, Jesse R. Goldstein, Andrea L. Rowe, Kelly E. King, Courtney E. Marusich, Julie A. Wiley, Jenny L. Carroll, F. Ivy Thorsell, Annika Heilig, Markus TI The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety SO ADDICTION BIOLOGY LA English DT Article DE Alcoholism; dynorphin; ethanol; reinstatement; self-administration; stress ID CORTICOTROPIN-RELEASING-FACTOR; N-TERMINAL KINASE; NOR-BINALTORPHIMINE; COCAINE-SEEKING; PRIMING INJECTIONS; NUCLEUS-ACCUMBENS; AGONIST U50,488H; ETHANOL INTAKE; DRUG-SEEKING; STRESS AB The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety (hangover anxiety). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism. C1 [Schank, Jesse R.; Goldstein, Andrea L.; Rowe, Kelly E.; King, Courtney E.; Thorsell, Annika; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Marusich, Julie A.; Wiley, Jenny L.; Carroll, F. Ivy] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Schank, JR (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,Bldg 10-CRC,Room 1-5330, Bethesda, MD 20892 USA. EM jesse.schank@nih.gov RI Shipper, Andrea/G-7407-2014; OI Shipper, Andrea/0000-0003-2819-4276; Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 FU National Institute on Alcohol Abuse and Alcoholism; National Institute of Drug Abuse [DA09045] FX The Authors would like to thank Dr. Andrea Cippitelli for methodological advice. This research was funded by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program and by National Institute of Drug Abuse Grant #DA09045. NR 59 TC 38 Z9 40 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAY PY 2012 VL 17 IS 3 BP 634 EP 647 DI 10.1111/j.1369-1600.2012.00455.x PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 928QR UT WOS:000302998400013 PM 22515275 ER PT J AU Ghany, MG Feld, JJ Zhao, X Heller, T Doo, E Rotman, Y Nagabhyru, P Koh, C Kleiner, DE Wright, EC Liang, TJ Hoofnagle, JH AF Ghany, M. G. Feld, J. J. Zhao, X. Heller, T. Doo, E. Rotman, Y. Nagabhyru, P. Koh, C. Kleiner, D. E. Wright, E. C. Liang, T. J. Hoofnagle, J. H. TI Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID DIPIVOXIL; VIRUS; ENTECAVIR; RESISTANCE AB Background Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. Aim To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. Methods Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. Results A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naive subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). Conclusions Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (Clinical. Trials.gov NCT00023309). C1 [Ghany, M. G.; Feld, J. J.; Heller, T.; Doo, E.; Rotman, Y.; Nagabhyru, P.; Koh, C.; Liang, T. J.; Hoofnagle, J. H.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, X.; Wright, E. C.] NIDDKD, Off Director, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDKD, Liver Dis Branch, NIH, Bldg 10,Room 9B 16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, National Institutes of Health. NR 23 TC 13 Z9 14 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAY PY 2012 VL 35 IS 9 BP 1027 EP 1035 DI 10.1111/j.1365-2036.2012.05059.x PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 927HP UT WOS:000302898400005 PM 22449251 ER PT J AU Mannelli, P Peindl, K Wu, LT Patkar, AA Gorelick, DA AF Mannelli, Paolo Peindl, Kathleen Wu, Li-Tzy Patkar, Ashwin A. Gorelick, David A. TI The Combination Very Low-Dose Naltrexone-Clonidine in the Management of Opioid Withdrawal SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE addiction; detoxification; antagonist; adrenergic; pharmacotherapies ID NALOXONE-PRECIPITATED WITHDRAWAL; OPIATE WITHDRAWAL; DETOXIFICATION; METHADONE; LOFEXIDINE; ADDICTION; RECEPTORS AB Background: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy. Objectives: We investigated the effects of a VLNTX-clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial. Methods: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1-.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program. Results: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments. Conclusions and Scientific Significance: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal. C1 [Mannelli, Paolo; Peindl, Kathleen; Wu, Li-Tzy; Patkar, Ashwin A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. RP Mannelli, P (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, 2218 Elder St,Suite 123, Durham, NC 27705 USA. EM paolo.mannelli@duke.edu FU Intramural NIH HHS; NIDA NIH HHS [DA15469, R21 DA015469, U10 DA013727] NR 29 TC 1 Z9 1 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD MAY PY 2012 VL 38 IS 3 BP 200 EP 205 DI 10.3109/00952990.2011.644003 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 923RT UT WOS:000302637200002 PM 22233189 ER PT J AU Shah, R Diaz, SD Arria, A LaGasse, LL Derauf, C Newman, E Smith, LM Huestis, MA Haning, W Strauss, A Della Grotta, S Dansereau, LM Roberts, MB Neal, C Lester, BM AF Shah, Rizwan Diaz, Sabrina D. Arria, Amelia LaGasse, Linda L. Derauf, Chris Newman, Elana Smith, Lynne M. Huestis, Marilyn A. Haning, William Strauss, Arthur Della Grotta, Sheri Dansereau, Lynne M. Roberts, Mary B. Neal, Charles Lester, Barry M. TI Prenatal Methamphetamine Exposure and Short-Term Maternal and Infant Medical Outcomes SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE amphetamine; methamphetamine; drug; antenatal; neonate ID LIFE-STYLE; AMPHETAMINE ADDICTION; PSYCHIATRIC-SYMPTOMS; INTRAUTERINE GROWTH; PREGNANT-WOMEN; FETAL-GROWTH; ENVIRONMENT; ABUSE; DRUGS AB Objective Examine maternal and infant medical outcomes of prenatal exposure to methamphetamine (MA). Study Design Four hundred and twelve mother-infant pairs (204 MA-exposed and 208 unexposed matched comparisons) were enrolled in the Infant Development, Environment and Lifestyle (IDEAL) study. Exposure was determined by maternal self-report during this pregnancy and/or positive meconium toxicology. Maternal interviews assessed prenatal drug use, pregnancy course, and sociodemographic information. Medical chart reviews provided medical history, obstetric complications, infant outcomes, and discharge placement. Results MA-using mothers were more likely to be poor, to have a psychiatric disorder/emotional illness and less prenatal care, and to be less likely to breast-feed their infant than comparison mothers. After adjusting for covariates, MA-exposed infants were more likely to exhibit poor suck, to have smaller head circumferences and length, to require neonatal intensive care unit (NICU) admission, and to be referred to child protective services (CPS). Several outcomes previously reported from studies that lacked adequate control groups or adjustment for covariates were not significantly different in this study. Conclusion Prenatal MA exposure is associated with maternal psychiatric disorder/emotional illness, poor suck, NICU admission, and CPS involvement, and MA-exposed infants were less likely to be breast-fed; however, the absence of many serious complications, such as fetal distress, chronic hypertension, preeclampsia, placenta previa, abruptio placentae, and cardiac defects, suggests confounding variables influenced prior studies. C1 [Diaz, Sabrina D.; Smith, Lynne M.] Harbor UCLA Med Ctr, LABiomed Inst, Los Angeles, CA USA. [Diaz, Sabrina D.; Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Shah, Rizwan] Iowa Hlth, Blank Hosp Reg Child Protect Ctr, Des Moines, IA USA. [Arria, Amelia] Univ Maryland, Sch Publ Hlth, Ctr Young Adult Hlth & Dev, College Pk, MD 20742 USA. [LaGasse, Linda L.; Della Grotta, Sheri; Dansereau, Lynne M.; Roberts, Mary B.; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Warren Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI USA. [Derauf, Chris; Haning, William; Neal, Charles] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Strauss, Arthur] Long Beach Mem Med Ctr, Miller Childrens Hosp, Long Beach, CA USA. RP Diaz, SD (reprint author), Harbor UCLA Med Ctr, 1124 W Carson St,RB 1, Torrance, CA 90502 USA. EM scopes@labiomed.org OI Arria, Amelia/0000-0002-6360-9265 FU National Institute on Drug Abuse [R01DA014918]; National Center on Research Resources [M01RR00425, U54RR026136] FX This study was supported by grants from the National Institute on Drug Abuse (R01DA014918) and the National Center on Research Resources (M01RR00425 and U54RR026136). NR 37 TC 10 Z9 11 U1 2 U2 17 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD MAY PY 2012 VL 29 IS 5 BP 391 EP 400 DI 10.1055/s-0032-1304818 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 928DV UT WOS:000302962200011 PM 22399214 ER PT J AU Shizukuda, Y Smith, KP Tripodi, DJ Arena, R Yau, YY Bolan, CD Waclawiw, MA Leitman, SF Rosing, DR AF Shizukuda, Yukitaka Smith, Kevin P. Tripodi, Dorothy J. Arena, Ross Yau, Yu-Ying Bolan, Charles D. Waclawiw, Myron A. Leitman, Susan F. Rosing, Douglas R. TI Changes in Exercise Capacity in Subjects with Cardiac Asymptomatic Hereditary Hemochromatosis During a Follow-Up After 5 yrs SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Hereditary Hemochromatosis; Exercise Capacity; Cardiopulmonary Exercise Test; Prospective Study ID HEART-FAILURE; VENTILATORY EFFICIENCY; ECHOCARDIOGRAPHY; MANAGEMENT; THRESHOLD; TREADMILL; INDEXES; STRESS; HFE AB Shizukuda Y, Smith KP, Tripodi DJ, Arena R, Yau Y-Y, Bolan CD, Waclawiw MA, Leitman SF, Rosing DR: Changes in exercise capacity in subjects with cardiac asymptomatic hereditary hemochromatosis during a follow-up after 5 yrs. Am J Phys Med Rehabil 2012;91:418-424. Objective: A long-term effect of hereditary hemochromatosis (HH) on aerobic exercise capacity (AEC) has not been well described. Design: Forty-three HH and 21 volunteer control subjects who were asymptomatic underwent cardiopulmonary exercise testing using the Bruce protocol. AEC was assessed with minute ventilation ((V) over dotE), oxygen uptake ((V) over dotO(2)), and carbon dioxide production ((V) over dotCO(2)) at baseline and at a follow-up assessment after 5 yrs. A paired t test was used for analyses of normality data; otherwise, Wilcoxon's signed rank-sum test was used. Results: Thirty-three HH subjects and 18 volunteer control subjects returned for a repeat cardiopulmonary exercise testing at the fifth-year follow-up (80% overall return rate). At the fifth-year follow-up, AEC was not different between the two groups. Compared with baseline measurements, exercise time, peak (V) over dotO(2), and the (V) over dotE/(V) over dotCO(2) slope did not differ statistically at the fifth-year follow-up between both groups. Iron depletion through phlebotomy for 5 yrs did not significantly affect AEC in newly diagnosed HH subjects at baseline (n = 14) and cardiac arrhythmias during exercise tended to decrease after 5 yrs of therapy in this group. Conclusions: The AEC of asymptomatic HH subjects treated using conventional therapy is not statistically affected by the disease during a 5-yr period. C1 [Shizukuda, Yukitaka] Univ Cincinnati, Dept Internal Med, Div Cardiovasc Dis, Cincinnati, OH 45267 USA. [Shizukuda, Yukitaka; Smith, Kevin P.; Tripodi, Dorothy J.; Rosing, Douglas R.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Shizukuda, Yukitaka] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Arena, Ross] Univ New Mexico, Dept Orthopaed, Phys Therapy Program, Albuquerque, NM 87131 USA. [Yau, Yu-Ying; Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bolan, Charles D.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Shizukuda, Y (reprint author), Univ Cincinnati, Dept Internal Med, Div Cardiovasc Dis, 231 Albert Sabin Way,ML 0542, Cincinnati, OH 45267 USA. RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 FU Intramural NIH HHS [Z99 HL999999]; NCI NIH HHS [R01 CA094118] NR 30 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD MAY PY 2012 VL 91 IS 5 BP 418 EP 424 DI 10.1097/PHM.0b013e3182465f5f PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 929IH UT WOS:000303054000006 PM 22311055 ER PT J AU Shavers, VL Klein, WMP Fagan, P AF Shavers, Vickie L. Klein, William M. P. Fagan, Pebbles TI Research on Race/Ethnicity and Health Care Discrimination: Where We Are and Where We Need to Go SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Shavers, Vickie L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fagan, Pebbles] Univ Hawaii, Canc Prevent & Control Program, Ctr Canc, Honolulu, HI 96822 USA. RP Shavers, VL (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 18 TC 15 Z9 15 U1 0 U2 10 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2012 VL 102 IS 5 BP 930 EP 932 DI 10.2105/AJPH.2012.300708 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 928FT UT WOS:000302969300027 PM 22494001 ER PT J AU Shavers, VL Fagan, P Jones, D Klein, WMP Boyington, J Moten, C Rorie, E AF Shavers, Vickie L. Fagan, Pebbles Jones, Dionne Klein, William M. P. Boyington, Josephine Moten, Carmen Rorie, Edward TI The State of Research on Racial/Ethnic Discrimination in The Receipt of Health Care SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PERCEIVED RACIAL-DISCRIMINATION; AFRICAN-AMERICAN MEN; BLACK-WOMENS-HEALTH; QUALITY-OF-CARE; ETHNIC-MINORITIES; MEDICAL-STUDENTS; CULTURAL COMPETENCE; COMMUNITY SAMPLE; BLOOD-PRESSURE; ASSOCIATION AB Objectives. We conducted a review to examine current literature on the effects of interpersonal and institutional racism and discrimination occurring within health care settings on the health care received by racial/ethnic minority patients. Methods. We searched the Psych Net, PubMed, and Scopus databases for articles on US populations published between January 1, 2008 and November 1, 2011. We used various combinations of the following search terms: discrimination, perceived discrimination, race, ethnicity, racism, institutional racism, stereotype, prejudice or bias, and health or health care. Fifty-eight articles were reviewed. Results. Patient perception of discriminatory treatment and implicit provider biases were the most frequently examined topics in health care settings. Few studies examined the overall prevalence of racial/ethnic discrimination and none examined temporal trends. In general, measures used were insufficient for examining the impact of interpersonal discrimination or institutional racism within health care settings on racial/ethnic disparities in health care. Conclusions. Better instrumentation, innovative methodology, and strategies are needed for identifying and tracking racial/ethnic discrimination in health care settings. (Am J Public Health. 2012;102:953-966. doi:10.2105/AJPH.2012.300773) C1 [Shavers, Vickie L.; Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fagan, Pebbles] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Boyington, Josephine] NHLBI, NIH, Bethesda, MD 20892 USA. [Moten, Carmen] Natl Canc Inst Rockville, Ctr Reduce Canc Hlth Dispar, Rockville, MD USA. [Rorie, Edward] Nova Res Co, Bethesda, MD USA. RP Shavers, VL (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 105 TC 71 Z9 72 U1 6 U2 43 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2012 VL 102 IS 5 BP 953 EP 966 DI 10.2105/AJPH.2012.300773 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 928FT UT WOS:000302969300031 PM 22494002 ER PT J AU Zhong, MH De Angelo, P Osborne, L Paniz-Mondolfi, AE Geller, M Yang, YF Linehan, WM Merino, MJ Cordon-Cardo, C Cai, DM AF Zhong, Minghao De Angelo, Patricia Osborne, Lisa Paniz-Mondolfi, Alberto E. Geller, Matthew Yang, Youfeng Linehan, W. Marston Merino, Maria J. Cordon-Cardo, Carlos Cai, Dongming TI Translocation Renal Cell Carcinomas in Adults: A Single-institution Experience SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE translocation renal cell carcinoma; TFE3; TFEB ID OF-THE-LITERATURE; SOFT PART SARCOMA; TFE3 GENE FUSIONS; KIDNEY CANCER; MELANOMA; MITF; NEOPLASMS; IMMUNOHISTOCHEMISTRY; DIAGNOSIS; ONCOGENE AB Translocation renal cell carcinoma is a newly recognized subtype of renal cell carcinoma (RCC) with chromosomal translocations involving TFE3 (Xp11.2) or, less frequently, TFEB (6p21). Xp11 translocation RCC was originally described as a pediatric neoplasm representing 20% to 40% of pediatric RCCs, with a much lower frequency in the adult population. TFEB translocation RCC is very rare, with approximately 10 cases reported in the literature. Here, we describe the clinicopathologic features of adult translocation RCC from a single institution. Using tissue microarray, immunohistochemistry, cytogenetic examination, and fluorescence in situ hybridization, we identified 6 (similar to 5%) cases of TFE3 translocation RCC and 1 (< 1%) case of TFEB translocation RCC in 121 consecutive adult RCC cases between 2001 and 2009. Our results suggest that weak TFE3 staining of a significant proportion of RCC cases may be because of expression of the full-length TFE3 protein rather than the chimeric fusion protein resulting from chromosomal translocation. C1 [Zhong, Minghao; Cordon-Cardo, Carlos; Cai, Dongming] Mt Sinai Sch Med, New York, NY 10029 USA. [Paniz-Mondolfi, Alberto E.] St Lukes Roosevelt Hosp, New York, NY USA. [Geller, Matthew] Winthrop Univ Hosp, Mineola, NY 11501 USA. [Zhong, Minghao] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ 07103 USA. [De Angelo, Patricia; Osborne, Lisa] Univ Med & Dent New Jersey, New Jersey Med Sch, Inst Genom Med, Newark, NJ 07103 USA. [Yang, Youfeng; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhong, MH (reprint author), Mt Sinai Sch Med, New York, NY 10029 USA. EM minghaozhong@gmail.com FU NJMS Pathology Department FX This study was partly supported by the NJMS Pathology Department Resident Research Fund. NR 34 TC 28 Z9 32 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAY PY 2012 VL 36 IS 5 BP 654 EP 662 DI 10.1097/PAS.0b013e31824f24a6 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 926EL UT WOS:000302814000002 PM 22446944 ER PT J AU Eberle, FC Song, JY Xi, LQ Raffeld, M Harris, NL Wilson, WH Pittaluga, S Jaffe, ES AF Eberle, Franziska C. Song, Joo Y. Xi, Liqiang Raffeld, Mark Harris, Nancy Lee Wilson, Wyndham H. Pittaluga, Stefania Jaffe, Elaine S. TI Nodal Involvement by Cutaneous CD30-positive T-cell Lymphoma Mimicking Classical Hodgkin Lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE CD30-positive T-cell lymphoma; classical Hodgkin lymphoma; lymphomatoid papulosis; mycosis fungoides; transformation; primary cutaneous CD30-positive T-cell lymphoproliferative; disorder ID REED-STERNBERG CELLS; MYCOSIS-FUNGOIDES; GENE REARRANGEMENTS; MOLECULAR EVIDENCE; ACTIVATOR PROTEIN; DISEASE; PAPULOSIS; EXPRESSION; FEATURES; ORIGIN AB An association between classical Hodgkin lymphoma (cHL) and mycosis fungoides (MF) or lymphomatoid papulosis has been reported in the literature. However, there can be considerable morphologic and immunophenotypic overlap between cHL and nodal involvement by CD30-positive T-cell lymphoproliferative disorders (CD30-T-LPD). To examine this potential association, biopsies from patients with a history of MF or primary cutaneous CD30-T-LPD and lymph node biopsies reported as either CD30-positive T-cell lymphoma (TCL) with Hodgkin-like cells or cHL were retrieved from the authors' institution. Of 11 cases identified, 10 were considered CD30-positive TCL with Hodgkin-like cells, whereas 1 was confirmed as cHL upon review. Five cases originally diagnosed as cHL were revised as CD30-positive TCL. Cases of CD30-positive TCL with Hodgkin-like cells showed a male predominance (M:F, 4:1) with a median age of 53 years (range, 44 to 72 y). Nearly all patients (9/10) initially presented with skin lesions. In 7/10 patients the draining lymph node was involved, whereas in 3 cases this could not be confirmed. Tumor cells morphologically resembled Hodgkin/Reed-Sternberg cells; they were uniformly strongly positive for CD30, and CD15 was expressed in 9/10 (90%) cases. A T-cell derivation was confirmed by T-cell antigen expression (7/10) and clonal rearrangement of T-cell receptor genes (9/10). In 3 cases a common T-cell clone was identified in skin and lymph node. B-cell markers (CD20/PAX5) were consistently negative. In 1 case the diagnosis of cHL followed by lymphomatoid papulosis was confirmed, with Hodgkin/Reed-Sternberg cells expressing PAX5, CD30, and CD15. In situ hybridization studies for Epstein Barr virus were negative. We show that cHL is less often associated with MF and primary cutaneous CD30-T-LPD than previously thought and that the coexpression of CD30 and CD15 in these TCLs may lead to a mistaken diagnosis of cHL. C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Harris, Nancy Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov RI Song, Joo/E-5356-2016; OI Song, Joo/0000-0003-3497-2513; Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute, NIH FX Supported by funding from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 28 TC 16 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAY PY 2012 VL 36 IS 5 BP 716 EP 725 DI 10.1097/PAS.0b013e3182487158 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 926EL UT WOS:000302814000009 PM 22367293 ER PT J AU Cui, L Wang, ZL Jiang, HY Parker, D Wang, HY Su, XZ Cui, LW AF Cui, Long Wang, Zenglei Jiang, Hongying Parker, Daniel Wang, Haiyan Su, Xin-Zhuan Cui, Liwang TI Lack of Association of the S769N Mutation in Plasmodium falciparum SERCA (PfATP6) with Resistance to Artemisinins SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IN-VITRO SENSITIVITY; MALARIA PARASITES; THALASSEMIC ERYTHROCYTES; COMBINATION THERAPIES; NA+/H+ EXCHANGER; DRUG-RESISTANCE; POINT MUTATIONS; MYANMAR BORDER; GENE; BINDING AB The recent emergence of artemisinin (ART) resistance in Plasmodium falciparum in western Cambodia, manifested as delayed parasite clearance, is a big threat to the long-term efficacy of this family of antimalarial drugs. Among the multiple candidate genes associated with ART resistance in P. falciparum, the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase PfATP6 has been postulated as a specific target of ARTs. The PfATP6 gene harbors multiple single-nucleotide polymorphisms in field parasite populations, and S769N has been associated with decreased sensitivity to artemether in parasite populations from French Guiana. In this study, we used an allelic exchange strategy to engineer parasite lines carrying the S769N mutations in P. falciparum strain 3D7 and evaluated whether introduction of this mutation modulated parasite sensitivity to ART derivatives. Using three transgenic lines carrying the 769N mutation and two transgenic lines carrying the wild-type 769S as controls, we found that S769N did not affect PfATP6 gene expression. We compared the sensitivities of these parasite lines to three ART derivatives, artemether, artesunate, and dihydroartemisinin, in 18 biological experiments and detected no significant effect of the S769N mutation on parasite response to these ART derivatives. This study provides further evidence for the lack of association of PfATP6 with ART resistance. C1 [Cui, Long; Wang, Zenglei; Parker, Daniel; Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Jiang, Hongying; Su, Xin-Zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Wang, Haiyan] Kansas State Univ, Dept Stat, Manhattan, KS 66506 USA. RP Cui, LW (reprint author), Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. EM luc2@psu.edu RI Parker, Daniel/B-5471-2013; OI Parker, Daniel/0000-0002-5352-7338; Su, Xinzhuan/0000-0003-3246-3248 FU NIAID, NIH [1R21AI085518, U19AI089672]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by NIAID, NIH (1R21AI085518 and U19AI089672) and by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 64 TC 18 Z9 20 U1 0 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2012 VL 56 IS 5 BP 2546 EP 2552 DI 10.1128/AAC.05943-11 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 925VQ UT WOS:000302790400046 PM 22354307 ER PT J AU Vanpouille, C Lisco, A Introini, A Grivel, JC Munawwar, A Merbah, M Schinazi, RF Derudas, M McGuigan, C Balzarini, J Margolis, L AF Vanpouille, Christophe Lisco, Andrea Introini, Andrea Grivel, Jean-Charles Munawwar, Arshi Merbah, Melanie Schinazi, Raymond F. Derudas, Marco McGuigan, Christopher Balzarini, Jan Margolis, Leonid TI Exploiting the Anti-HIV-1 Activity of Acyclovir: Suppression of Primary and Drug-Resistant HIV Isolates and Potentiation of the Activity by Ribavirin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HERPES-SIMPLEX-VIRUS; REVERSE-TRANSCRIPTASE INHIBITOR; DUALLY INFECTED PERSONS; HSV SUPPRESSION; HEPATITIS-C; RNA LEVELS; IN-VIVO; THERAPY; VALACYCLOVIR AB Multiple clinical trials have demonstrated that herpes simplex virus 2 (HSV-2) suppressive therapy using acyclovir (ACV) or valacyclovir in HIV-1/HSV-2-infected persons increased the patient's survival and decreased the HIV-1 load. It has been shown that the incorporation of ACV-monophosphate into the nascent DNA chain instead of dGMP results in the termination of viral DNA elongation and directly inhibits laboratory strains of HIV-1. We evaluated here the anti-HIV activity of ACV against primary HIV-1 isolates of different clades and coreceptor specificity and against viral isolates resistant to currently used drugs, including zidovudine, lamivudine, nevirapine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs), a fusion inhibitor, and two protease inhibitors. We found that, at clinically relevant concentrations, ACV inhibits the replication of these isolates in human tissues infected ex vivo. Moreover, addition of ribavirin, an antiviral capable of depleting the pool of intracellular dGTP, potentiated the ACV-mediated HIV-1 suppression. These data warrant further clinical investigations of the benefits of using inexpensive and safe ACV alone or in combination with other drugs against HIV-1, especially to complement or delay highly active antiretroviral therapy (HAART) initiation in low-resource settings. C1 [Vanpouille, Christophe; Lisco, Andrea; Introini, Andrea; Grivel, Jean-Charles; Merbah, Melanie; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Munawwar, Arshi] All India Inst Med Sci, Dept Lab Med, Div Clin Microbiol, New Delhi, India. [Schinazi, Raymond F.] Emory Univ, Sch Med, Vet Affairs Med Ctr, Ctr AIDS Res,Dept Pediat, Decatur, GA 30033 USA. [Derudas, Marco; McGuigan, Christopher] Cardiff Univ, Sch Pharm, Cardiff, S Glam, Wales. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. RP Margolis, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM margolis@helix.nih.gov RI McGuigan, Chris/P-1580-2014; Schinazi, Raymond/B-6777-2017; OI McGuigan, Chris/0000-0001-8409-710X; Introini, Andrea/0000-0002-9929-8964 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; KU Leuven (GOA) [10/14]; NIH [5P30-AI-50409]; Department of Veterans Affairs 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, and the KU Leuven (GOA no. 10/14). Also, this work was supported in part by NIH grant 5P30-AI-50409 (R. F. S.) and by the Department of Veterans Affairs (R.F.S.). NR 45 TC 6 Z9 7 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2012 VL 56 IS 5 BP 2604 EP 2611 DI 10.1128/AAC.05986-11 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 925VQ UT WOS:000302790400055 PM 22314523 ER PT J AU Schlett, CL Ferencik, M Kriegel, MF Bamberg, F Ghoshhajra, BB Joshi, SB Nagurney, JT Fox, CS Truong, QA Hoffmann, U AF Schlett, Christopher L. Ferencik, Maros Kriegel, Matthias F. Bamberg, Fabian Ghoshhajra, Brian B. Joshi, Subodh B. Nagurney, John T. Fox, Caroline S. Truong, Quynh A. Hoffmann, Udo TI Association of pericardial fat and coronary high-risk lesions as determined by cardiac CT SO ATHEROSCLEROSIS LA English DT Article DE Coronary artery disease; Cardiac CT angiography; Peri-cardial fat; Adipose tissue; Vulnerable plaque; High-risk lesions ID EPICARDIAL ADIPOSE-TISSUE; MULTIDETECTOR COMPUTED-TOMOGRAPHY; VISCERAL ABDOMINAL FAT; ACUTE CHEST-PAIN; ARTERY-DISEASE; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; NONINVASIVE ASSESSMENT; ANGIOGRAPHY; CALCIFICATION AB Objective: Pericardial adipose tissue (PAT) is a pathogenic fat depot associated with coronary atherosclerosis and cardiovascular events. We hypothesized that higher PAT is associated with coronary high-risk lesions as determined by cardiac CT. Methods: We included 358 patients (38% female; median age 51 years) who were admitted to the ED with acute chest pain and underwent 64-slice CT angiography. The cardiac CT data sets were assessed for presence and morphology of CAD and PAT. Coronary high-risk lesions were defined as >50% luminal narrowing and at least two of the following characteristics: positive remodeling, low-density plaque, and spotty calcification. PAT was defined as any pixel with CT attenuation of -190 to -30 HU within the pericardial sac. Results: Based on cardiac CT, 50% of the patients (n = 180) had no CAD, 46% (n = 165) had CAD without high-risk lesions, and 13 patients had CAD with high-risk lesions. The median PAT in patients with high-risk lesions was significantly higher compared to patients without high-risk lesions and without any CAD (151.9 [109.0-179.4] cm(3) vs. 110.0 [81.5-137.4] cm(3), vs. 74.8 [58.2-111.7] cm(3), respectively p = 0.04 and p < 0.0001). These differences remained significant after adjusting for traditional risk factors including BMI (all p < 0.05). The area under the ROC curve for the identification of high-risk lesions was 0.756 in a logistic regression model with PAT as a continuous predictor. Conclusion: PAT volume is nearly twice as high in patients with high-risk coronary lesions as compared to those without CAD. PAT volume is significantly associated with high risk coronary lesion morphology independent of clinical characteristics and general obesity. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Schlett, Christopher L.; Ghoshhajra, Brian B.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Ferencik, Maros; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Schlett, Christopher L.; Ferencik, Maros; Kriegel, Matthias F.; Ghoshhajra, Brian B.; Joshi, Subodh B.; Nagurney, John T.; Fox, Caroline S.; Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bamberg, Fabian] Univ Munich, Klinikum Grosshadern, Dept Clin Radiol, D-81377 Munich, Germany. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM uhoffmann@partners.org RI 王, 强/F-4212-2011 FU NHLBI NIH HHS [L30 HL093806, K23 HL098370] NR 42 TC 25 Z9 25 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 2012 VL 222 IS 1 BP 129 EP 134 DI 10.1016/j.atherosclerosis.2012.02.029 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 928DJ UT WOS:000302960600020 PM 22417843 ER PT J AU Wassel, CL Lamina, C Nambi, V Coassin, S Mukamal, KJ Ganesh, SK Jacobs, DR Franceschini, N Papanicolaou, GJ Gibson, Q Yanek, LR van der Harst, P Ferguson, JF Crawford, DC Waite, LL Allison, MA Criqui, MH McDermott, MM Mehra, R Cupples, LA Hwang, SJ Redline, S Kaplan, RC Heiss, G Rotter, JI Boerwinkle, E Taylor, HA Eraso, LH Haun, M Li, MY Meisinger, C O'Connell, JR Shuldineri, AR Tybjaerg-Hansen, A Frikke-Schmidt, R Kollerits, B Rantner, B Dieplinger, B Stadler, M Mueller, T Haltmayer, M Klein-Weigel, P Summerer, M Wichmann, HE Asselbergs, FW Navis, G Leach, IM Brown-Gentry, K Goodloe, R Assimes, TL Becker, DM Cooke, JP Absher, DM Olin, JW Mitchell, BD Reilly, MP Mohler, ER North, KE Reiner, AP Kronenberg, F Murabito, JM AF Wassel, Christina L. Lamina, Claudia Nambi, Vijay Coassin, Stefan Mukamal, Kenneth J. Ganesh, Santhi K. Jacobs, David R., Jr. Franceschini, Nora Papanicolaou, George J. Gibson, Quince Yanek, Lisa R. van der Harst, Pim Ferguson, Jane F. Crawford, Dana C. Waite, Lindsay L. Allison, Matthew A. Criqui, Michael H. McDermott, Mary M. Mehra, Reena Cupples, L. Adrienne Hwang, Shih-Jen Redline, Susan Kaplan, Robert C. Heiss, Gerardo Rotter, Jerome I. Boerwinkle, Eric Taylor, Herman A. Eraso, Luis H. Haun, Margot Li, Mingyao Meisinger, Christa O'Connell, Jeffrey R. Shuldineri, Alan R. Tybjaerg-Hansen, Anne Frikke-Schmidt, Ruth Kollerits, Barbara Rantner, Barbara Dieplinger, Benjamin Stadler, Marietta Mueller, Thomas Haltmayer, Meinhard Klein-Weigel, Peter Summerer, Monika Wichmann, H. -Erich Asselbergs, Folkert W. Navis, Gerjan Leach, Irene Mateo Brown-Gentry, Kristin Goodloe, Robert Assimes, Themistocles L. Becker, Diane M. Cooke, John P. Absher, Devin M. Olin, Jeffrey W. Mitchell, Braxton D. Reilly, Muredach P. Mohler, Emile R., III North, Kari E. Reiner, Alexander P. Kronenberg, Florian Murabito, Joanne M. TI Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium SO ATHEROSCLEROSIS LA English DT Article DE Ankle brachial index; Peripheral artery disease; Genetics; Candidate gene array; Meta-analysis; Ethnicity ID PERIPHERAL ARTERIAL-DISEASE; GENOME-WIDE ASSOCIATION; RISK LOCI; APOLIPOPROTEIN(A) ISOFORMS; INSULIN-RESPONSE; FAMILY-HISTORY; SUSCEPTIBILITY; LIPOPROTEIN(A); POPULATION; ATHEROTHROMBOSIS AB Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of similar to 50,000 SNPs across similar to 2100 candidate genes to identify genetic variants for ABI. Methods and results: We studied subjects of European ancestry from 8 studies (n = 21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n = 7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI > 1.40) and PAD (defined as ABI < 0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p < 2 x 10(-6) to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (beta = -0.007, p = 6.02 x 10(-7)) and rs290481 in TCF7L2 (beta = -0.008, p = 7.01 x 10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 x 10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n = 15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p = 0.75; rs290481, p = 0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p = 1.14 x 10(-3); rs290481, p = 8.88 x 10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Wassel, Christina L.; Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, La Jolla, CA 92093 USA. [Lamina, Claudia; Coassin, Stefan; Haun, Margot; Kollerits, Barbara; Rantner, Barbara; Summerer, Monika; Kronenberg, Florian] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria. [Nambi, Vijay] Baylor Coll Med, Dept Med, Cardiol Sect, Houston, TX 77030 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Ganesh, Santhi K.] Univ Michigan Hlth Care Syst, Deparment Internal Med, Div Cardiovasc Med, Ann Arbor, MI USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Franceschini, Nora; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Gillings Global Sch Publ Hlth, Chapel Hill, NC USA. [Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Gibson, Quince; O'Connell, Jeffrey R.; Shuldineri, Alan R.; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol, Baltimore, MD 21201 USA. [Yanek, Lisa R.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [van der Harst, Pim; Leach, Irene Mateo] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Ferguson, Jane F.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Waite, Lindsay L.; Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Mehra, Reena] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hwang, Shih-Jen] NHLBI, Framingham Heart Study, Ctr Populat Study, Framingham, MA USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep Med, Boston, MA 02115 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS USA. [Eraso, Luis H.] Thomas Jefferson Univ Hosp, Jefferson Vasc Ctr, Philadelphia, PA 19107 USA. [Li, Mingyao] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Shuldineri, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Tybjaerg-Hansen, Anne; Frikke-Schmidt, Ruth] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Rantner, Barbara] Innsbruck Med Univ, Dept Vasc Surg, Innsbruck, Austria. [Dieplinger, Benjamin; Mueller, Thomas; Haltmayer, Meinhard] Konventhosp Barmherzige Brueder Linz, Dept Lab Med, Linz, Austria. [Stadler, Marietta] Hietzing Hosp, Med Dept Metab Dis & Nephrol 3, Vienna, Austria. [Klein-Weigel, Peter] DRK Kliniken Berlin Mitte, Klin Innere Med Schwerpunkt Angiol, Berlin, Germany. [Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Assimes, Themistocles L.; Cooke, John P.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Olin, Jeffrey W.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Olin, Jeffrey W.] Mt Sinai Sch Med, Marie Joseie & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. [Mohler, Emile R., III] Univ Penn, Div Cardiol, Vasc Med Sect, Perelman Sch Med, Philadelphia, PA 19104 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Wichmann, H. -Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Boston, MA USA. RP Murabito, JM (reprint author), 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM Murabito@bu.edu RI Ferguson, Jane/C-7154-2011; Crawford, Dana/C-1054-2012; Meisinger, Christine/B-5358-2014; Kronenberg, Florian/B-1736-2008; OI Mitchell, Braxton/0000-0003-4920-4744; Cooke, John/0000-0003-0033-9138; Meisinger, Christa/0000-0002-9026-6544; Allison, Matthew/0000-0003-0777-8272; Ferguson, Jane/0000-0001-6896-1025; Kronenberg, Florian/0000-0003-2229-1120; Eraso, Luis/0000-0002-7890-4902; Murabito, Joanne/0000-0002-0192-7516; Cupples, L. Adrienne/0000-0003-0273-7965; Mehra, Reena/0000-0002-6222-2675 FU National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI) [HHSN268200625226C, 5215810-55000000041] FX The Candidate Gene Association Resource (CARe) is supported by contract number HHSN268200625226C from the National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI), and subcontract number 5215810-55000000041 to C.L.W. A full listing of the grants and contracts that have supported CARe is provided at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx. Please see information in supplementary information file for a complete list of funding information for each study participating in this manuscript. NR 38 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 2012 VL 222 IS 1 BP 138 EP 147 DI 10.1016/j.atherosclerosis.2012.01.039 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 928DJ UT WOS:000302960600022 PM 22361517 ER PT J AU Sengupta, P Lippincott-Schwartz, J AF Sengupta, Prabuddha Lippincott-Schwartz, Jennifer TI Quantitative analysis of photoactivated localization microscopy (PALM) datasets using pair-correlation analysis SO BIOESSAYS LA English DT Article DE pair-correlation; PALM; quantitative analysis; super-resolution ID DRIVEN INTRAMOLECULAR DYNAMICS; GENETICALLY EXPRESSED PROBES; FLUORESCENT PROTEIN; DIFFRACTION-LIMIT; CELL-MEMBRANES; RESOLUTION; MOLECULES; TRACKING; NANOSCOPY; GFP AB Pointillistic based super-resolution techniques, such as photoactivated localization microscopy (PALM), involve multiple cycles of sequential activation, imaging, and precise localization of single fluorescent molecules. A super-resolution image, having nanoscopic structural information, is then constructed by compiling all the image sequences. Because the final image resolution is determined by the localization precision of detected single molecules and their density, accurate image reconstruction requires imaging of biological structures labeled with fluorescent molecules at high density. In such image datasets, stochastic variations in photon emission and intervening dark states lead to uncertainties in identification of single molecules. This, in turn, prevents the proper utilization of the wealth of information on molecular distribution and quantity. A recent strategy for overcoming this problem is pair-correlation analysis applied to PALM. Using rigorous statistical algorithms to estimate the number of detected proteins, this approach allows the spatial organization of molecules to be quantitatively described. C1 [Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MA USA. RP Sengupta, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MA USA. EM senguptp@mail.nih.gov OI Sengupta, Prabuddha/0000-0001-7094-6967 FU Intramural NIH HHS [Z01 HD008850-01] NR 54 TC 31 Z9 31 U1 2 U2 27 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD MAY PY 2012 VL 34 IS 5 SI SI BP 396 EP 405 DI 10.1002/bies.201200022 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 927GS UT WOS:000302895900012 PM 22447653 ER PT J AU Nandurdikar, RS Maciag, AE Holland, RJ Cao, Z Shami, PJ Anderson, LM Keefer, LK Saavedra, JE AF Nandurdikar, Rahul S. Maciag, Anna E. Holland, Ryan J. Cao, Zhao Shami, Paul J. Anderson, Lucy M. Keefer, Larry K. Saavedra, Joseph E. TI Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Nitric oxide; Diazeniumdiolate prodrugs; JS-K; Glutathione; Anti-cancer agents ID JS-K; IN-VITRO; VIVO; CELLS AB JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo anti-tumor activity. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Nandurdikar, Rahul S.; Holland, Ryan J.; Anderson, Lucy M.; Keefer, Larry K.] NCI, Drug Design Sect, Biol Chem Lab, Frederick, MD 21702 USA. [Maciag, Anna E.; Cao, Zhao; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Shami, Paul J.] Univ Utah, Div Hematol & Hematol Malignancies, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Nandurdikar, RS (reprint author), NCI, Drug Design Sect, Biol Chem Lab, Frederick, MD 21702 USA. EM nandurdikarr@mail.nih.gov; saavedjo@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. Sergey Tarasov and Ms. Marzena A. Dyba of the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick, for assistance with the high resolution mass spectrometry studies. We thank Mr. Ken Kosak of the University of Utah for providing the Pluronics P123 formulation. NR 7 TC 8 Z9 8 U1 1 U2 8 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 MAY 1 PY 2012 VL 20 IS 9 BP 3094 EP 3099 DI 10.1016/j.bmc.2012.02.045 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 928RW UT WOS:000303002100036 PM 22480849 ER PT J AU Lovell, KM Vasiljevik, T Araya, JJ Lozama, A Prevatt-Smith, KM Day, VW Dersch, CM Rothman, RB Butelman, ER Kreek, MJ Prisinzano, TE AF Lovell, Kimberly M. Vasiljevik, Tamara Araya, Juan J. Lozama, Anthony Prevatt-Smith, Katherine M. Day, Victor W. Dersch, Christina M. Rothman, Richard B. Butelman, Eduardo R. Kreek, Mary Jeanne Prisinzano, Thomas E. TI Semisynthetic neoclerodanes as kappa opioid receptor probes SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Natural product; Salvinorin A; Salvia divinorum; Kappa opioid receptor; Hallucinogen; Furan ID SALVINORIN-A; SALVIA-DIVINORUM; NATURAL-PRODUCTS; RHESUS-MONKEYS; LIGANDS; AGONIST; ANTAGONISTS; DITERPENES; COCAINE; TRANSFORMATIONS AB Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Lovell, Kimberly M.; Vasiljevik, Tamara; Araya, Juan J.; Prevatt-Smith, Katherine M.; Day, Victor W.; Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. [Lozama, Anthony] Univ Iowa, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, IRP, DHHS, Baltimore, MD 21224 USA. [Butelman, Eduardo R.; Kreek, Mary Jeanne] Rockefeller Univ, Lab Biol Addict Dis, New York, NY USA. RP Prisinzano, TE (reprint author), Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. EM prisinza@ku.edu FU National Institute on Drug Abuse [DA018151, DA05130, DA011113]; NIH [GM008545]; National Science Foundation [CHE-0923449]; University of Kansas; National Institute on Drug Abuse, NIH, DHHS FX The authors thank the National Institute on Drug Abuse (DA018151 to TEP, DA05130 to MJK, and DA011113 to ERB) and the NIH Dynamic Aspects of Chemical Biology training grant (GM008545 to KML and KPS) for financial support of ongoing research, and the National Science Foundation (CHE-0923449) and the University of Kansas for funds to purchase the x-ray instrumentation and computers. Portions of this work were supported by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation. The authors also thank Dr. Alfredo Ortega and Elihu Bautista for the pictures of Salvia sp. NR 51 TC 14 Z9 14 U1 0 U2 28 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 MAY 1 PY 2012 VL 20 IS 9 BP 3100 EP 3110 DI 10.1016/j.bmc.2012.02.040 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 928RW UT WOS:000303002100037 PM 22464684 ER PT J AU Tadmor, T Liphshitz, I Aviv, A Landgren, O Barchana, M Polliack, A AF Tadmor, Tamar Liphshitz, Irena Aviv, Ariel Landgren, Ola Barchana, Micha Polliack, Aaron TI Increased incidence of chronic lymphocytic leukaemia and lymphomas in patients with Merkel cell carcinoma - a population based study of 335 cases with neuroendocrine skin tumour SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Merkel cell carcinoma; haematological neoplasias; chronic; small cell lymphocytic leukaemia (CLL; CLL); lymphomas; malignancies ID POLYOMAVIRUS; CANCERS; RITUXIMAB AB Merkel cell carcinoma (MCC) is a rare aggressive skin tumour that appears to be associated with a large number of other tumours. We collected all reported cases in Israel and estimated its association with other tumours, including haematological malignancies. The population based Israel Cancer Registry identified 335 patients with MCC diagnosed between1989 and 2010. Ninety-seven percent were in the Jewish population; median age at diagnosis for Jewish patients was 73.4 and 55.6 years for the Arab population. Other associated malignancies were encountered in 92 patients (27.4%) with MCC (90 Jews, two Arabs). Of the Jewish cases, 66 presented with an associated malignancy before, and 24 after, the diagnosis of MCC. Solid tumours were not significantly increased among patients with MCC. Thirty-one of these associated cancers (34.4%) were haemato-oncological malignancies, 24 were detected before and seven after the diagnosis of MCC. The standardized incidence ratio (SIR) for haematological malignancy was 3.67 for males and 3.62 for females, and the most frequent haemato-oncological neoplasias recorded were chronic lymphocytic leukaemia (45%) and lymphomas (29%). Although MCC is rare, clinicians should be aware of the possible association with B-cell lymphoproliferative disorders when evaluating patients with neuroendocrine skin tumours. C1 [Tadmor, Tamar] Bnai Zion Med Ctr, Oncol Unit, IL-31048 Haifa, Israel. [Liphshitz, Irena] Minist Hlth, Natl Canc Registry, Jerusalem, Israel. [Aviv, Ariel] Emek Med Ctr, Oncol Unit, Afula, Israel. [Landgren, Ola] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Barchana, Micha] Univ Haifa, Sch Publ Hlth, IL-31999 Haifa, Israel. [Polliack, Aaron] Hadassah Univ Hosp, Dept Haematol, IL-91120 Jerusalem, Israel. [Polliack, Aaron] Hebrew Univ Jerusalem, Sch Med, IL-91010 Jerusalem, Israel. RP Tadmor, T (reprint author), Bnai Zion Med Ctr, Oncol Unit, 47 Golomb St, IL-31048 Haifa, Israel. EM tamar.tadmor@b-zion.org.il NR 24 TC 11 Z9 11 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2012 VL 157 IS 4 BP 457 EP 462 DI 10.1111/j.1365-2141.2012.09087.x PG 6 WC Hematology SC Hematology GA 927UF UT WOS:000302934900007 PM 22390778 ER PT J AU Rizzo, LV Vallochi, AL Belfort, R Holland, GN Nussenblatt, RB AF Rizzo, Luiz Vicente Vallochi, Adriana Lima Belfort, Rubens Holland, Gary N. Nussenblatt, Robert B. TI Toxoplasma gondii in the peripheral blood of patients with ocular toxoplasmosis response SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Letter C1 [Rizzo, Luiz Vicente] Hosp Israelita Albert Einstein, Sao Paulo, Brazil. [Vallochi, Adriana Lima] Inst Oswaldo Cruz, BR-20001 Rio De Janeiro, Brazil. [Belfort, Rubens] Univ Fed Sao Paulo, Escola Paulista Med, Dept Ophthalmol, Sao Paulo, Brazil. [Holland, Gary N.] Univ Calif Los Angeles, Jules Stein Eye Inst, Ocular Inflammatory Dis Ctr, Los Angeles, CA 90024 USA. [Holland, Gary N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Rizzo, LV (reprint author), Av Albert Einstein 627-701, BR-05652000 Morumbi Sao Paulo, SP, Brazil. EM lvrizzo@einstein.br RI Rizzo, Luiz Vicente/B-4458-2009; Belfort Jr, Rubens/E-2252-2012 OI Belfort Jr, Rubens/0000-0002-8422-3898 NR 1 TC 0 Z9 0 U1 0 U2 3 PU B M J 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 MAY PY 2012 VL 96 IS 5 BP 766 EP 766 DI 10.1136/bjophthalmol-2011-301237 PG 1 WC Ophthalmology SC Ophthalmology GA 927UX UT WOS:000302936900034 ER PT J AU Ling, NXY Lee, J Ellis, M Liao, ML Mau, SL Guest, D Janssen, PH Kovac, P Bacic, A Pettolino, FA AF Ling, Naomi X. -Y. Lee, Joanne Ellis, Miriam Liao, Ming-Long Mau, Shaio-Lim Guest, David Janssen, Peter H. Kovac, Pavol Bacic, Antony Pettolino, Filomena A. TI An exo-beta-(1 -> 3)-D-galactanase from Streptomyces sp provides insights into type II arabinogalactan structure SO CARBOHYDRATE RESEARCH LA English DT Article DE beta-D-Galactanases; Arabinogalactan-protein; Streptomyces sp.; De-arabinosylated gum arabic; CAZy family GH 43 ID GUM-ARABIC GLYCOPROTEIN; METHYL BETA-GLYCOSIDES; O-GLYCOSYLATION CODES; RAPHANUS-SATIVUS L; MOLECULAR CHARACTERIZATION; TRICHODERMA-VIRIDE; BLOCKWISE APPROACH; ASPERGILLUS-NIGER; ACACIA-SENEGAL; PROTEINS AB An exo-beta-(1 -> 3)-D-galactanase (SGalase1) that specifically cleaves the beta-(1 -> 3)-D-galactan backbone of arabinogalactan-proteins (AGPs) was isolated from culture filtrates of a soil Streptomyces sp. Internal peptide sequence information was used to clone and recombinantly express the gene in E. coli. The molecular mass of the isolated enzyme was similar to 45 kDa, similar to the 48.2 kDa mass predicted from the amino acid sequence. The pI, pH and temperature optima for the enzyme were similar to 7.45, 3.8 and 48 degrees C, respectively. The native and recombinant enzymes specifically hydrolysed beta-(1 -> 3)-D-galacto-oligo-or poly-saccharides from the upstream (non-reducing) end, typical of an exo-acting enzyme. A second homologous Streptomyces gene (SGalase2) was also cloned and expressed. SGalase2 was similar in size (47.9 kDa) and enzyme activity to SGalase1 but differed in its pH optimum (pH 5). Both SGalase1 and SGalase2 are predicted to belong to the CAZy glycosyl hydrolase family GH 43 based on activity, sequence homology and phylogenetic analysis. The K-m and V-max of the native exo-beta-(1 -> 3)-D-galactanase for de-arabinosylated gum arabic (dGA) were 19 mg/ml and 9.7 mu mol D-Gal/ min/mg protein, respectively. The activity of these enzymes is well suited for the study of type II galactan structures and provides an important tool for the investigation of the biological role of AGPs in plants. De-arabinosylated gum arabic (dGA) was used as a model to investigate the use of these enzymes in defining type II galactan structure. Exhaustive hydrolysis of dGA resulted in a limited number of oligosaccharide products with a trisaccharide of Gal(2)GlcA(1) predominating. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Ling, Naomi X. -Y.; Lee, Joanne; Ellis, Miriam; Liao, Ming-Long; Mau, Shaio-Lim; Bacic, Antony; Pettolino, Filomena A.] Univ Melbourne, Plant Cell Biol Res Ctr, Sch Bot, Melbourne, Vic 3010, Australia. [Bacic, Antony] Univ Melbourne, ARC Ctr Excellence Plant Cell Walls, Sch Bot, Melbourne, Vic 3010, Australia. [Guest, David] Univ Sydney, Fac Agr Food & Nat Resources, Eveleigh, NSW 2015, Australia. [Janssen, Peter H.] AgResearch Ltd, Grasslands Res Ctr, Palmerston North 4442, New Zealand. [Kovac, Pavol] Inst Diabet & Digest & Kidney Dis NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Pettolino, FA (reprint author), CSIRO Plant Ind, Black Mt Labs, Canberra, ACT 2601, Australia. EM Filomena.Pettolino@csiro.au RI Pettolino, Filomena/I-1493-2012; Guest, David/A-9481-2011; OI Guest, David/0000-0002-4138-5635; Lee, Joanne/0000-0003-0333-3524 FU Co-operative Research Centre (CRC) for Bioproducts; Melbourne International Research Scholarship (MIRS) FX Microbial isolation work for the source of enzyme was carried out by Kathryn Davis (Department of Microbiology and Immunology, University of Melbourne). All sample-derived tryptic peptide analyses were run by Dr. Siria Natera, and the MS and MS/MS data were interpreted and de novo sequenced by Ms. Kristina Ford and Dr. Siria Natera (School of Botany, The University of Melbourne). This project was supported by funds from the Co-operative Research Centre (CRC) for Bioproducts and Melbourne International Research Scholarship (MIRS). NR 69 TC 9 Z9 9 U1 1 U2 19 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD MAY 1 PY 2012 VL 352 BP 70 EP 81 DI 10.1016/j.carres.2012.02.033 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 925RF UT WOS:000302778000009 PM 22464224 ER PT J AU Solier, S Zhang, YW Ballestrero, A Pommier, Y Zoppoli, G AF Solier, S. Zhang, Y. -W. Ballestrero, A. Pommier, Y. Zoppoli, G. TI DNA Damage Response Pathways and Cell Cycle Checkpoints in Colorectal Cancer: Current Concepts and Future Perspectives for Targeted Treatment SO CURRENT CANCER DRUG TARGETS LA English DT Review DE Colorectal cancer; Chk2; cell cycle; DNA damage response; irinotecan; oxaliplatin ID GROWTH-FACTOR RECEPTOR; PEUTZ-JEGHERS-SYNDROME; PLATINUM-BASED CHEMOTHERAPY; TOPOISOMERASE-I INHIBITORS; CHEK2 1100DELC MUTATION; ANTICANCER DRUG SCREEN; HUMAN COLON-CANCER; POLY(ADP-RIBOSE) POLYMERASE; MITOTIC CHECKPOINT; LUNG-CANCER AB Although several drugs have been designed in the last few years to target specific key pathways and functions in colorectal cancer (CRC), the backbone of CRC treatment is still made up of compounds which rely on DNA damage to accomplish their role. DNA damage response (DDR) and checkpoint pathways are intertwined signaling networks that arrest cell cycle, recognize and repair genetic mistakes which arise during DNA replication and transcription, as well as through the exposure to chemical and physical agents that interact with nucleic acids. The good but highly variable activity of DNA damaging agents in the treatment of CRC suggests that intrinsic alterations in DDR pathways and cell cycle checkpoints may contribute differentially to the way cancer cells react to DNA damage. In the present review, our aim is to depict the recent advances in understanding the molecular basis of the activity of DNA damaging agents used for the treatment of CRC. We focus on the known and potential drug targets that are part of these complex and intertwined pathways. We describe the potential role of the checkpoints in CRC, and how their pharmacological manipulation could lead to chemopotentiation or synergism with currently used drugs. Novel therapeutic agents playing a role in DDR and checkpoint inhibition are assessed. We discuss the possible rationale for combining PARP inhibition with DNA damaging agents, and we address the link between DDR and EGFR pathways in CRC. C1 [Solier, S.; Zhang, Y. -W.; Pommier, Y.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ballestrero, A.; Zoppoli, G.] Univ Genoa, Dept Internal Med DiMI, Genoa, Italy. RP Zoppoli, G (reprint author), Avancorpo II Piano DiMI, Room 223,Vle Benedetto XV 6, I-16132 Genoa, Italy. EM gabriele.zoppoli@unige.it RI ZHANG, YONGWEI/E-6252-2012; Zoppoli, Gabriele/B-6935-2016 OI Zoppoli, Gabriele/0000-0003-3890-5588 FU AIRC [10570] FX This work was in part supported by an AIRC "My First AIRC Grant", ID No. 10570. NR 196 TC 10 Z9 12 U1 2 U2 17 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD MAY PY 2012 VL 12 IS 4 BP 356 EP 371 PG 16 WC Oncology SC Oncology GA 927ZZ UT WOS:000302950600006 PM 22385513 ER PT J AU Andersen, JB Thorgeirsson, SS AF Andersen, Jesper B. Thorgeirsson, Snorri S. TI Genetic profiling of intrahepatic cholangiocarcinoma SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE cholangiocarcinoma; extrahepatic cholangiocarcinoma; intrahepatic cholangiocarcinoma ID COMPARATIVE GENOMIC HYBRIDIZATION; PRIMARY SCLEROSING CHOLANGITIS; MALIGNANT HUMAN CHOLANGIOCYTES; POTENTIAL THERAPEUTIC TARGETS; CPG-ISLAND METHYLATION; GROWTH-FACTOR RECEPTOR; TUMOR-SUPPRESSOR GENE; K-RAS MUTATIONS; BILIARY-TRACT; EPIGENETIC ALTERATIONS AB Purpose of review Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. Recent findings In comparison with other cancers, genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study, samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. Summary We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single-gene studies will also be discussed. C1 [Andersen, Jesper B.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, CCR, NIH, Bldg 37,Room 4146A,37 Convent Dr, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244 FU Center for Cancer Research, NCI, NIH FX No potential conflict of interest related to this study was reported. The study was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 65 TC 39 Z9 41 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD MAY PY 2012 VL 28 IS 3 BP 266 EP 272 DI 10.1097/MOG.0b013e3283523c7e PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 927YE UT WOS:000302945700014 PM 22395571 ER PT J AU Metenou, S Babu, S Nutman, TB AF Metenou, Simon Babu, Subash Nutman, Thomas B. TI Impact of filarial infections on coincident intracellular pathogens: Mycobacterium tuberculosis and Plasmodium falciparum SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE filarial infections; immunomodulation; malaria; tuberculosis ID PATENT LYMPHATIC FILARIASIS; PARASITE-SPECIFIC ANERGY; T-CELLS; IMMUNE-RESPONSES; BANCROFTIAN FILARIASIS; DENDRITIC CELLS; ANTIGEN PRESENTATION; STAGE MALARIA; IMMUNOLOGICAL RESPONSIVENESS; WUCHERERIA-BANCROFTI AB Purpose of review To examine the consequences of the immune modulation seen in chronic filarial infection on responses to intracellular pathogens (and their antigens) that are often co-endemic with filarial infections, namely Plasmodium and Mycobacterium tuberculosis. Recent findings Much of the recent data on filaria/mycobacteria or filaria/Plasmodium co-infection has focused on the modulation of mycobacteria-specific or malaria-specific responses by chronic filarial infection. As such, filarial infections very clearly alter the magnitude and quality of the mycobacteria-specific or malaria-specific cytokine responses, responses that have been typically associated with control of these intracellular pathogens. Summary Although phylogenetically distinct, mycobacteria and Plasmodium spp. often share the same geographical niche with filarial infections. The complex interplay between filarial parasites that are associated with immunomodulation and those microbial pathogens that require a proinflammatory or unmodulated response for their control is easily demonstrable ex vivo, but whether this interplay affects disease outcome in tuberculosis or malaria remains an open question. C1 [Metenou, Simon; Nutman, Thomas B.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Babu, Subash] ICER, NIRT, Madras, Tamil Nadu, India. RP Nutman, TB (reprint author), Bldg 4,Room B1-03,4 Ctr Dr, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov RI Metenou, Simon/C-1101-2013 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health, USA FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and National Institutes of Health, USA. NR 68 TC 23 Z9 23 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2012 VL 7 IS 3 BP 231 EP 238 DI 10.1097/COH.0b013e3283522c3d PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 925TA UT WOS:000302783200005 PM 22418448 ER PT J AU Nandy, K AF Nandy, Kaustav TI Interactive segmentation and tracking in optical microscopic images SO CYTOMETRY PART A LA English DT Editorial Material DE interactive segmentation; tissue segmentation; cell tracking; seeded watershed algorithm; optical microscopy ID CELLS C1 NCI, Opt Microscopy & Anal Lab, SAIC Frederick Inc, Adv Technol Program, Frederick, MD 21702 USA. RP Nandy, K (reprint author), NCI, Opt Microscopy & Anal Lab, SAIC Frederick Inc, Adv Technol Program, POB B, Frederick, MD 21702 USA. EM nandyk@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 12 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2012 VL 81A IS 5 BP 357 EP 359 DI 10.1002/cyto.a.22055 PG 3 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 928SN UT WOS:000303004300003 PM 22499415 ER PT J AU Foulds, KE Donaldson, M Roederer, M AF Foulds, Kathryn E. Donaldson, Mitzi Roederer, Mario TI OMIP-005: Quality and phenotype of antigen-responsive rhesus macaque T cells SO CYTOMETRY PART A LA English DT Article DE intracellular cytokine; T cells; vaccines; HIV C1 [Foulds, Kathryn E.; Donaldson, Mitzi; Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Foulds, KE (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5507, Bethesda, MD 20892 USA. EM FouldsK@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH; Collaboration for AIDS Vaccine Discovery (CAVD) [38650] FX Grant sponsor: National Institute of Allergy and Infectious Diseases, NIH (Intramural Research Program); Grant sponsor: Collaboration for AIDS Vaccine Discovery (CAVD) award; Grant number: #38650; NR 4 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2012 VL 81A IS 5 BP 360 EP 361 DI 10.1002/cyto.a.22008 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 928SN UT WOS:000303004300004 PM 22438313 ER PT J AU Lamoreaux, L Koup, RA Roederer, M AF Lamoreaux, Laurie Koup, Richard A. Roederer, Mario TI OMIP-009: Characterization of antigen-specific human T-cells SO CYTOMETRY PART A LA English DT Article DE intracellular cytokines; vaccines; T cells; HIV C1 [Lamoreaux, Laurie; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lamoreaux, L (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 3613, Bethesda, MD 20892 USA. EM llamorea@mail.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH; Collaboration for AIDS Vaccine Discovery (CAVD) [38650] FX The authors thank Ellen Turk and Jennifer Fischer for assistance in developing and optimizing the panel; Pratip Chattopadhyay and Joanne Yu for advice in optimizing the multicolor panel and characterizing reagents; and Steven Perfetto and Richard Nguyen for expert flow cytometry advice. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, and the Collaboration for AIDS Vaccine Discovery (CAVD) award #38650. NR 3 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2012 VL 81A IS 5 BP 362 EP 363 DI 10.1002/cyto.a.22042 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 928SN UT WOS:000303004300005 PM 22438322 ER PT J AU Orlov, NV Weeraratna, AT Hewitt, SM Coletta, CE Delaney, JD Eckley, D Shamir, L Goldberg, IG AF Orlov, Nikita V. Weeraratna, Ashani T. Hewitt, Stephen M. Coletta, Christopher E. Delaney, John D. Mark Eckley, D. Shamir, Lior Goldberg, Ilya G. TI Automatic detection of melanoma progression by histological analysis of secondary sites SO CYTOMETRY PART A LA English DT Article DE melanoma progression; histopathological image analysis; nonparametric image analysis; H&E data; tissue classification ID FEATURE-SELECTION; CANCER DIAGNOSIS; IMAGE-ANALYSIS; CLASSIFICATION; RECOGNITION; METASTASIS; PATHOLOGY; LYMPHOMA; FEATURES; TISSUES AB We present results from machine classification of melanoma biopsies sectioned and stained with hematoxylin/eosin (H&E) on tissue microarrays (TMA). The four stages of melanoma progression were represented by seven tissue types, including benign nevus, primary tumors with radial and vertical growth patterns (stage I) and four secondary metastatic tumors: subcutaneous (stage II), lymph node (stage III), gastrointestinal and soft tissue (stage IV). Our experiment setup comprised 14,208 image samples based on 164 TMA cores. In our experiments, we constructed an HE color space by digitally deconvolving the RGB images into separate H (hematoxylin) and E (eosin) channels. We also compared three different classifiers: Weighted Neighbor Distance (WND), Radial Basis Functions (RBF), and k-Nearest Neighbors (kNN). We found that the HE color space consistently outperformed other color spaces with all three classifiers, while the different classifiers did not have as large of an effect on accuracy. This showed that a more physiologically relevant representation of color can have a larger effect on correct image interpretation than downstream processing steps. We were able to correctly classify individual fields of view with an average of 96% accuracy when randomly splitting the dataset into training and test fields. We also obtained a classification accuracy of 100% when testing entire cores that were not previously used in training (four random trials with one test core for each of 7 classes, 28 tests total). Because each core corresponded to a different patient, this test more closely mimics a clinically relevant setting where new patients are evaluated based on training with previous cases. The analysis method used in this study contains no parameters or adjustments that are specific to melanoma morphology, suggesting it can be used for analyzing other tissues and phenotypes, as well as potentially different image modalities and contrast techniques. Published 2012 Wiley Periodicals, Inc. C1 [Orlov, Nikita V.; Coletta, Christopher E.; Delaney, John D.; Mark Eckley, D.; Goldberg, Ilya G.] NIA, NIH, Genet Lab, Baltimore, MD 21224 USA. [Weeraratna, Ashani T.] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA. [Hewitt, Stephen M.] NCI, NIH, Tissue Array Res Program, Adv Technol Ctr, Bethesda, MD 20892 USA. [Shamir, Lior] Lawrence Tech Univ, Dept Comp Sci, Southfield, MI USA. RP Orlov, NV (reprint author), 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM norlov@nih.gov RI Goldberg, Ilya/H-5307-2011; OI Goldberg, Ilya/0000-0001-8514-6110; Hewitt, Stephen/0000-0001-8283-1788 FU NIH, National Institute on Aging [Z01: AG000685-02] FX Grant sponsor: Intramural Research Program of the NIH, National Institute on Aging; Grant number: Z01: AG000685-02 NR 53 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2012 VL 81A IS 5 BP 364 EP 373 DI 10.1002/cyto.a.22044 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 928SN UT WOS:000303004300006 PM 22467531 ER PT J AU Tembhare, P Yuan, CM Xi, LQ Marti, G Raffeld, M Stetler-Stevenson, M AF Tembhare, Prashant Yuan, Constance M. Xi, Liqiang Marti, Gerald Raffeld, Mark Stetler-Stevenson, Maryalice TI Case study interpretation-Portland: Case 1 SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article ID B-CELL LYMPHOCYTOSIS; LEUKEMIA; BIOLOGY; CLONES; MBL C1 [Tembhare, Prashant] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Marti, Gerald] US FDA, Ctr Biol Evaluat & Res, NIH, Bethesda, MD USA. RP Tembhare, P (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2A-33,Mail Stop 1500, Bethesda, MD 20892 USA. EM tembharep@mail.nih.gov FU NIH, NCI FX Grant sponsor: Intramural Research Program of the NIH, NCI. NR 8 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAY PY 2012 VL 82B IS 3 BP 177 EP 179 DI 10.1002/cyto.b.21012 PG 3 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 927VA UT WOS:000302937200010 PM 22431420 ER PT J AU Blackburn, J Ohazama, A Kawasaki, K Otsuka-Tanaka, Y Liu, BG Honda, K Rountree, RB Hu, YL Kawasaki, M Birchmeier, W Schmidt-Ullrich, R Kinoshita, A Schutte, BC Hammond, NL Dixon, MJ Sharpe, PT AF Blackburn, James Ohazama, Atsushi Kawasaki, Katsushige Otsuka-Tanaka, Yoko Liu, Bigang Honda, Kenya Rountree, Ryan B. Hu, Yinling Kawasaki, Maiko Birchmeier, Walter Schmidt-Ullrich, Ruth Kinoshita, Akira Schutte, Brian C. Hammond, Nigel L. Dixon, Michael J. Sharpe, Paul T. TI The role of Irf6 in tooth epithelial invagination SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Ikk alpha; Irf6; Wnt; Incisor; Invagination; Epithelium; Tooth development ID NF-KAPPA-B; DER-WOUDE-SYNDROME; POPLITEAL PTERYGIUM SYNDROME; GAMMA-SECRETASE INHIBITORS; IKK-ALPHA; TRANSCRIPTION FACTORS; GENE INDUCTION; INTERFERON RESPONSES; SIGNALING PATHWAYS; TMJ DEVELOPMENT AB Thickening and the subsequent invagination of the epithelium are an important initial step in Ectodermal organ development. Ikk alpha has been shown to play a critical role in controlling epithelial growth, since Ikk alpha mutant mice show protrusions (evaginations) of incisor tooth, whisker and hair follicle epithelium rather than invagination. We show here that mutation of the Interferon regulatory factor (11) family, Irf6 also results in evagination of incisor epithelium. In common with Ikk alpha mutants, Irf6 mutant evagination occurs in a NF-kappa B-independent manner and shows the same molecular changes as those in Ikk alpha mutants. Irf6 thus also plays a critical role in regulating epithelial invagination. In addition, we also found that canonical Wnt signaling is upregulated in evaginated incisor epithelium of both Ikk alpha and Irf6 mutant embryos. (C) 2012 Elsevier Inc. All rights reserved. C1 [Blackburn, James; Ohazama, Atsushi; Kawasaki, Katsushige; Otsuka-Tanaka, Yoko; Kawasaki, Maiko; Sharpe, Paul T.] Kings Coll London, Inst Dent, Dept Craniofacial Dev, London SE1 9RT, England. [Blackburn, James; Ohazama, Atsushi; Kawasaki, Katsushige; Otsuka-Tanaka, Yoko; Kawasaki, Maiko; Sharpe, Paul T.] Kings Coll London, Inst Dent, Comprehens Biomed Res Ctr, London SE1 9RT, England. [Liu, Bigang] Univ Texas MD Anderson Canc Ctr, Smithville, TX USA. [Honda, Kenya] Univ Tokyo, Grad Sch Med, Dept Immunol, Tokyo, Japan. [Honda, Kenya] Univ Tokyo, Fac Med, Tokyo 113, Japan. [Rountree, Ryan B.] Amgen Inc, Dept Oncol, Seattle, WA USA. [Hu, Yinling] NCI, Expt Immunol Lab, Inflammat & Tumorigenesis Sect, Frederick, MD 21701 USA. [Kawasaki, Maiko] Niigata Univ, Grad Sch Med & Dent Sci, Dept Oral Hlth Sci, Course Oral Life Sci,Div Bioprosthodont, Niigata, Japan. [Birchmeier, Walter] Max Delbruck Ctr Mol Med, Dept Canc Res, D-13092 Berlin, Germany. [Schmidt-Ullrich, Ruth] Max Delbruck Ctr Mol Med, Dept Signal Transduct Tumor Cells, D-13092 Berlin, Germany. [Kinoshita, Akira] Nagasaki Univ, Dept Human Genet, Grad Sch Biomed Sci, Nagasaki 852, Japan. [Kinoshita, Akira; Schutte, Brian C.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Hammond, Nigel L.; Dixon, Michael J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Life Sci, Manchester, Lancs, England. [Hammond, Nigel L.; Dixon, Michael J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Dent, Manchester, Lancs, England. [Ohazama, Atsushi] Showa Univ, Sch Dent, Dept Periodontol, Ohta Ku, Tokyo 142, Japan. RP Ohazama, A (reprint author), Kings Coll London, Inst Dent, Dept Craniofacial Dev, Floor 27,Guys Tower, London SE1 9RT, England. EM Atsushi.2.Ohazama@kcl.ac.uk; paul.sharpe@kcl.ac.uk FU MRC; Ministry of Education, Culture, Sports, Science and Technology of Japan [16592080]; JSPS; Nihon University; NIH [DE13513] FX We would like to thank Amgen for Rip4 mutant mice, Ken Brady for TEM analysis, Dr. Koyama for HistoneH4C plasmids (Ochiai et al., 2010; Yasuda et al., 2010) and Tony Brain for SEM analysis. This work was supported by the MRC and was partly funded by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 16592080). K.K. is supported by JSPS International Program for Young Researcher Overseas Visits. Y.O.-K. is supported by Nihon University. S.C.A. and A.K. were supported by NIH DE13513. NR 77 TC 10 Z9 10 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 1 PY 2012 VL 365 IS 1 BP 61 EP 70 DI 10.1016/j.ydbio.2012.02.009 PG 10 WC Developmental Biology SC Developmental Biology GA 928ZG UT WOS:000303030400006 PM 22366192 ER PT J AU English, MA Lei, L Blake, T Wincovitch, SM Sood, R Azuma, M Hickstein, D Liu, PP AF English, Milton A. Lei, Lin Blake, Trevor Wincovitch, Stephen M., Sr. Sood, Raman Azuma, Mizuki Hickstein, Dennis Liu, P. Paul TI Incomplete splicing, cell division defects, and hematopoietic blockage in dhx8 mutant zebrafish SO DEVELOPMENTAL DYNAMICS LA English DT Article DE dhx8 mutant zebrafish; hematopoiesis; cell division defects ID HELICASE-LIKE PROTEIN; MESSENGER-RNA; DEFINITIVE HEMATOPOIESIS; TRANSGENIC ZEBRAFISH; ENDOTHELIAL LINEAGES; FACTOR PRP22; EXPRESSION; EMBRYO; GENE; SPLICEOSOME AB Background: Vertebrate hematopoiesis is a complex developmental process that is controlled by genes in diverse pathways. To identify novel genes involved in early hematopoiesis, we conducted an ENU (N-ethyl-N-nitrosourea) mutagenesis screen in zebrafish. The mummy (mmy) line was investigated because of its multiple hematopoietic defects. Results: Homozygous mmy embryos lacked circulating blood cell types and were dead by 30 hr post-fertilization (hpf). The mmy mutants did not express myeloid markers and had significantly decreased expression of progenitor and erythroid markers in primitive hematopoiesis. Through positional cloning, we identified a truncation mutation in dhx8 in the mmy fish. dhx8 is the zebrafish ortholog of the yeast splicing factor prp22, which is a DEAH-box RNA helicase. mmy mutants had splicing defects in many genes, including several hematopoietic genes. mmy embryos also showed cell division defects as characterized by disorganized mitotic spindles and formation of multiple spindle poles in mitotic cells. These cell division defects were confirmed by DHX8 knockdown in HeLa cells. Conclusions: Together, our results confirm that dhx8 is involved in mRNA splicing and suggest that it is also important for cell division during mitosis. This is the first vertebrate model for dhx8, whose function is essential for primitive hematopoiesis in developing embryos. Developmental Dynamics 241:879889, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [English, Milton A.; Lei, Lin; Blake, Trevor; Wincovitch, Stephen M., Sr.; Sood, Raman; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Azuma, Mizuki; Hickstein, Dennis; Liu, P. Paul] NCI, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute; National Cancer Institute, NIH; UNCF/Merck FX Grant sponsor: Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, NIH.; This study was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, NIH. M.A.E. was supported by a fellowship from UNCF/Merck. We thank Christine and Bernard Thisse for in situ hybridization of dhx8 during embryonic development 9Thisse and Thisse, 2008), Julia Fekecs for help with graphics illustrations, and Abdel Elkahloun and Niraj S. Trivedi for performing the microarray hybridizations and analysis. NR 58 TC 9 Z9 9 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAY PY 2012 VL 241 IS 5 BP 879 EP 889 DI 10.1002/dvdy.23774 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 926VY UT WOS:000302861200005 PM 22411201 ER PT J AU Mitterberger, MC Kim, G Rostek, U Levine, RL Zwerschke, W AF Mitterberger, Maria C. Kim, Geumsoo Rostek, Ursula Levine, Rodney L. Zwerschke, Werner TI Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-gamma 2 SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Adipocyte; Adipogenesis; Aging; Caloric restriction; Carbonic anhydrase Ill; Oxidative stress; Preadipocyte; PPAR gamma 2; FABP4 ID OXIDATIVE STRESS; GENE-EXPRESSION; S-THIOLATION; PPAR-GAMMA; ADIPOCYTE DIFFERENTIATION; PHOSPHATASE-ACTIVITY; PROTEIN SULFHYDRYLS; INSULIN-RESISTANCE; SKELETAL-MUSCLE; ENERGY-BALANCE AB Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO2 have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII(-/-) MEFs compared with CAIII(+/+) cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) and CCAAT/enhancer binding protein-alpha. We found a considerable (approximately 1000-fold) increase in the PPAR gamma 2 expression in the CAIII(-/-) MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR gamma 2 and FABP4. When both CAIII and PPAR gamma 2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR gamma 2 gene expression. (C) 2012 Elsevier Inc. All rights reserved. C1 [Mitterberger, Maria C.; Rostek, Ursula; Zwerschke, Werner] Austrian Acad Sci, Inst Biomed Aging Res, Cell Metab & Differentiat Res Grp, A-6020 Innsbruck, Austria. [Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Zwerschke, W (reprint author), Austrian Acad Sci, Inst Biomed Aging Res, Cell Metab & Differentiat Res Grp, Rennweg 10, A-6020 Innsbruck, Austria. EM werner.zwerschke@oeaw.ac.at RI Levine, Rodney/D-9885-2011 FU Austrian Academy of Sciences; National Heart, Lung, and Blood Institute FX We are grateful to D. Trono (Lausanne, Switzerland) for the plasmid pMD2.G and psPAX2. This work was supported by funding from the Austrian Academy of Sciences (M.C.M., U.R., W.Z.) and by the Intramural Research Program of the National Heart, Lung, and Blood Institute (G.K., R.L.L). NR 49 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 1 PY 2012 VL 318 IS 8 BP 877 EP 886 DI 10.1016/j.yexcr.2012.02.011 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 925MR UT WOS:000302765800002 PM 22507175 ER PT J AU Simon, SL Coleman, CN Noska, MA Bowman, T AF Simon, Steven L. Coleman, C. Norman Noska, Michael A. Bowman, Thomas TI RESPONSE OF THE US DEPARTMENT OF HEALTH AND HUMAN SERVICES IN PROTECTING CIVILIAN AMERICANS IN JAPAN DURING THE FUKUSHIMA NUCLEAR CRISIS SO HEALTH PHYSICS LA English DT Article DE operational topics; emergency planning; exposure, radiation; radiation safety; emergency response AB Following the earthquake and tsunami in northern Japan on 11 March 2011 and the ensuing damage to the Fukushima Daiichi Nuclear Power Plant complex, a request by the U. S. Ambassador to Japan to the U. S. Department of Health and Human Services (DHHS) Assistant Secretary for Preparedness and Response (ASPR) resulted in deployment of a five-person team of subject matter experts to the U. S. Embassy. The primary purpose of the deployment was to provide the U. S. Embassy in Tokyo with guidance on health and medical issues related to potential radiation exposure of U. S. citizens in Japan, including employees of the U. S. Department of State at consulates in Japan and American citizens living in or visiting Japan. At the request of the Government of Japan (GOJ), the deployed health team also assisted Japanese experts in their public health response to the radiation incident. Over a 3-wk period in Japan and continuing for weeks after their return to the U. S., the team provided expertise in the areas of medical and radiation oncology; health physics; assessment of radiation dose and cancer risk, particularly to U. S. citizens living in Tokyo and the surrounding areas; food and water contamination and the acceptable limits; countermeasures to exposure such as potassium iodide (KI); the use of KI and an offered donation from the United States;, evacuation and re-entry issues; and health/emergency-related communication strategies. This paper describes the various strategies used and observations made by the DHHS team during the first 2 mo after the Fukushima crisis began. Health Phys. 102(5):570-579; 2012 C1 [Simon, Steven L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Coleman, C. Norman] Dept Hlth & Human Serv, Off Preparedness & Emergency Operat, Washington, DC USA. [Noska, Michael A.] US FDA, Silver Spring, MD USA. [Bowman, Thomas] Ctr Dis Control & Prevent, Div Strateg Natl Stockpile, Off Publ Hlth Preparedness & Response, Atlanta, GA USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU DHHS; NIH; NCI; NCI Division of Cancer Epidemiology FX The authors are appreciative of support from the DHHS and individual agencies they represent and especially Dr. Nicole Lurie, the DHHS Assistant Secretary for Preparedness and Response. In addition, the authors are appreciative of the support from the Directors of the NIH, NCI, and the NCI Division of Cancer Epidemiology, the FDA Office of International Programs, and the FDA Office of Crisis Management for their logistic support. The authors gratefully acknowledge the dedication and expertise of a team member, Jana Telfer of the CDC, in the area of risk communications. NR 24 TC 3 Z9 3 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD MAY PY 2012 VL 102 IS 5 BP 570 EP 579 DI 10.1097/HP.0b013e31824c79e5 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 925VG UT WOS:000302789300014 ER PT J AU Miller, TL Borkowsky, W DiMeglio, LA Dooley, L Geffner, ME Hazra, R McFarland, EJ Mendez, AJ Patel, K Siberry, GK Van Dyke, RB Worrell, CJ Jacobson, DL AF Miller, T. L. Borkowsky, W. DiMeglio, L. A. Dooley, L. Geffner, M. E. Hazra, R. McFarland, E. J. Mendez, A. J. Patel, K. Siberry, G. K. Van Dyke, R. B. Worrell, C. J. Jacobson, D. L. CA PHACS TI Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children SO HIV MEDICINE LA English DT Article DE children; HIV; AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers ID INTIMA-MEDIA THICKNESS; C-REACTIVE PROTEIN; HUMAN IMMUNODEFICIENCY VIRUS-1; BETA-CELL FUNCTION; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; RISK-FACTORS; ENDOTHELIAL ACTIVATION; MYOCARDIAL-INFARCTION; LONGITUDINAL CHANGES AB Objectives HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/ AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. Methods A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. Results The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P-and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). Conclusions HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication. C1 [Miller, T. L.] Univ Miami, Miller Sch Med, Div Pediat Clin Res, Dept Pediat, Miami, FL 33101 USA. [Borkowsky, W.] NYU, Sch Med, New York, NY USA. [DiMeglio, L. A.] Indiana Univ Sch Med, Sect Pediat Endocrinol & Diabetol, Dept Pediat, Indianapolis, IN USA. [Dooley, L.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Geffner, M. E.] USC, Keck Sch Med, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA USA. [Hazra, R.; Siberry, G. K.; Worrell, C. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [McFarland, E. J.] Univ Colorado, Dept Pediat, Denver Sch Med, Denver, CO 80202 USA. [Mendez, A. J.] Univ Miami, Miller Sch Med, Diabet Res Inst, Dept Med,Div Endocrinol Diabet & Metab, Miami, FL 33101 USA. [Patel, K.; Jacobson, D. L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Dept Epidemiol, Boston, MA 02115 USA. [Van Dyke, R. B.] Tulane Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70118 USA. RP Miller, TL (reprint author), Univ Miami, Batchelor Childrens Res Inst, Miller Sch Med, Div Pediat Clin Res,Dept Pediat D820, POB 016820, Miami, FL 33101 USA. EM tracie.miller@miami.edu OI DiMeglio, Linda/0000-0002-8033-6078 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism [U01 HD052102-04]; Tulane University School of Medicine [U01 HD052104-01]; NIH/NCRR Colorado CTSI [UL1 RR025780] FX The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) (Principal Investigator: George R. Seage, III; Project Director: Julie Alperen) and the Tulane University School of Medicine (U01 HD052104-01) (Principal Investigator: Russell B. Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc. (Principal Investigator: Mercy Swatson). This study was supported by NIH/NCRR Colorado CTSI Grant Number UL1 RR025780. Its contents are the authors' sole responsibility. NR 57 TC 26 Z9 27 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-2662 J9 HIV MED JI HIV Med. PD MAY PY 2012 VL 13 IS 5 BP 264 EP 275 DI 10.1111/j.1468-1293.2011.00970.x PG 12 WC Infectious Diseases SC Infectious Diseases GA 923LD UT WOS:000302619900002 PM 22136114 ER PT J AU Mills, JL Carter, TC Kay, DM Browne, ML Brody, LC Liu, AY Romitti, PA Caggana, M Druschel, CM AF Mills, James L. Carter, Tonia C. Kay, Denise M. Browne, Marilyn L. Brody, Lawrence C. Liu, Aiyi Romitti, Paul A. Caggana, Michele Druschel, Charlotte M. TI Folate and vitamin B12-related genes and risk for omphalocele SO HUMAN GENETICS LA English DT Article ID NEURAL-TUBE DEFECTS; NEW-YORK-STATE; BIRTH-DEFECTS; PREVENTION; GASTROSCHISIS; POLYMORPHISMS; SURVEILLANCE; METABOLISM; IMPACT AB Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (p.Q8R), and the MTHFR gene, rs1801131 (c.1298A > C), were significantly associated with omphalocele. In African-Americans, significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (p.R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles. C1 [Mills, James L.; Carter, Tonia C.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. [Kay, Denise M.; Caggana, Michele] New York State Dept Hlth, Div Genet, Wadsworth Ctr, Albany, NY 12201 USA. [Browne, Marilyn L.; Druschel, Charlotte M.] New York State Dept Hlth, Congenital Malformat Registry, Troy, NY 12180 USA. [Browne, Marilyn L.; Druschel, Charlotte M.] SUNY Albany, Dept Epidemiol & Biostat, Sch Publ Hlth, Rensselaer, NY 12144 USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52242 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Bldg,Room 7B03, Bethesda, MD 20892 USA. EM jamesmills@nih.gov OI Kay, Denise/0000-0002-9928-2698; Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200703431C NICHD, N01-DK-7-3431] FX The authors thank April J. Atkins, Robert J. Sicko, and Emily C. McGrath for laboratory and technical assistance. We are grateful to Sandra D. Richardson for data management. 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 number: HHSN267200703431C NICHD No. N01-DK-7-3431. NR 23 TC 8 Z9 8 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2012 VL 131 IS 5 BP 739 EP 746 DI 10.1007/s00439-011-1117-3 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 926FM UT WOS:000302816700009 PM 22116453 ER PT J AU Judd, LL Schettler, PJ Akiskal, H Coryell, W Fawcett, J Fiedorowicz, JG Solomon, DA Keller, MB AF Judd, Lewis L. Schettler, Pamela J. Akiskal, Hagop Coryell, William Fawcett, Jan Fiedorowicz, Jess G. Solomon, David A. Keller, Martin B. TI Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation ID BRANCH COLLABORATIVE PROGRAM; MIXED STATES; PSYCHOSOCIAL DISABILITY; NATURAL-HISTORY; II DISORDERS; STEP-BD; VALIDATION; PSYCHOBIOLOGY; DEFINITION; RECOVERY AB Background: There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of 'depressive mixed state.' This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined. Methods: Bipolar (type I or II) patients with an MDE at intake (N =142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation. Results: Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms. Limitations: The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment. Conclusions: The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality. (C) 2012 Elsevier B.V. All rights reserved. C1 [Judd, Lewis L.; Akiskal, Hagop; Coryell, William; Fawcett, Jan; Solomon, David A.; Keller, Martin B.] NIMH, Collaborat Program Psychobiol Depress, Bethesda, MD USA. [Judd, Lewis L.; Schettler, Pamela J.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Akiskal, Hagop] Vet Adm Hosp, San Diego, CA USA. [Coryell, William; Fiedorowicz, Jess G.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Fawcett, Jan] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. [Fiedorowicz, Jess G.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Solomon, David A.] Brown Univ, Dept Psychiat & Human Behav, Sch Med, Providence, RI 02912 USA. [Solomon, David A.] UpToDate Inc, Waltham, MA USA. RP Judd, LL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM ljudd@ucsd.edu FU National Institute of Mental (NIMH); Neurosearch FX The initial funding source for the database utilized in this manuscript was the National Institute of Mental (NIMH). The NIMH had no further role in the design, analysis and interpretation of data; in the writing of this report; and in the decision to submit the paper for publication.; Drs. Judd, Akiskal, Coryell, and Fawcett declare that they have no conflicts of interest or potential conflicts of interest. During the past three years Dr. Schettler has provided statistical consulting services to Brain Cell, Inc., Methylation Sciences, Novartis BioVentures, and Clintara LLC. Dr. Fiedorowicz currently serves in an unpaid capacity on a colleague's study that is supported by Neurosearch. Dr. Solomon is an employee of UpToDate, Inc. During the past three years Dr. Keller has served as a consultant to CENEREX, Forest Laboratories, Medtronic, Organon, Pfizer, Sierra Neuropharmaceuticals, Shire, and Wyeth; has served on the advisory boards for CENEREX, Forest Laboratories, and Organon; and has conducted research using Pfizer and Wyeth products. NR 33 TC 37 Z9 37 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY PY 2012 VL 138 IS 3 BP 440 EP 448 DI 10.1016/j.jad.2011.12.046 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 924AW UT WOS:000302663900029 PM 22314261 ER PT J AU Oliveras-Rentas, RE Kenworthy, L Roberson, RB Martin, A Wallace, GL AF Oliveras-Rentas, Rafael E. Kenworthy, Lauren Roberson, Richard B., III Martin, Alex Wallace, Gregory L. TI WISC-IV Profile in High-Functioning Autism Spectrum Disorders: Impaired Processing Speed is Associated with Increased Autism Communication Symptoms and Decreased Adaptive Communication Abilities SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; IQ; Processing speed; Symptomatology; Adaptive behavior; ADHD; Intelligence ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PERVASIVE DEVELOPMENTAL DISORDER; WECHSLER INTELLIGENCE SCALE; DIAGNOSTIC INTERVIEW; BEHAVIOR SCALES; ADHD SYMPTOMS; CHILDREN; IQ; INDIVIDUALS; VINELAND AB Changes in the Wechsler Intelligence Scales for Children-IV (WISC-IV) may affect the IQ profile characteristic of autism spectrum disorders (ASD). Moreover, the association of particular component cognitive abilities (unlike overall IQ) with symptomatology and adaptive functioning in ASD remains unclear. This archival study characterizes the WISC-IV IQ profile among 56 high-functioning (IQ > 70) children with ASD and correlates WISC-IV performance with ASD and ADHD symptomatology and adaptive functioning. The ASD WISC-IV profile included strengths on Matrix Reasoning and Similarities, weaknesses on Comprehension (which correlated negatively with social symptoms) and the subtests comprising the Processing Speed Index (Coding, Symbol Search). Processing speed task performance correlated negatively with communication symptoms and positively with communication abilities, indicating its importance to functional outcomes in ASD. C1 [Roberson, Richard B., III; Martin, Alex; Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Oliveras-Rentas, Rafael E.; Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. RP Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 4C104,MSC 1366, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI martin, alex/B-6176-2009; OI Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [ZIA MH002920-03] NR 56 TC 36 Z9 37 U1 8 U2 46 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 MAY PY 2012 VL 42 IS 5 BP 655 EP 664 DI 10.1007/s10803-011-1289-7 PG 10 WC Psychology, Developmental SC Psychology GA 925OU UT WOS:000302771500001 PM 21638108 ER PT J AU Cao, ZG Zhang, H Zhou, X Han, XL Ren, YS Gao, T Xiao, Y de Crombrugghe, B Somerman, MJ Feng, JQ AF Cao, Zhengguo Zhang, Hua Zhou, Xin Han, Xianglong Ren, Yinshi Gao, Tian Xiao, Yin de Crombrugghe, Benoit Somerman, Martha J. Feng, Jian Q. TI Genetic evidence for the vital function of osterix in cementogenesis SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSX; CEMENTUM; CEMENTOGENESIS; DMP1; TOOTH ROOT ID TRANSCRIPTION FACTOR OSTERIX; HORMONE-RELATED PROTEIN; EPITHELIAL ROOT SHEATH; BONE-FORMATION; OSTEOBLAST DIFFERENTIATION; TOOTH DEVELOPMENT; IN-VITRO; DENTIN; EXPRESSION; MOUSE AB To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal- and spatial-expression pattern of Osx and the formation of cellular cementum. We then generated 3.6-kilobase (kb) collagen type I (3.6-kb Col 1)-Osx transgenic mice, which displayed accelerated cementum formation versus wild-type (WT) controls. Importantly, the conditional deletion of Osx in the mesenchymal cells with two different Cre systems (the 2.3-kb Col 1 and an inducible CAGCre estrogen receptor [CreER]) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the Osx gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered scanning electron microscopy (SEM) and resin-casted SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support: (1) the mesenchymal origin of cellular cementum (from periodontal ligament [PDL] progenitor cells); (2) the vital role of OSX in controlling the formation of cellular cementum; and (3) the limited remodeling of cellular cementum in adult mice. (c) 2012 American Society for Bone and Mineral Research. C1 [Cao, Zhengguo] Texas A&M Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, Dallas, TX 75246 USA. [Cao, Zhengguo] Wuhan Univ, State Key Lab Breeding Base Basic Sci Stomatol Hu, Wuhan 430072, Peoples R China. [Cao, Zhengguo] Wuhan Univ, Key Lab Oral Biomed, Minist Educ, Dept Periodontol,Sch & Hosp Stomatol, Wuhan 430072, Peoples R China. [Zhou, Xin; de Crombrugghe, Benoit] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Xiao, Yin] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Somerman, Martha J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Cao, ZG (reprint author), Texas A&M Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, 3302 Gaston Ave, Dallas, TX 75246 USA. EM jfeng@bcd.tamhsc.edu OI Xiao, Yin/0000-0003-1785-3491 FU NIH [DE018486]; National Natural Science Foundation of China [81170933] FX This study was supported by grants from the NIH (DE018486 to JQF) and the National Natural Science Foundation of China (81170933 to ZC). NR 46 TC 37 Z9 39 U1 0 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2012 VL 27 IS 5 BP 1080 EP 1092 DI 10.1002/jbmr.1552 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 927VW UT WOS:000302939400012 PM 22246569 ER PT J AU Bhattacharyya, N Wiench, M Dumitrescu, C Connolly, BM Bugge, TH Patel, HV Gafni, RI Cherman, N Cho, M Hager, GL Collins, MT AF Bhattacharyya, Nisan Wiench, Malgorzata Dumitrescu, Claudia Connolly, Brian M. Bugge, Thomas H. Patel, Himatkumar V. Gafni, Rachel I. Cherman, Natasha Cho, Monique Hager, Gordon L. Collins, Michael T. TI Mechanism of FGF23 processing in fibrous dysplasia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FGF23; FIBROUS DYSPLASIA; McCUNE-ALBRIGHT SYNDROME; GNAS; Gsa; ppGalNAcT3; FURIN; PHOSPHATE METABOLISM; RICKETS; OSTEOMALACIA; PROCESSING ID DOMINANT HYPOPHOSPHATEMIC RICKETS; FAMILIAL TUMORAL CALCINOSIS; FIBROBLAST GROWTH FACTOR-23; PHOSPHATE HOMEOSTASIS; O-GLYCOSYLATION; INDUCED OSTEOMALACIA; MINERAL METABOLISM; CLONING; FGF-23; BONE AB Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23?+?iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein Gsa that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative Gsa mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. (c) 2012 American Society for Bone and Mineral Research. C1 [Bhattacharyya, Nisan; Dumitrescu, Claudia; Gafni, Rachel I.; Cherman, Natasha; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Wiench, Malgorzata; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Connolly, Brian M.; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Patel, Himatkumar V.] Natl Inst Diabet & Kidney Dis, Sect Biol Chem, NIH, Bethesda, MD USA. [Cho, Monique] Natl Inst Diabet & Kidney Dis, Kidney Dis Branch, NIH, Bethesda, MD USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 218, Bethesda, MD 20892 USA. EM mc247k@nih.gov NR 34 TC 43 Z9 44 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2012 VL 27 IS 5 BP 1132 EP 1141 DI 10.1002/jbmr.1546 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 927VW UT WOS:000302939400016 PM 22247037 ER PT J AU Barbour, KE Houston, DK Cummings, SR Boudreau, R Prasad, T Sheu, Y Bauer, DC Tooze, JA Kritchevsky, SB Tylavsky, FA Harris, TB Cauley, JA AF Barbour, Kamil E. Houston, Denise K. Cummings, Steven R. Boudreau, Robert Prasad, Tanushree Sheu, Yahtyng Bauer, Douglas C. Tooze, Janet A. Kritchevsky, Stephen B. Tylavsky, Frances A. Harris, Tamara B. Cauley, Jane A. CA Hlth ABC Study TI Calciotropic hormones and the risk of hip and nonspine fractures in older adults: The health ABC study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE SERUM 25-HYDROXYVITAMIN D; PARATHYROID HORMONE; HIP FRACTURES; NONSPINE FRACTURES ID SERUM 25-HYDROXYVITAMIN D; VITAMIN-D DEFICIENCY; SECONDARY HYPERPARATHYROIDISM; D SUPPLEMENTATION; BONE LOSS; WOMEN; ASSOCIATION; MARKERS; MEN; DISABILITY AB The effects of vitamin D and parathyroid hormone (PTH) levels on incident fracture remain uncertain. To test the hypothesis that increasing serum 25-hydroxyvitamin D [25(OH)D] and decreasing PTH levels are associated with decreased risk of hip and any nonspine fracture, we conducted a prospective cohort study among 2614 community-dwelling white and black participants, aged =70 years, from the Health, Aging and Body Composition (Health ABC) Study. Serum and plasma samples were drawn at year 2, which formed the baseline for this analysis. Serum 25(OH)D and intact PTH (1-84) were measured using radioimmunoassay with DiaSorin reagents and EDTA plasma with a two-site immunoradiometric assay kit, respectively. Incident fractures (hip and any nonspine) were assessed after year 2, every 6 months, by self-report and validated by radiology reports. The median (interquartile range) follow-up times for hip and any nonspine fractures were 6.4 (6.16.5) and 6.4 (5.56.5) years, respectively. Cox proportional hazards regression was used to estimate the hazard ratios (HR) with 95% confidence intervals (CI) for fracture. There were 84 hip and 247 nonspine fractures that occurred over the follow-up period. The multivariable adjusted HRs (95% CIs) of hip fracture for participants in the lowest (=17.78?ng/mL), second (17.79 to 24.36?ng/mL), and third quartiles (24.37 to 31.94?ng/mL) of 25(OH)D were 1.92 (0.97 to 3.83), 0.75 (0.32 to 1.72) and 1.86 (1.00 to 3.45), respectively, compared with participants in the highest 25(OH)D quartile (>31.94?ng/mL) (p trend?=?0.217). Additional adjustment for IL-6 (p?=?0.107), PTH (p?=?0.124), and hip areal bone mineral density (p?=?0.137) attenuated HRs of hip fracture in the lowest quartile by 16.3%, 17.4%, and 26.1%, respectively. There was no evidence of an association between 25(OH)D and any nonspine fractures, or between PTH and hip or any nonspine fractures. We found limited evidence to support an association between calciotropic hormones and hip and nonspine fractures in older men and women. (c) 2012 American Society for Bone and Mineral Research. C1 [Barbour, Kamil E.; Boudreau, Robert; Prasad, Tanushree; Sheu, Yahtyng; Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Houston, Denise K.; Tooze, Janet A.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Sticht Ctr Aging, Dept Internal Med, Winston Salem, NC USA. [Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tylavsky, Frances A.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Barbour, KE (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, 130 N Bellefield Ave, Pittsburgh, PA 15213 USA. EM barbourk@edc.pitt.edu OI Boudreau, Robert/0000-0003-0162-5187; Kritchevsky, Stephen/0000-0003-3336-6781; Cauley, Jane A/0000-0003-0752-4408 FU NIH, National Institute on Aging FX The Health Aging and Body Composition Study (Health ABC) includes the contract numbers N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, RO1-AG028050, RO1-NR012459, and WFUHS11200. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 6 Z9 7 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2012 VL 27 IS 5 BP 1177 EP 1185 DI 10.1002/jbmr.1545 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 927VW UT WOS:000302939400021 PM 22228250 ER PT J AU Wentzensen, N Gravitt, PE Long, R Schiffman, M Dunn, ST Carreon, JD Allen, RA Gunja, M Zuna, RE Sherman, ME Gold, MA Walker, JL Wang, SS AF Wentzensen, Nicolas Gravitt, Patti E. Long, Rodney Schiffman, Mark Dunn, S. Terence Carreon, J. Daniel Allen, Richard A. Gunja, Munira Zuna, Rosemary E. Sherman, Mark E. Gold, Michael A. Walker, Joan L. Wang, Sophia S. TI Human Papillomavirus Load Measured by Linear Array Correlates with Quantitative PCR in Cervical Cytology Specimens SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID REAL-TIME PCR; EARLY END-POINTS; VIRAL LOAD; NATURAL-HISTORY; CANCER; DETERMINANTS; LESIONS; WOMEN; RISK; PROGRESSION AB Carcinogenic human papillomavirus (HPV) infections are necessary causes of most anogenital cancers. Viral load has been proposed as a marker for progression to cancer precursors but has been confirmed only for HPV16. Challenges in studying viral load are related to the lack of validated assays for a large number of genotypes. We compared viral load measured by Linear Array (LA) HPV genotyping with the gold standard, quantitative PCR (Q-PCR). LA genotyping and Q-PCR were performed in 143 cytology specimens from women referred to colposcopy. LA signal strength was measured by densitometry. Correlation coefficients and receiver operating characteristic (ROC) analyses were used to evaluate analytical and clinical performance. We observed a moderate to strong correlation between the two quantitative viral load measurements, ranging from an R value of 0.61 for HPV31 to an R value of 0.86 for HPV52. We also observed agreement between visual LA signal strength evaluation and Q-PCR. Both quantifications agreed on the disease stages with highest viral load, which varied by type (cervical intraepithelial neoplasia grade 2 [CIN2] for HPV52, CIN3 for HPV16 and HPV33, and cancer for HPV18 and HPV31). The area under the curve (AUC) for HPV16 Q-PCR at the CIN3 cutoff was 0.72 (P = 0.004), and the AUC for HPV18 LA at the CIN2 cutoff was 0.78 (P = 0.04). Quantification of LA signals correlates with the current gold standard for viral load, Q-PCR. Analyses of viral load need to address multiple infections and type attribution to evaluate whether viral load has clinical value beyond the established HPV16 finding. Our findings support conducting comprehensive studies of viral load and cervical cancer precursors using quantitative LA genotyping data. C1 [Wentzensen, Nicolas; Schiffman, Mark; Carreon, J. Daniel; Gunja, Munira; Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Long, Rodney] Natl Lib Med, Commun Engn Branch, Bethesda, MD USA. [Dunn, S. Terence; Allen, Richard A.; Zuna, Rosemary E.; Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Dunn, S. Terence; Allen, Richard A.; Zuna, Rosemary E.; Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Gold, Michael A.] Vanderbilt Univ, Dept Obstet & Gynecol, Nashville, TN USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM wentzenn@mail.nih.gov FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 18 TC 15 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2012 VL 50 IS 5 BP 1564 EP 1570 DI 10.1128/JCM.06240-11 PG 7 WC Microbiology SC Microbiology GA 927II UT WOS:000302900500011 PM 22337992 ER PT J AU Becker, A Dark, T Mason, T Goodwin, B AF Becker, A. Dark, T. Mason, T. Goodwin, B. TI 2005 Hurricane Surveillance: Measures to Reduce Carbon Monoxide Poisoning in All Floridians SO JOURNAL OF ENVIRONMENTAL HEALTH LA English DT Article ID CARBOXYHEMOGLOBIN AB The 2005 Florida hurricanes caused widespread power outages, increasing generator use that directly resulted in a surge in carbon monoxide (CO) poisonings. Of the 126 CO poisonings documented, 77% were related to generator use and 43% of these generators were placed outside but near a window. African-Americans and Latinos had a higher incidence of CO poisoning. The strength of the authors' study described here was the inclusion of the first responder network in one surveillance system for hurricane response. Notable advances have occurred since the authors' study, including CO poisoning listed as a reportable condition, regulation requiring CO detectors, CO generator warning labeling, and the development of a local surveillance and classification program for the county health departments. To prepare for future multiple hurricane seasons, comprehensive outreach should be focused at the local level through the first responder network and community groups to reduce CO poisonings in all populations. C1 [Dark, T.] Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Inst Publ Hlth, Tallahassee, FL 32307 USA. [Mason, T.] Univ S Florida, Tampa, FL 33620 USA. [Goodwin, B.] Natl Ctr Adv Translat Sci, Reno, NV USA. RP Dark, T (reprint author), Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Inst Publ Hlth, Tallahassee, FL 32307 USA. EM tyra.dark@famu.edu FU Agency for Toxic Substances and Disease Registry [U61/ATU474148-3] FX This work was funded by a grant received from the Agency for Toxic Substances and Disease Registry (U61/ATU474148-3). Data were previously reported in Becker et al., Florida Environmental Health Association Journal, 195, 20-24. NR 21 TC 0 Z9 0 U1 0 U2 2 PU NATL ENVIRON HEALTH ASSOC PI DENVER PA 720 S COLORADO BLVD SUITE 970, SOUTH TOWER, DENVER, CO 80246 USA SN 0022-0892 J9 J ENVIRON HEALTH JI J. Environ. Health PD MAY PY 2012 VL 74 IS 9 BP 16 EP 21 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 929UF UT WOS:000303090500003 PM 22590847 ER PT J AU Soto, E Romero, R Kusanovic, JP Ogge, G Hussein, Y Yeo, L Hassan, SS Kim, CJ Chaiworapongsa, T AF Soto, Eleazar Romero, Roberto Kusanovic, Juan Pedro Ogge, Giovanna Hussein, Youssef Yeo, Lami Hassan, Sonia S. Kim, Chong Jai Chaiworapongsa, Tinnakorn TI Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); soluble vascular endothelial growth factor receptor-2 (sVEGFR-2); ischemic placenta ID ENDOTHELIAL GROWTH-FACTOR; UTERINE ARTERY DOPPLER; PREGNANCY-INDUCED HYPERTENSION; FOR-GESTATIONAL-AGE; FACTOR RECEPTOR-1 CONCENTRATION; TYROSINE KINASE-1 EXPRESSION; HEALTHY NULLIPAROUS WOMEN; INNATE-IMMUNE-SYSTEM; SOLUBLE ENDOGLIN; UNITED-STATES AB Objective: An imbalance between maternal angiogenic/anti-angiogenic factors concentrations has been observed in preeclampsia (PE) and other obstetrical syndromes. However, the frequency of pathologic findings in the placenta and the changes in maternal plasma angiogenic/anti-angiogenic factor concentrations differ between late-and early-onset PE. The aim of this study was to determine if the maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 and 2 (sVEGFR-1 and sVEGFR-2) are different in late-onset PE with and without placental pathologic findings consistent with maternal underperfusion. Study design: A cross-sectional study was conducted including 64 uncomplicated women and 66 women with late-onset PE (>34 weeks) who had blood samples and placenta available for pathologic examination. Patients with late-onset PE were divided into those with and without placental histologic findings consistent with maternal underperfusion as proposed by the Society for Pediatric Pathology. Maternal plasma concentrations of PlGF, sEng, sVEGFR-1 and sVEGRF-2 were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) the prevalence of placental histological findings consistent with maternal underperfusion among women with late-onset PE was higher than that of those with an uncomplicated pregnancy (47% (31/66) vs. 7.8% (5/64), respectively; p < 0.01); 2) patients with late-onset PE and histological findings consistent with maternal underperfusion had a significantly lower median plasma concentration of PlGF, plasma PlGF/sVEGFR-1 ratio and plasma PlGF/sEng ratio than those with late-onset PE without placental underperfusion lesions (each p < 0.05); 3) the most common pathological findings in the placenta of patient with PE were lesions consistent with villous changes (77%, 24/31); and 4) isolated vascular lesions in the placenta were found only in 2 cases (6.5%), and the rest had a combination of villous and vascular lesions. Conclusions: Nearly half of the patients with late-onset PE have placental lesions consistent with maternal underperfusion. These lesions are associated with an imbalance in the maternal concentration of angiogenic/anti-angiogenic factors. We propose that there is a link between maternal underperfusion and an anti-angiogenic state characterized by the changes in the concentrations of angiogenic and anti-angiogenic factors in women with late onset PE. C1 [Soto, Eleazar; Romero, Roberto; Kusanovic, Juan Pedro; Ogge, Giovanna; Hussein, Youssef; Yeo, Lami; Hassan, Sonia S.; Kim, Chong Jai; Chaiworapongsa, Tinnakorn] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Soto, Eleazar; Kusanovic, Juan Pedro; Ogge, Giovanna; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. RP Chaiworapongsa, T (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; tchaiwor@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 154 TC 43 Z9 45 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAY PY 2012 VL 25 IS 5 BP 498 EP 507 DI 10.3109/14767058.2011.591461 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 926ZI UT WOS:000302873200010 PM 21867402 ER PT J AU Palumbo, S Toscano, CD Parente, L Weigert, R Bosetti, F AF Palumbo, Sara Toscano, Christopher D. Parente, Laura Weigert, Roberto Bosetti, Francesca TI The cyclooxygenase-2 pathway via the PGE2 EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; cuprizone; cyclooxygenases; demyelination; EP2; myelin ID CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; PROSTANOID RECEPTORS; GENE-EXPRESSION; BRAIN; INHIBITORS; DISEASE; CELLS; COX-2; MODEL AB Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis, COX-2 derived prostaglandins (PGs) are elevated in the CSF and COX-2 is up-regulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE2-EP2 receptor precede histological demyelination. COX-2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone-induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE2 EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for multiple sclerosis. C1 [Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Parente, Laura; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Bosetti, F (reprint author), NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, 9 Mem Dr,Room 1S126 MSC 0947, Bethesda, MD 20892 USA. EM frances@mail.nih.gov RI palumbo, sara/B-1603-2013 OI palumbo, sara/0000-0002-3809-6058 FU NIH, National Institute on Aging; National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and National Institute of Dental and Craniofacial Research. NR 43 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2012 VL 121 IS 3 BP 418 EP 427 DI 10.1111/j.1471-4159.2011.07363.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 923JN UT WOS:000302615700010 PM 21699540 ER PT J AU Boghossian, NS Horbar, JD Carpenter, JH Murray, JC Bell, EF AF Boghossian, Nansi S. Horbar, Jeffrey D. Carpenter, Joseph H. Murray, Jeffrey C. Bell, Edward F. CA Vermont Oxford Network TI Major Chromosomal Anomalies among Very Low Birth Weight Infants in the Vermont Oxford Network SO JOURNAL OF PEDIATRICS LA English DT Article ID NATURAL-HISTORY; PRETERM INFANTS; TRISOMY-18; SURVIVAL; MANAGEMENT; MALFORMATIONS; PREVALENCE; RATES AB Objective To examine prevalence, characteristics, interventions, and mortality of very low birth weight (VLBW) infants with trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), or triploidy. Study design Infants with birth weight 401-1500 g admitted to centers of the Vermont Oxford Network during 1994-2009 were studied. A majority of the analyses are presented as descriptive data. Median survival times and their 95% CIs were estimated using the Kaplan-Meier approach. Results Of 539 509 VLBW infants, 1681 (0.31%) were diagnosed with T21, 1416 (0.26%) with T18, 435 (0.08%) with T13, and 116 (0.02%) with triploidy. Infants with T18 were the most likely to be growth restricted (79.7%). Major surgery was reported for 30.4% of infants with T21, 9.2% with T18, 6.4% with T13, and 4.8% with triploidy. Hospital mortality occurred among 33.1% of infants with T21, 89.0% with T18, 92.4% with T13, and 90.5% with triploidy. Median survival time was 4 days (95% CI, 3-4) among infants with T18 and 3 days (95% CI, 2-4) among both infants with T13 and infants with triploidy. Conclusion In this cohort of VLBW infants, survival among infants with T18, T13, or triploidy was very poor. This information can be used to counsel families. (J Pediatr 2012;160:774-80). C1 [Boghossian, Nansi S.; Murray, Jeffrey C.; Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Horbar, Jeffrey D.; Carpenter, Joseph H.] Vermont Oxford Network, Burlington, VT USA. [Horbar, Jeffrey D.] Univ Vermont, Dept Pediat, Burlington, VT USA. RP Boghossian, NS (reprint author), NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res Eunice Kennedy S, 6100 Execut Blvd,Room 7B03C, Bethesda, MD 20892 USA. EM nansi.boghossinan@nih.gov FU NICHD NIH HHS [R01 HD057192, R01 HD052953] NR 28 TC 7 Z9 8 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2012 VL 160 IS 5 BP 774 EP U318 DI 10.1016/j.jpeds.2011.11.005 PG 18 WC Pediatrics SC Pediatrics GA 928OQ UT WOS:000302992800018 PM 22177989 ER PT J AU Carlo, WA Goudar, SS Pasha, O Chomba, E McClure, EM Biasini, FJ Wallander, JL Thorsten, V Chakraborty, H Wright, LL AF Carlo, Waldemar A. Goudar, Shivaprasad S. Pasha, Omrana Chomba, Elwyn McClure, Elizabeth M. Biasini, Fred J. Wallander, Jan L. Thorsten, Vanessa Chakraborty, Hrishikesh Wright, Linda L. TI Neurodevelopmental Outcomes in Infants Requiring Resuscitation in Developing Countries SO JOURNAL OF PEDIATRICS LA English DT Article ID PERINATAL-MORTALITY; NEONATAL ENCEPHALOPATHY; BIRTH ASPHYXIA; APGAR SCORE; AGE; POPULATION; ADAPTATION; SUBSEQUENT; DISABILITY; KATHMANDU AB Objective To determine whether resuscitation of infants who failed to develop effective breathing at birth increases survivors with neurodevelopmental impairment. Study design Infants unresponsive to stimulation who received bag and mask ventilation at birth in a resuscitation trial and infants who did not require any resuscitation were randomized to early neurodevelopmental intervention or control groups. Infants were examined by trained neurodevelopmental evaluators masked to both their resuscitation history and intervention group. The 12-month neurodevelopmental outcome data for both resuscitated and non-resuscitated infants randomized to the control groups are reported. Results The study provided no evidence of a difference between the resuscitated infants (n = 86) and the non-resuscitated infants (n = 115) in the percentage of infants at 12 months with a Mental Developmental Index <85 on the Bayley Scales of Infant Development-II (primary outcome; 18% versus 12%; P=.22) and in other neurodevelopmental outcomes. Conclusions Most infants who received resuscitation with bag and mask ventilation at birth have 12-month neurodevelopmental outcomes in the reference range. Longer follow-up is needed because of increased risk for neurodevelopmental impairments. (J Pediatr 2012;160:781-85). C1 [Carlo, Waldemar A.; Biasini, Fred J.] Univ Alabama Birmingham, Birmingham, AL 35233 USA. [Carlo, Waldemar A.; Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Goudar, Shivaprasad S.] Jawaharlal Nehru Med Coll, Belgaum, India. [Pasha, Omrana] Aga Kahn Univ Med Coll, Karachi, Pakistan. [Chomba, Elwyn] Univ Zambia, Lusaka, Zambia. [McClure, Elizabeth M.; Thorsten, Vanessa; Chakraborty, Hrishikesh] Res Triangle Inst Int, Durham, NC USA. [Wallander, Jan L.] Univ Calif, Merced, CA USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, 1700 6th Ave S 176F,Suite 9380R, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research; National Institute of Neurological Disorders and Stroke [HD43464, HD42372, HD40607, HD40636]; Fogarty International Center [TW006703]; Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham FX Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research and the National Institute of Neurological Disorders and Stroke (grants HD43464, HD42372, HD40607, and HD40636) and the Fogarty International Center (grant TW006703), and the Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham. The authors declare no conflicts of interest. NR 24 TC 7 Z9 7 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2012 VL 160 IS 5 BP 781 EP U324 DI 10.1016/j.jpeds.2011.10.007 PG 6 WC Pediatrics SC Pediatrics GA 928OQ UT WOS:000302992800019 PM 22099522 ER PT J AU Koek, W France, CP Cheng, KJ Rice, KC AF Koek, Wouter France, Charles P. Cheng, Kejun Rice, Kenner C. TI Effects of the GABA(B) Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and gamma-Hydroxybutyrate-Discriminating Pigeons SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ALCOHOL-PREFERRING RATS; ALLOSTERIC MODULATOR; DIFFERENTIAL ANTAGONISM; MOTIVATIONAL PROPERTIES; BINDING CHARACTERISTICS; TIME-COURSE; IN-VIVO; GS39783; ACID; GHB AB In vivo effects of GABA(B) receptor-positive modulators suggest them to have therapeutic potential to treat central nervous system disorders such as anxiety and drug abuse. Although these effects are thought to be mediated by positive modulation of GABA(B) receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA(B) receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). In pigeons discriminating baclofen from saline, gamma-hydroxybutyrate (GHB) produced 100% baclofen-appropriate responding, and the GABA(B) antagonist 3-aminopropyl(dimethoxymethyl) phosphinic acid (CGP35348) blocked the effects of both drugs. CGP7930 and rac-BHFF produced at most 41 and 74% baclofen-appropriate responding, respectively, and enhanced the discriminative stimulus effects of baclofen, but not of GHB. In pigeons discriminating GHB from saline, CGP7930 and rac-BHFF produced at most 1 and 49% GHB-appropriate responding, respectively, and enhanced the effects of baclofen, but not of GHB. Enhancement of the discriminative stimulus effects of baclofen by rac-BHFF and CGP7930 is further evidence of their effectiveness as GABA(B) receptor-positive modulators in vivo. Furthermore, lack of complete substitution of the positive modulators rac-BHFF and CGP7930 for baclofen and GHB suggests that their discriminative stimulus effects differ from those of GABA(B) receptor agonists. Finally, together with converging evidence that the GABA(B) receptor populations mediating the effects of baclofen and GHB are not identical, the present findings suggest that these populations differ in their susceptibility to positive modulatory effects. Such differences could allow for more selective therapeutic targeting of the GABA(B) system. C1 [Koek, Wouter; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Koek, Wouter; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Cheng, Kejun; Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Koek, W (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr,Mail Code 7792, San Antonio, TX 78229 USA. EM koek@uthscsa.edu FU National Institutes of Health National Institute on Drug Abuse [DA15692, DA17918]; National Institute on Drug Abuse; National Institutes of Health National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA15692, DA17918]; the Intramural Research Programs of the National Institute on Drug Abuse; and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism. NR 47 TC 12 Z9 12 U1 0 U2 5 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 MAY PY 2012 VL 341 IS 2 BP 369 EP 376 DI 10.1124/jpet.111.190975 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 927JM UT WOS:000302903500007 PM 22319197 ER PT J AU Miller, AC Rashid, RM Falzon, L Elamin, EM Zehtabchi, S AF Miller, Andrew C. Rashid, Rashid M. Falzon, Louise Elamin, Elamin M. Zehtabchi, Shahriar TI Silver sulfadiazine for the treatment of partial-thickness burns and venous stasis ulcers SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE burns; silver sulfadiazine; stasis dermatitis ulcer; wounds and injuries ID TRIAL; WOUNDS; RATS AB Background: For decades silver-containing antibiotics such as silver sulfadiazine (SSD) have been applied as standard topical therapy for patients with partial-thickness burns and venous stasis ulcers. This evidence-based review intends to answer the following research question: in ambulatory patients with partial-thickness burns or stasis dermatitis ulcers, does the use of topical SSD compared with nonantibiotic dressings improve mortality, wound healing, re-epithelialization, or infection rates? Methods: MEDLINE, EMBASE, Cochrane Library, and other databases were searched. We considered trials that enrolled patients of any age with partial-thickness burns or venous stasis ulcers and randomized them to either topical SSD or placebo, saline-soaked gauze, paraffin gauze, sterile dry dressing, or nonantibiotic moist dressing. Outcomes included mortality, wound healing, speed of re-epithelialization, and infection rates. Results: For burns, our search revealed 400 potential articles. No human studies met the inclusion criteria. Only 7 animal studies (1 mouse, 4 rat, and 2 pig) were relevant to the proposed question. These animal studies provided conflicting results. Whereas some support the use of SSD for treatment of partial-thickness burns, others question its effectiveness. For stasis dermatitis ulcer, the search identified 50 articles for review, of which 20 abstracts were reviewed, and one article met the inclusion criteria. This study did not show any significant improvement in the rate of complete healing in SSD group compared with placebo either at 4 weeks (relative risk 6.2, 95% confidence interval 0.8-48) or at 1 year (relative risk 5.2, 95% confidence interval 0.6-41.6) of follow-up. Conclusion: There is insufficient evidence to either support or refute the routine use of SSD for ambulatory patients with either partial-thickness burns or stasis dermatitis ulcers to decrease mortality, prevent infection, or augment wound healing in human beings. (J Am Acad Dermatol 2012;66:e159-65.) C1 [Miller, Andrew C.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Miller, Andrew C.] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Rashid, Rashid M.] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX USA. [Falzon, Louise] Columbia Univ, Med Ctr, Ctr Behav Cardiovasc Hlth, New York, NY USA. [Elamin, Elamin M.] James A Haley Vet Hosp, Dept Pulm Crit Care & Sleep Med, Tampa, FL 33612 USA. [Zehtabchi, Shahriar] Suny Downstate Med Ctr, Dept Emergency Med, Brooklyn, NY USA. [Zehtabchi, Shahriar] Kings Cty Hosp Ctr, Brooklyn, NY USA. RP Rashid, RM (reprint author), 6655 Travis,Suite 980, Houston, TX 77030 USA. EM rashidrashid.mdphd@yahoo.com OI Falzon, Louise/0000-0002-9449-6056; Miller, Andrew/0000-0001-8474-5090 NR 18 TC 11 Z9 11 U1 0 U2 11 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 MAY PY 2012 VL 66 IS 5 BP E159 EP E165 DI 10.1016/j.jaad.2010.06.014 PG 7 WC Dermatology SC Dermatology GA 926UZ UT WOS:000302858700004 PM 20724028 ER PT J AU Lau, YF Wright, AR Subbarao, K AF Lau, Yuk-Fai Wright, Amber R. Subbarao, Kanta TI The Contribution of Systemic and Pulmonary Immune Effectors to Vaccine-Induced Protection from H5N1 Influenza Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CD8(+) T-CELLS; A VIRUS; IMMUNOGLOBULIN-A; HETEROSUBTYPIC IMMUNITY; ANTIBODY-RESPONSES; LOCAL IMMUNITY; H1N1 VACCINE; CROSS-REACT; B-CELLS; LIVE AB Live attenuated influenza vaccines (LAIVs) are effective in providing protection against influenza challenge in animal models and in preventing disease in humans. We previously showed that LAIVs elicit a range of immune effectors and that successful induction of pulmonary cellular and humoral immunity in mice requires pulmonary replication of the vaccine virus. An upper respiratory tract immunization (URTI) model was developed in mice to mimic the human situation, in which the vaccine virus does not replicate in the lower respiratory tract, allowing us to assess the protective efficacy of an H5N1 LAIV against highly pathogenic H5N1 virus challenge in the absence of significant pulmonary immunity. Our results show that, after one dose of an H5N1 LAIV, pulmonary influenza-specific lymphocytes are the main contributors to clearance of challenge virus from the lungs and that contributions of influenza-specific enzyme-linked immunosorbent assay (ELISA) antibodies in serum and splenic CD8(+) T cells were negligible. Complete protection from H5N1 challenge was achieved after two doses of H5N1 LAIV and was associated with maturation of the antibody response. Although passive transfer of sera from mice that received two doses of vaccine prevented lethality in naive recipients following challenge, the mice showed significant weight loss, with high pulmonary titers of the H5N1 virus. These data highlight the importance of mucosal immunity in mediating optimal protection against H5N1 infection. Understanding the requirements for effective induction and establishment of these protective immune effectors in the respiratory tract paves the way for a more rational and effective vaccine approach in the future. C1 [Lau, Yuk-Fai; Wright, Amber R.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH Bethesda, Bethesda, MD USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH Bethesda, Bethesda, MD USA. EM ksubbarao@niaid.nih.gov FU National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). NR 51 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2012 VL 86 IS 9 BP 5089 EP 5098 DI 10.1128/JVI.07205-11 PG 10 WC Virology SC Virology GA 925RD UT WOS:000302777800032 PM 22379093 ER PT J AU Pagan, I Holmes, EC Simon-Loriere, E AF Pagan, Israel Holmes, Edward C. Simon-Loriere, Etienne TI Level of Gene Expression Is a Major Determinant of Protein Evolution in the Viral Order Mononegavirales SO JOURNAL OF VIROLOGY LA English DT Article ID STRAND RNA VIRUSES; CODON USAGE BIAS; MOLECULAR EVOLUTION; SUBSTITUTION RATES; HIGH-THROUGHPUT; P PROTEIN; YEAST; DISPENSABILITY; IDENTIFICATION; CENTRALITY AB Although the rate at which proteins change is a key parameter in molecular evolution, its determinants are poorly understood in viruses. A variety of factors, including gene length, codon usage bias, protein abundance, protein function, and gene expression level, have been shown to affect the rate of protein evolution in a diverse array of organisms. However, the role of these factors in viral evolution has yet to be addressed. The polar 3'-5' stepwise attenuation of transcription in the Mononegavirales, a group of single-strand negative-sense RNA viruses, provides a unique system to explore the determinants of protein evolution in viruses. We analyzed the relative importance of a variety of factors in shaping patterns of sequence variation in full-length genomes from 13 Mononegavirales species. Our analysis suggests that the level of gene expression, and by extension the relative genomic position of each gene, is a key determinant of the protein evolution in these viruses. This appears to be the consequence of selection for translational robustness, but not for translational accuracy, in highly expressed genes. The small genome size and number of proteins encoded by these viruses allowed us to identify other protein-specific factors that may also play a role in virus evolution, such as host-virus interactions and functional constraints. Finally, we explored the evolutionary pressures acting on noncoding regions in Mononegavirales genomes and observed that, despite being less constrained than coding regions, their evolutionary rates are also associated with genomic position. C1 [Pagan, Israel; Holmes, Edward C.; Simon-Loriere, Etienne] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pagan, I (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM jesusisrael.pagan@upm.es RI Pagan, Israel/H-1843-2015; OI Pagan, Israel/0000-0001-8876-1194; Holmes, Edward/0000-0001-9596-3552; , Etienne/0000-0001-8420-7743 FU Marie Curie Fellowship [PIOF-GA-2009-236470]; National Institutes of Health [R01 GM080533-5] FX This study was supported by a Marie Curie Fellowship PIOF-GA-2009-236470 to I.P. and National Institutes of Health grant R01 GM080533-5 to E.C.H. NR 72 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2012 VL 86 IS 9 BP 5253 EP 5263 DI 10.1128/JVI.06050-11 PG 11 WC Virology SC Virology GA 925RD UT WOS:000302777800045 PM 22345453 ER PT J AU Blazkova, J Murray, D Justement, JS Funk, EK Nelson, AK Moir, S Chun, TW Fauci, AS AF Blazkova, Jana Murray, Danielle Justement, J. Shawn Funk, Emily K. Nelson, Amy K. Moir, Susan Chun, Tae-Wook Fauci, Anthony S. TI Paucity of HIV DNA Methylation in Latently Infected, Resting CD4(+) T Cells from Infected Individuals Receiving Antiretroviral Therapy SO JOURNAL OF VIROLOGY LA English DT Article ID CPG METHYLATION; TRANSCRIPTIONAL ACTIVITY; PLASMA VIREMIA; SUPPRESSION; RESERVOIR; VECTORS AB Maintenance of HIV latency in vitro has been linked to methylation of HIV DNA. However, examinations of the degree of methylation of HIV DNA in the latently infected, resting CD4(+) T cells of infected individuals receiving antiretroviral therapy have been limited. Here, we show that methylation of the HIV 5' long terminal repeat (LTR) in the latent viral reservoir of HIV-infected aviremic individuals receiving therapy is rare, suggesting that other mechanisms are likely involved in the persistence of viral latency. C1 [Blazkova, Jana; Murray, Danielle; Justement, J. Shawn; Funk, Emily K.; Nelson, Amy K.; Moir, Susan; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov NR 13 TC 31 Z9 31 U1 0 U2 1 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 MAY PY 2012 VL 86 IS 9 BP 5390 EP 5392 DI 10.1128/JVI.00040-12 PG 3 WC Virology SC Virology GA 925RD UT WOS:000302777800060 PM 22345448 ER PT J AU San-Juan-Vergara, H Sampayo-Escobar, V Reyes, N Cha, B Pacheco-Lugo, L Wong, T Peeples, ME Collins, PL Castano, ME Mohapatra, SS AF San-Juan-Vergara, Homero Sampayo-Escobar, Viviana Reyes, Niradiz Cha, Byeong Pacheco-Lugo, Lisandro Wong, Terianne Peeples, Mark E. Collins, Peter L. Castano, Maria Eugenia Mohapatra, Shyam S. TI Cholesterol-Rich Microdomains as Docking Platforms for Respiratory Syncytial Virus in Normal Human Bronchial Epithelial Cells (vol 86, pg 1832, 2012) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [San-Juan-Vergara, Homero] Fdn Univ Norte, Dept Med, Barranquilla, Colombia. Univ S Florida, Dept Internal Med, Div Translat Med, Nanomed Res Ctr, Tampa, FL 33612 USA. Univ Cartagena, Fac Med, Cartagena De Indias, Colombia. Univ S Florida, Coll Med, Lisa Muma Weitz Lab Adv Microscopy & Cell Imaging, Tampa, FL USA. Univ Simon Bolivar, Fac Med, Barranquilla, Colombia. Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. James A Haley VA Hosp, Tampa, FL USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP San-Juan-Vergara, H (reprint author), Fdn Univ Norte, Dept Med, Barranquilla, Colombia. RI Mohapatra, Shyam/C-2500-2012 NR 1 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 VL 86 IS 9 BP 5408 EP 5408 DI 10.1128/JVI.00558-12 PG 1 WC Virology SC Virology GA 925RD UT WOS:000302777800068 ER PT J AU Ferris, RL Stefanika, P Xi, LQ Gooding, W Seethala, RR Godfrey, TE AF Ferris, Robert L. Stefanika, Patrick Xi, Liqiang Gooding, William Seethala, Raja R. Godfrey, Tony E. TI Rapid molecular detection of metastatic head and neck squamous cell carcinoma as an intraoperative adjunct to sentinel lymph node biopsy SO LARYNGOSCOPE LA English DT Article DE Sentinel node biopsy; molecular staging; oral cancer; metastasis; real-time polymerase chain reaction; Level of Evidence: 4 ID ORAL-CAVITY; CANCER PATIENTS; ELEVATED LEVELS; MESSENGER-RNA; DISSECTION; MICROMETASTASES; EXPRESSION; OROPHARYNX; MANAGEMENT AB Objectives/Hypothesis: Clinical staging of early head and neck squamous cell carcinoma (SCCHN) is often inaccurate, leading to elective neck dissection to detect the 30% of patients with micrometastatic disease. Sentinel node biopsy accurately stages the regional lymphatics, but intraoperative pathology is only moderately sensitive, and final pathology takes several days to complete. To facilitate immediate neck dissection where necessary, we have identified several promising marker genes of SCCHN metastasis and developed a rapid, accurate, and automated quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) assay for intraoperative use. Study Design: Prospective tissue collection, retrospective pathologic correlation with qRT-PCR. Methods: From a 40-gene marker screen, we quantified expression of 11 potential tumor genes using a test set of primary tumors (n = 32) and metastatic (n 19) and benign (n 10) lymph nodes. Eight patients' paired primary tumor and metastatic nodes were included. A validation set of 442 grossly tumor-negative nodes was evaluated for expression of the most promising markers, comparing metastasis detection by qRT-PCR with pathologic analysis (hematoxylin and eosin and immunohistochemistry). A novel multiplexed, automated, single-tube qRT-PCR assay was used to analyze more than 100 lymph nodes using a two-marker, 35-minute assay to determine its negative predictive value. Results: Based on expression of 11 tumor-associated genes from the marker screen, the two most promising markers of SCCHN metastasis in the test set, pemphigus vulgaris antigen (PVA) and tumor-associated calcium signal transducer 1 (TACSTD1), also known as epithelial cell adhesion molecule (EpCAM), were selected. Development of a multiplexed qRT-PCR assay for the detection of metastasis compared favorably with pathologic analysis in the additional 442-node set. A rapid, multiplexed assay using PVA and TACSTD1 demonstrated excellent reproducibility, linearity, and accuracy (approximate to 96% negative predictive value) for identifying positive (n 40) and negative (n 62) nodes in a validation subset. Conclusions: Detection of metastatic SCCHN using multiplexed qRT-PCR can be rapid, accurate, and automated and may enable sentinel node biopsy to be used for intraoperative decision-making. PCR amplification of tumor marker genes is an effective method of intraoperative molecular staging of SCCHN and could more appropriately guide application of neck dissection in pN+ SCCHN patients, sparing 60% to 70% of pN0 patients from unnecessary neck dissection. This technique may also be used for identifying residual neck disease posttreatment, using outpatient fine-needle aspiration biopsy specimens. C1 [Ferris, Robert L.] Univ Pittsburgh, Inst Eye & Ear, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15213 USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. [Seethala, Raja R.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Xi, Liqiang] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gooding, William] Univ Pittsburgh, Biostat Facil, Inst Canc, Pittsburgh, PA 15213 USA. [Godfrey, Tony E.] Univ Rochester, Dept Surg, Rochester, NY USA. [Stefanika, Patrick] Bratislava Univ, Dept Otolaryngol, Bratislava, Slovakia. RP Ferris, RL (reprint author), Univ Pittsburgh, Inst Eye & Ear, Dept Otolaryngol, Suite 500,203 Lothrop St, Pittsburgh, PA 15213 USA. EM ferrl@upmc.edu RI Godfrey, Tony/A-5572-2013; OI Godfrey, Tony/0000-0002-3283-6983; Ferris, Robert/0000-0001-6605-2071 FU NCI, University of Pittsburgh Oral Cancer Center [R01 CA90665] FX Funding was provided by NCI R01 CA90665 (R.L.F., T.E.G.), University of Pittsburgh Oral Cancer Center pilot grant. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 32 TC 15 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD MAY PY 2012 VL 122 IS 5 BP 1020 EP 1030 DI 10.1002/lary.22467 PG 11 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 927XY UT WOS:000302945100016 PM 22447185 ER PT J AU Neta, G Yu, CL Brenner, A Gu, FY Hutchinson, A Pfeiffer, R Sturgis, EM Xu, L Linet, MS Alexander, BH Chanock, S Sigurdson, AJ AF Neta, Gila Yu, Chu-Ling Brenner, Alina Gu, Fangyi Hutchinson, Amy Pfeiffer, Ruth Sturgis, Erich M. Xu, Li Linet, Martha S. Alexander, Bruce H. Chanock, Stephen Sigurdson, Alice J. TI Common genetic variants in the 8q24 region and risk of papillary thyroid cancer SO LARYNGOSCOPE LA English DT Article DE 8q24; thyroid cancer; single nucleotide polymorphisms; Level of Evidence: 3b ID GENOME-WIDE ASSOCIATION; US RADIOLOGIC TECHNOLOGISTS; PROSTATE-CANCER; SUSCEPTIBILITY LOCUS; COLORECTAL-CANCER; MULTIPLE LOCI; CARCINOMA AB Objectives/Hypothesis: Single nucleotide polymorphisms (SNPs) in the 8q24 chromosomal region identified from genome-wide scans have been associated with the risk of several cancers, including breast (rs1562430), prostate (rs1447295), and colon (rs6983267). A genome-wide scan in 26 families with papillary thyroid cancer (PTC) also found susceptibility loci in 8q24, supporting a closer evaluation of this chromosomal region in relation to the risk of sporadic PTC. Study Design: Case-control study. Methods: We evaluated 157 tag SNPs in the 8q24 chromosomal region between 120.91 Mb and 128.78 Mb (including rs1562430, rs1447295, and rs6983267) in a case-control study of 344 PTC cases and 452 age and gender frequency-matched controls. We used logistic regression to estimate odds ratios and compute P values of linear trend for PTC with genotypes of interest. To account for multiple comparisons, we applied the false discovery rate (FDR) method. Results: We did not find a significant association between rs1562430, rs1447295, or rs6983267 and PTC risk. We found that one SNP (rs4733616) was associated with PTC risk at P = .003, and 12 other SNPs were associated with PTC risk at P < .05. However, no SNPs remained significant after FDR correction. Conclusions: Our findings do not support a strong association between SNPs in the 8q24 chromosomal region and risk of sporadic PTC, but several SNPs with small effects might exist. C1 [Neta, Gila; Yu, Chu-Ling; Brenner, Alina; Linet, Martha S.; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Gu, Fangyi] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Pfeiffer, Ruth] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Hutchinson, Amy] SAIC Frederick Inc, Core Genotyping Facil, NCI Frederick, Frederick, MD USA. [Sturgis, Erich M.; Xu, Li] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Alexander, Bruce H.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN USA. [Chanock, Stephen] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. RP Neta, G (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S,Room 7049,6120 Execut Blvd, Bethesda, MD 20852 USA. EM netagil@mail.nih.gov RI Xu, Li/B-9535-2012; Gu, Fangyi/I-5957-2014 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; American Thyroid Association; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, and by a grant from the American Thyroid Association (PI: E. M. Sturgis). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 19 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD MAY PY 2012 VL 122 IS 5 BP 1040 EP 1042 DI 10.1002/lary.23209 PG 3 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 927XY UT WOS:000302945100019 PM 22275265 ER PT J AU Feng, X Zhang, T Ralston, E Ludlow, CL AF Feng, Xin Zhang, Tan Ralston, Evelyn Ludlow, Christy L. TI Differences in neuromuscular junctions of laryngeal and limb muscles in rats SO LARYNGOSCOPE LA English DT Article DE Laryngeal muscle; neuromuscular junction; single fiber; cluster fragments; gender difference; rat ID ABDUCTOR SPASMODIC DYSPHONIA; MDX MOUSE; THYROARYTENOID MUSCLE; MULTI-INNERVATION; BOTULINUM TOXIN; FIBERS; EXPRESSION; DIAPHRAGM; FATIGUE; SYNAPSE AB Objectives/Hypothesis: Laryngeal muscles are specialized for fine control of voice, speech, and swallowing, and may differ from limb muscles in many aspects. Because muscles and their controlling motor neurons communicate via neuromuscular junctions (NMJs), we hypothesized that NMJs in laryngeal muscles have specialized characteristics different from limb muscles. Study Design: In vivo study. Methods: Single muscle fibers from 12 Sprague-Dawley rats (six male, six female) were used to analyze the postsynaptic side of NMJs from laryngeal thyroarytenoid (TA), cricothyroid (CT), posterior cricoarytenoid (PCA), limb soleus (SOL), and extensor digitorum longus (EDL) muscles. NMJs were labeled with rhodamine-conjugated a-bungarotoxin. With confocal microscopy, we counted cluster fragments and measured the NMJ area, both absolute and normalized (corrected by muscle fiber diameter), for at least 10 single fibers from each muscle of each animal. Differences between genders were also compared. Results: Cluster fragments of postsynaptic NMJs were more numerous in PCA and TA compared to CT, SOL, and EDL muscles (P <.01) in both male and female rats. NMJ cluster fragments were more numerous in female than in male rats only in the TA muscle (P <.01). The absolute area covered by the NMJs showed SOL > EDL > PCA > CT > TA (P <.01); however, with normalization the SOL EDL PCA > CT TA. Conclusions: Differences found in NMJ surface and organization between laryngeal and limb muscle fibers may relate to specialized laryngeal muscle functions. Differences in NMJs between male and female rats were found only in the TA muscle, suggesting an underlying mechanism for some gender-specific laryngeal disorders related to abnormal TA muscle activity. C1 [Feng, Xin] Wake Forest Univ, Bowman Gray Sch Med, Dept Otolaryngol, Winston Salem, NC 27157 USA. [Feng, Xin; Ludlow, Christy L.] NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Tan; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD USA. [Ludlow, Christy L.] James Madison Univ, Dept Commun Sci & Disorders, Harrisonburg, VA 22807 USA. RP Feng, X (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Otolaryngol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM xfeng@wakehealth.edu OI Ludlow, Christy/0000-0002-2015-6171 FU National Institute of Neurological Disorders and Stroke; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health; Department of Otolaryngology, Wake Forest University School of Medicine; [U54 NS065701] FX This work was supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and by the Department of Otolaryngology, Wake Forest University School of Medicine.; Dr. Ludlow is a consultant for Passy Muir Inc. and Alfred Mann Foundation, and receives support from U54 NS065701. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 32 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD MAY PY 2012 VL 122 IS 5 BP 1093 EP 1098 DI 10.1002/lary.23218 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 927XY UT WOS:000302945100028 PM 22374515 ER PT J AU Shaked, A Feng, S Punch, J Reyes, J Levitsky, J Klintmalm, G Zimmerman, M DesMarais, M Kopeskie, H Priore, A Bridges, N Sayre, P AF Shaked, A. Feng, S. Punch, J. Reyes, J. Levitsky, J. Klintmalm, G. Zimmerman, M. DesMarais, M. Kopeskie, H. Priore, A. Bridges, N. Sayre, P. TI Initial Outcomes of ITN030ST: Early Post-Liver Transplant Immunosuppression Withdrawal SO LIVER TRANSPLANTATION LA English DT Meeting Abstract CT 18th Annual International Congress on ILTS CY MAY 16-19, 2012 CL San Francisco, CA SP ILTS C1 [Shaked, A.] UPenn, Philadelphia, PA USA. [Feng, S.; DesMarais, M.; Sayre, P.] UCSF, San Francisco, CA USA. [Punch, J.] U Michigan, Ann Arbor, MI USA. [Reyes, J.] U Washington, Seattle, WA USA. [Levitsky, J.] Northwestern, Chicago, IL USA. [Klintmalm, G.] Baylor, Dallas, TX USA. [Zimmerman, M.] U Colorado, Denver, CO USA. [Kopeskie, H.] RhoFed, Chapel Hill, NC USA. [Priore, A.; Bridges, N.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD MAY PY 2012 VL 18 SU 1 BP S106 EP S106 PG 1 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 929EE UT WOS:000303043200083 ER PT J AU Ramesh, A Small, ST Kloos, ZA Kazura, JW Nutman, TB Serre, D Zimmerman, PA AF Ramesh, Akshaya Small, Scott T. Kloos, Zachary A. Kazura, James W. Nutman, Thomas B. Serre, David Zimmerman, Peter A. TI The complete mitochondrial genome sequence of the filarial nematode Wuchereria bancrofti from three geographic isolates provides evidence of complex demographic history SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Filariasis; Mitochondrial genome; DNA sequence; Phylogeny ID RNA SECONDARY STRUCTURE; ELONGATION-FACTOR TU; PHYLOGENETIC ANALYSIS; POPULATION-GENETICS; PARASITIC NEMATODES; NECATOR-AMERICANUS; CODON USAGE; TRNASCAN-SE; DNA; PROGRAM AB Mitochondrial (mt) genome sequences have enabled comparison of population genetics and evolution for numerous free-living and parasitic nematodes. Here we define the complete mt genome of Wuchereria bancrofti through analysis of isolates from Papua New Guinea, India and West Africa. Sequences were assembled for each isolate and annotated with reference to the mt genome sequence for Brugia malayi. The length of the W. bancrofti mt genome is approximately 13,637 nucleotides, contains 2 ribosomal RNAs (rrns), 22 transfer RNAs (trns), 12 protein-coding genes, and is characterized by a 74.6% AT content. The W. bancrofti mt gene order is identical to that reported for Onchocerca volvulus, Dirofilaria immitis, Setaria digitata and B. malayi. In addition to using translational start codons identified previously in the mt protein-coding genes of other filarial nematodes, W. bancrofti appears to be unique in using TGT as a translational start codon. Similarly, use of incomplete stop codons in mt protein-coding genes appears to be more common in W. bancrofti than in other human filarial parasites. The complete mt genome sequence reported here provides new genetic markers for investigating phylogenetic and geographic relationships between isolates, and assessing population diversity within endemic regions. The sequence polymorphism enables new strategies to monitor the progress of public health interventions to control and eliminate this important human parasite. We illustrate the utility of this sequence and single nucleotide polymorphisms by inferring the divergence times between the three W. bancrofti isolates, suggesting predictions into their origin and migration. (C) 2012 Elsevier B.V. All rights reserved. C1 [Ramesh, Akshaya; Small, Scott T.; Kloos, Zachary A.; Kazura, James W.; Zimmerman, Peter A.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Ramesh, Akshaya; Zimmerman, Peter A.] Case Western Reserve Univ, Dept Biol, Cleveland, OH 44106 USA. [Nutman, Thomas B.] NIH, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Serre, David] Cleveland Clin, Genom Med Inst, Cleveland, OH 44195 USA. RP Zimmerman, PA (reprint author), Case Western Reserve Univ, Ctr Global Hlth & Dis, Biomed Res Bldg,Room E426,2109 Adelbert Rd, Cleveland, OH 44106 USA. EM paz@case.edu OI Zimmerman, Peter/0000-0002-5349-4513 FU National Institutes of Health [AI065717]; Fogarty International Center [TW007872, AI007024]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID) FX We thank study participants in PNG, as well as Dr. S. Bennuru for his assistance with primer design. We also thank Dr. R. Gutell for generating the rrnS and rrnL secondary structure diagrams (Fig. S3a-c) and the Broad Institute for access to the W. bancrofti mtDNA sequence data. We acknowledge financial support for this study through grants from the National Institutes of Health (AI065717 to J.W. Kazura and P.A. Zimmerman), the Fogarty International Center (Ecology of Infectious Diseases, TW007872 to P.A. Zimmerman, a T32 Postdoctoral Fellowship to S.T. Small (AI007024), and support from the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID) to Dr. T.B. Nutman. NR 57 TC 20 Z9 20 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD MAY PY 2012 VL 183 IS 1 BP 32 EP 41 DI 10.1016/j.molbiopara.2012.01.004 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 929OL UT WOS:000303075100005 PM 22326389 ER PT J AU Luo, JF Gao, YT Chow, WH Shu, XO Li, HL Yang, G Cai, QY Li, GL Rothman, N Cai, H Shrubsole, MJ Franke, AA Zheng, W Dai, Q AF Luo, Jianfeng Gao, Yu-Tang Chow, Wong-Ho Shu, Xiao-ou Li, Honglan Yang, Gong Cai, Qiuyin Li, Guoliang Rothman, Nathaniel Cai, Hui Shrubsole, Martha J. Franke, Adrian A. Zheng, Wei Dai, Qi TI Urinary polyphenols, glutathione S-transferases copy number variation, and breast cancer risk: Results from the Shanghai women's health study SO MOLECULAR CARCINOGENESIS LA English DT Article DE tea polyphenols; flavonol; flavanol; genomic polymorphism; interaction ID GREEN TEA; GENETIC POLYMORPHISMS; COLORECTAL-CANCER; DIETARY ISOTHIOCYANATES; MOLECULAR EPIDEMIOLOGY; GSTP1 POLYMORPHISMS; AMERICAN WOMEN; BLACK TEA; GSTM1; GSTT1 AB In vitro studies have found that flavanol epigallocatechin (EGC) and flavonols, but not flavanol epicatechin (EC), activate glutathione S-transferases (GSTs), a family of phase II enzymes that detoxify reactive oxygen species, such as catechol estrogen metabolites. This study was designed to investigate prospectively whether urinary excretion of tea polyphenols interacts with GST polymorphisms to influence breast cancer risk. We conducted a study of 352 incident breast cancer cases and 701 individually matched controls nested within the Shanghai Women's Health Study cohort of women aged 4070?yr at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR was used to quantify the copy number variation in the GSTM1 and GSTT1 genes. Urinary excretion of flavonols and flavanols, particularly EGC (P?=?0.02), was significantly higher among women null for GSTM1 than those positive for GSTM1. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, with a P-value of 0.04 for the interaction between EGC and GSTM1 polymorphism. In contrast, among women possessing both GSTM1 and GSTT1, breast cancer risk increased with levels of flavonols, particularly kaempferol. The differential associations between polyphenols and breast cancer risk by GST polymorphisms, if confirmed, may provide a new avenue for the personalized prevention of breast cancer. Mol. Carcinog. (c) 2011 Wiley Periodicals, Inc. C1 [Dai, Qi] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Sch Med,Inst Med & Publ Hl, Nashville, TN 37203 USA. [Luo, Jianfeng] Fudan Univ, Dept Hlth Stat & Social Med, Key Lab Publ Hlth Safety, Minist Educ,Sch Publ Hlth, Shanghai 200433, Peoples R China. [Gao, Yu-Tang; Li, Honglan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Franke, Adrian A.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. RP Dai, Q (reprint author), Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Sch Med,Inst Med & Publ Hl, 6th Floor,Suite 600,2525 W End Ave, Nashville, TN 37203 USA. RI Shrubsole, Martha/K-5052-2015; LI, GUOLIANG/E-7359-2015 OI Shrubsole, Martha/0000-0002-5591-7575; LI, GUOLIANG/0000-0001-8493-4684 FU USPHS [R01CA106591, R37CA70867]; NIH [N02 CP1101066, S10 RR020890-01] FX This study was supported by USPHS grant R01CA106591 and R37CA70867. Biological sample collection in the parent study was supported in part by NIH intramural program (N02 CP1101066) for the parent study. The authors thank Laurie Custer for the skillful performance of LC/MS assays. We also acknowledge the support by NIH grant S10 RR020890-01. NR 54 TC 8 Z9 9 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2012 VL 51 IS 5 BP 379 EP 388 DI 10.1002/mc.20799 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 923MI UT WOS:000302623000002 PM 21557334 ER PT J AU Rakocevic, G Floeter, MK AF Rakocevic, Goran Floeter, Mary Kay TI Autoimmune stiff person syndrome and related myelopathies: Understanding of electrophysiological and immunological processes SO MUSCLE & NERVE LA English DT Review DE anti-GAD antibodies; autoimmunity; GABA; paraneoplastic disorders; stiff person syndrome ID GLUTAMIC-ACID-DECARBOXYLASE; PARANEOPLASTIC NEUROLOGICAL SYNDROMES; ANTI-GAD ANTIBODIES; DEPENDENT DIABETES-MELLITUS; CEREBELLAR GABAERGIC TRANSMISSION; MATERNAL PASSIVE TRANSFER; PLACEBO-CONTROLLED TRIAL; CELL LUNG-CARCINOMA; HUMAN MOTOR CORTEX; BREAST-CANCER AB Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cellmediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS. Muscle Nerve, 2012 C1 [Rakocevic, Goran] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA. [Floeter, Mary Kay] Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, Bethesda, MD USA. RP Rakocevic, G (reprint author), Thomas Jefferson Univ, Dept Neurol, 900 Walnut St,Suite 200, Philadelphia, PA 19107 USA. EM goran.rakocevic@jefferson.edu FU National Institutes of Health, NINDS FX This study was supported by a grant from the Intramural Research Program of the National Institutes of Health, NINDS (to M.K.F.). NR 165 TC 19 Z9 22 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD MAY PY 2012 VL 45 IS 5 BP 623 EP 634 DI 10.1002/mus.23234 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 924WV UT WOS:000302722900002 PM 22499087 ER PT J AU Shupp, JW Petraitiene, R Jaskille, AD Pavlovich, AR Matt, SE Nguyen, DT Kath, MA Jeng, JC Jordan, MH Finkelman, M Walsh, TJ Shoham, S AF Shupp, Jeffrey W. Petraitiene, Ruta Jaskille, Amin D. Pavlovich, Anna R. Matt, Sarah E. Nguyen, Do T. Kath, Melissa A. Jeng, James C. Jordan, Marion H. Finkelman, Malcolm Walsh, Thomas J. Shoham, Shmuel TI Early serum (1 -> 3)-beta-D-glucan levels in patients with burn injury SO MYCOSES LA English DT Article DE Diagnosis of candidemia; burn wound infection ID INVASIVE FUNGAL-INFECTIONS; EARLY POSTBURN PERIOD; WOUND MANIPULATION; DIAGNOSIS; GLUCAN; BLOOD; CANDIDIASIS; BACTEREMIA; ASSAY AB Serum (1?3)-beta-D-glucan (BG) is increasingly used as diagnostic marker for invasive fungal infections. Exposure to gauze may lead to false-positive BG assays. The role of BG is unclear in thermally injured patients who frequently require extensive gauze coverage; therefore, we prospectively evaluated BG levels in burn-injured patients. Serum BG levels were measured in 18 burn patients immediately before application of the first dressing and 12 h after. Patients were stratified by extent of total body surface area (TBSA) requiring gauze coverage: <20%, 2039%, 4060% and >60%. BG levels were obtained from patients with non-burn trauma as controls. BG results were positive (>80 pg ml-1) in 9/18 (50%) patients at baseline and in 8/18 (44%) 12 h after application of the first dressing. BG levels were positive in 1/5 (20%) of patients with <20% TBSA requiring gauze and in 10/13 (77%) with =20% (P < 0.05). None of the control patients had positive BG at any time point and none of the patients had candidemia at baseline. Mean serum BG levels decreased (19.44 pg ml-1) after gauze placement. False-positive serum BG elevations are common in this patient population. Positivity correlates with extent of TBSA injured, but is not impacted by the gauze itself. C1 [Shupp, Jeffrey W.; Jaskille, Amin D.; Pavlovich, Anna R.; Matt, Sarah E.; Kath, Melissa A.; Jeng, James C.; Jordan, Marion H.] Washington Hosp Ctr, Burn Ctr, Dept Surg, Washington, DC 20010 USA. [Shupp, Jeffrey W.; Jaskille, Amin D.; Pavlovich, Anna R.; Matt, Sarah E.; Kath, Melissa A.; Jeng, James C.; Jordan, Marion H.; Shoham, Shmuel] MedStar Hlth Res Inst, Hyattsville, MD USA. [Nguyen, Do T.] Georgetown Univ, Sch Med, Washington, DC USA. [Finkelman, Malcolm] Associates Cape Cod Inc, E Falmouth, MA USA. [Petraitiene, Ruta; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Petraitiene, Ruta; Walsh, Thomas J.] Cornell Univ, Transplantat Oncol Infect Dis Program, Div Infect Dis, Dept Med,Weill Cornell Med Coll, New York, NY 10021 USA. [Shoham, Shmuel] Washington Hosp Ctr, Infect Dis Sect, Dept Med, Washington, DC 20010 USA. RP Shupp, JW (reprint author), 110 Irving St NW, Washington, DC 20010 USA. EM jeffrey.w.shupp@medstar.net NR 17 TC 1 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0933-7407 J9 MYCOSES JI Mycoses PD MAY PY 2012 VL 55 IS 3 BP 224 EP 227 DI 10.1111/j.1439-0507.2011.02068.x PG 4 WC Dermatology; Mycology SC Dermatology; Mycology GA 928PJ UT WOS:000302994900017 PM 21771107 ER PT J AU Sengupta, I Nadaud, PS Helmus, JJ Schwieters, CD Jaroniec, CP AF Sengupta, Ishita Nadaud, Philippe S. Helmus, Jonathan J. Schwieters, Charles D. Jaroniec, Christopher P. TI Protein fold determined by paramagnetic magic-angle spinning solid-state NMR spectroscopy SO NATURE CHEMISTRY LA English DT Article ID SITE-DIRECTED SPIN; RANGE STRUCTURAL RESTRAINTS; NUCLEAR-MAGNETIC-RESONANCE; 3D STRUCTURE DETERMINATION; STAPHYLOCOCCAL NUCLEASE; STRUCTURE REFINEMENT; DISTANCE RESTRAINTS; AMYLOID FIBRILS; CHEMICAL-SHIFTS; RELAXATION AB Biomacromolecules that are challenging for the usual structural techniques can be studied with atomic resolution by solid-state NMR spectroscopy. However, the paucity of distance restraints >5 angstrom, traditionally derived from measurements of magnetic dipole-dipole couplings between protein nuclei, is a major bottleneck that hampers such structure elucidation efforts. Here, we describe a general approach that enables the rapid determination of global protein fold in the solid phase via measurements of nuclear paramagnetic relaxation enhancements (PREs) in several analogues of the protein of interest containing covalently attached paramagnetic tags, without the use of conventional internuclear distance restraints. The method is demonstrated using six cysteine-EDTA-Cu2+ mutants of the 56-residue B1 immunoglobulin-binding domain of protein G, for which similar to 230 longitudinal backbone N-15 PREs corresponding to distances of similar to 10-20 angstrom were obtained. The mean protein fold determined in this manner agrees with the X-ray structure with a backbone atom root-mean-square deviation of 1.8 angstrom. C1 [Sengupta, Ishita; Nadaud, Philippe S.; Helmus, Jonathan J.; Jaroniec, Christopher P.] Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Jaroniec, CP (reprint author), Ohio State Univ, Dept Chem, 100 W 18th Ave, Columbus, OH 43210 USA. EM jaroniec@chemistry.ohio-state.edu RI Jaroniec, Christopher/A-4948-2008; OI Jaroniec, Christopher/0000-0003-0364-2888 FU National Science Foundation [MCB-0745754]; National Institutes of Health of the Center for Information Technology FX This research was supported by the National Science Foundation (CAREER award MCB-0745754 to C.P.J.). C.D.S. was supported by the National Institutes of Health Intramural Research Program of the Center for Information Technology. The GB1 plasmid was kindly provided by A.M. Gronenborn. NR 50 TC 47 Z9 47 U1 4 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 J9 NAT CHEM JI Nat. Chem. PD MAY PY 2012 VL 4 IS 5 BP 410 EP 417 DI 10.1038/NCHEM.1299 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 930BF UT WOS:000303109700017 PM 22522262 ER PT J AU Denk, W Briggman, KL Helmstaedter, M AF Denk, Winfried Briggman, Kevin L. Helmstaedter, Moritz TI Structural neurobiology: missing link to a mechanistic understanding of neural computation SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID SCANNING-ELECTRON-MICROSCOPY; WHOLE-CELL RECORDINGS; IN-VIVO; FLUORESCENCE MICROSCOPY; CAENORHABDITIS-ELEGANS; NETWORK ACTIVITY; NERVOUS-SYSTEM; NEURONS; SINGLE; BRAIN AB High-resolution, comprehensive structural information is often the final arbiter between competing mechanistic models of biological processes, and can serve as inspiration for new hypotheses. In molecular biology, definitive structural data at atomic resolution are available for many macromolecules; however, information about the structure of the brain is much less complete, both in scope and resolution. Several technical developments over the past decade, such as serial block-face electron microscopy and trans-synaptic viral tracing, have made the structural biology of neural circuits conceivable: we may be able to obtain the structural information needed to reconstruct the network of cellular connections for large parts of, or even an entire, mouse brain within a decade or so. Given that the brain's algorithms are ultimately encoded by this network, knowing where all of these connections are should, at the very least, provide the data needed to distinguish between models of neural computation. C1 [Denk, Winfried] Max Planck Inst Med Res, D-69120 Heidelberg, Germany. [Briggman, Kevin L.] NINDS, Bethesda, MD 20892 USA. [Helmstaedter, Moritz] Max Planck Inst Neurobiol, D-82152 Martinsried, Germany. RP Denk, W (reprint author), Max Planck Inst Med Res, Jahnstr 29, D-69120 Heidelberg, Germany. EM denk@mpimf-heidelberg.mpg.de RI denk, winfried/I-6627-2012 NR 84 TC 81 Z9 81 U1 3 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD MAY PY 2012 VL 13 IS 5 BP 351 EP 358 DI 10.1038/nrn3169 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 929KC UT WOS:000303059600013 PM 22353782 ER PT J AU Ibrahim, L DiazGranados, N Franco-Chaves, J Brutsche, N Henter, ID Kronstein, P Moaddel, R Wainer, I Luckenbaugh, DA Manji, HK Zarate, CA AF Ibrahim, Lobna DiazGranados, Nancy Franco-Chaves, Jose Brutsche, Nancy Henter, Ioline D. Kronstein, Phillip Moaddel, Ruin Wainer, Irving Luckenbaugh, David A. Manji, Husseini K. Zarate, Carlos A., Jr. TI Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE antidepressant; depression; glutamate; ketamine; NMDA; riluzole ID D-ASPARTATE ANTAGONIST; RESISTANT MAJOR DEPRESSION; MOOD DISORDERS; RATING-SCALE; TRIAL; IDEATION; STATES AB The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of >= 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n = 21) or placebo (n = 21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE = 2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone. Neuropsychopharmacology (2012) 37, 1526-1533; doi: 10.1038/npp.2011.338; published online 1 February 2012 C1 [Ibrahim, Lobna; DiazGranados, Nancy; Franco-Chaves, Jose; Brutsche, Nancy; Kronstein, Phillip; Luckenbaugh, David A.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [DiazGranados, Nancy] Univ Texas Hlth Sci Ctr, San Antonio, TX USA. [Henter, Ioline D.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Kronstein, Phillip] US FDA, Silver Spring, MD USA. [Moaddel, Ruin; Wainer, Irving] NIA, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH, 10 Ctr Dr,CRC,Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health (NIMH-NIH) FX This study was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (NIMH-NIH). The author(s) declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. A patent application for the use of ketamine in depression has been submitted listing Drs Zarate and Manji among the inventors; they have assigned their rights on the patent to the U. S. government, but will share a percentage of any royalties that may be received by the government. NR 33 TC 115 Z9 117 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2012 VL 37 IS 6 BP 1526 EP 1533 DI 10.1038/npp.2011.338 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 927GY UT WOS:000302896600019 PM 22298121 ER PT J AU Camp, MC MacPherson, KP Lederle, L Graybeal, C Gaburro, S DeBrouse, LM Ihne, JL Bravo, JA O'Connor, RM Ciocchi, S Wellman, CL Luthi, A Cryan, JF Singewald, N Holmes, A AF Camp, Marguerite C. MacPherson, Kathryn P. Lederle, Lauren Graybeal, Carolyn Gaburro, Stefano DeBrouse, Lauren M. Ihne, Jessica L. Bravo, Javier A. O'Connor, Richard M. Ciocchi, Stephane Wellman, Cara L. Luethi, Andreas Cryan, John F. Singewald, Nicolas Holmes, Andrew TI Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE gene; vmPFC; anxiety; depression; PTSD; infralimbic; stress ID POSTTRAUMATIC-STRESS-DISORDER; DEPRESSIVE-LIKE BEHAVIOR; HEART-RATE-VARIABILITY; PREFRONTAL CORTEX; RATE DYNAMICS; ADRENAL AXIS; MICE; EXTINCTION; RECEPTOR; ANXIETY AB Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear. Neuropsychopharmacology (2012) 37, 1534-1547; doi: 10.1038/npp.2011.340; published online 15 February 2012 C1 [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 21044 USA. [Gaburro, Stefano; Singewald, Nicolas] Univ Innsbruck, Dept Pharmacol & Toxicol, A-6020 Innsbruck, Austria. [Bravo, Javier A.; Cryan, John F.] Natl Univ Ireland Univ Coll Cork, Alimentary Pharmabiot Ctr, Cork, Ireland. [O'Connor, Richard M.; Cryan, John F.] Natl Univ Ireland Univ Coll Cork, Sch Pharm, Dept Pharmacol & Therapeut, Cork, Ireland. [Ciocchi, Stephane; Luethi, Andreas] Friedrich Miescher Inst, CH-4002 Basel, Switzerland. [Wellman, Cara L.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. RP Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Bethesda, MD 21044 USA. EM holmesan@mail.nih.gov RI Cryan, John/A-6950-2013 OI O'Connor, Richard/0000-0001-5351-8856; Reed, Jessica/0000-0003-0550-7284; Cryan, John/0000-0001-5887-2723 FU NIAAA; Austrian Science Fund [F4410-B19] FX We thank Daniela Pollak, Fred Helmstetter, and O Stiedl for valuable discussions and methods advice, and Heather Cameron for RIA equipment. This study was supported by the NIAAA Intramural Research Program and the Austrian Science Fund (F4410-B19). NR 62 TC 38 Z9 38 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2012 VL 37 IS 6 BP 1534 EP 1547 DI 10.1038/npp.2011.340 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 927GY UT WOS:000302896600020 PM 22334122 ER PT J AU Budde, MD Gold, E Jordan, EK Smith-Brown, M Frank, JA AF Budde, Matthew D. Gold, Eric Jordan, E. Kay Smith-Brown, Melissa Frank, Joseph A. TI Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain SO NMR IN BIOMEDICINE LA English DT Article DE MRI; phase contrast; vascular remodeling; brain metastasis; vessel co-option; ferumoxides ID ENDOTHELIAL GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; METASTASIS; TUMORS; ANGIOGENESIS; HYPOXIA; MODEL; CELL; OXYGENATION AB The early growth of micrometastatic breast cancer in the brain often occurs through vessel co-option and is independent of angiogenesis. Remodeling of the existing vasculature is an important step in the evolution of co-opting micrometastases into angiogenesis-dependent solid tumor masses. The purpose of this study was to determine whether phase contrast MRI, an intrinsic source of contrast exquisitely sensitive to the magnetic susceptibility properties of deoxygenated hemoglobin, could detect vascular changes occurring independent of angiogenesis in a rat model of breast cancer metastases to the brain. Twelve nude rats were administered 106 MDA-MB-231BRL brain-seeking breast cancer cells through intracardiac injection. Serial, multiparametric MRI of the brain was performed weekly until metastatic disease was detected. The results demonstrated that images of the signal phase (area under the receiver operating characteristic curve, 0.97) were more sensitive than T2* gradient echo magnitude images (area under the receiver operating characteristic curve, 0.73) to metastatic brain lesions. The difference between the two techniques was probably the result of the confounding effects of edema on the magnitude of the signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability measured with contrast-enhanced MRI by 12?weeks. Tumor size was correlated with permeability (R2?=?0.23, p?90th centile) and macrosomia (>4000 g) or not. We used a longitudinal random effects model with quadratic fixed and random effects to predict term LGA and macrosomia at birth. Receiver-operator curves and mean-squared error were used to measure accuracy of the prediction. Ultrasound examination around 37 weeks had the best accuracy in predicting LGA and macrosomia at birth. Adding multiple ultrasound examinations at earlier gestations did not improve the accuracy. Adjusting for maternal characteristics had limited impact on the accuracy of prediction. Thus, a single ultrasound examination at late gestation close to birth is the simplest method currently available to predict LGA and macrosomia. C1 [Albert, Paul S.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, MOE, Xinhua Hosp, Shanghai 200030, Peoples R China. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Childrens Environm Hlth, Xinhua Hosp, Shanghai 200030, Peoples R China. [Zhang, Jun] Sch Publ Hlth, Shanghai, Peoples R China. RP Albert, PS (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. EM albertp@mail.nih.gov OI Grewal, Jagteshwar/0000-0002-0141-4876 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported in part by the intramural research programme of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 20 TC 5 Z9 5 U1 0 U2 1 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 MAY PY 2012 VL 26 IS 3 BP 199 EP 207 DI 10.1111/j.1365-3016.2012.01261.x PG 9 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 921IL UT WOS:000302471200004 PM 22471679 ER PT J AU Kharrazi, M Pearl, M Yang, J DeLorenze, GN Bean, CJ Callaghan, WM Grant, A Lackritz, E Romero, R Satten, GA Simhan, H Torres, AR Westover, JB Yolken, R Williamson, DM AF Kharrazi, Martin Pearl, Michelle Yang, Juan DeLorenze, Gerald N. Bean, Christopher J. Callaghan, William M. Grant, Althea Lackritz, Eve Romero, Roberto Satten, Glen A. Simhan, Hyagriv Torres, Anthony R. Westover, Jonna B. Yolken, Robert Williamson, Dhelia M. TI California Very Preterm Birth Study: design and characteristics of the population- and biospecimen bank-based nested case-control study SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Study design; California Very Preterm Birth Study ID TUMOR-NECROSIS-FACTOR; SINGLE-NUCLEOTIDE POLYMORPHISMS; CYTOKINE GENE POLYMORPHISMS; PROGESTERONE-RECEPTOR GENE; THAN-G POLYMORPHISM; FACTOR-ALPHA GENE; PREMATURE-RUPTURE; AFRICAN-AMERICANS; FETAL MEMBRANES; THROMBOPHILIC POLYMORPHISMS AB Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the US. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from state-wide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants of different types of VPTB with the ultimate aim of reducing infant mortality, morbidity and racial disparities in these health outcomes in the US and elsewhere. C1 [Kharrazi, Martin] Calif Dept Publ Hlth, Program Res & Demonstrat Sect, Genet Dis Screening Program, Richmond, CA 94804 USA. [Pearl, Michelle; Yang, Juan] Sequoia Fdn, La Jolla, CA USA. [DeLorenze, Gerald N.] Kaiser Permanente, Div Res, Oakland, CA USA. [Bean, Christopher J.; Grant, Althea] Ctr Dis Control & Prevent, Div Blood Disorders, Atlanta, GA USA. [Callaghan, William M.; Lackritz, Eve; Satten, Glen A.; Williamson, Dhelia M.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Simhan, Hyagriv] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Torres, Anthony R.; Westover, Jonna B.] Utah State Univ, Ctr Persons Disabil, Logan, UT 84322 USA. [Yolken, Robert] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Kharrazi, M (reprint author), Calif Dept Publ Hlth, Program Res & Demonstrat Sect, Genet Dis Screening Program, 850 Marina Bay Pkwy,Room F175,Mail Stop 8200, Richmond, CA 94804 USA. EM marty.kharrazi@cdph.ca.gov OI Satten, Glen/0000-0001-7275-5371 FU Centers for Disease Control and Prevention; March of Dimes Birth Defects Foundation [21-FY05-1248]; Tobacco Related Disease Research Program [8RT-0115] FX This study was funded in part by the Centers for Disease Control and Prevention and the March of Dimes Birth Defects Foundation (project #21-FY05-1248). Project Baby's Breath, which created the initial prenatal specimen bank used by this study, was funded by the Tobacco Related Disease Research Program (grant #8RT-0115) (Drs Martin Kharrazi and Gerald N. DeLorenze, Co-PIs). Drs John Harris and Gary Shaw were responsible for the creation of the second prenatal specimen bank. Dr George Cunningham was responsible for the creation of the newborn specimen bank. California Birth Defects Monitoring Program staff (Jennifer Nicholson, Brandy Stephenson, Butch Arciaga and Cori DeTarr) conducted hospital abstraction under the supervision of Barbara Warmerdam. Steve Graham and Oren Bergman conducted record linkage of the screening and vital records data files. Megan Wier contributed to the study design and the conduct of the study in its early phases. Angela DiLaura and Marissa Root assisted with project coordination. Dr Michael S. Kramer gave valuable input on the early development of the abstraction form and F. Carol Bruce gave feedback on the conduct of the study. NR 86 TC 6 Z9 6 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2012 VL 26 IS 3 BP 250 EP 263 DI 10.1111/j.1365-3016.2011.01252.x PG 14 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 921IL UT WOS:000302471200009 PM 22471684 ER PT J AU Ito, T Igarashi, H Jensen, RT AF Ito, Tetsuhide Igarashi, Hisato Jensen, Robert T. TI Serum Pancreastatin The Long Sought Universal, Sensitive, Specific Tumor Marker for Neuroendocrine Tumors? SO PANCREAS LA English DT Editorial Material ID CHROMOGRANIN-A; PEPTIDES; GASTRINOMAS; PROHORMONE; SURVIVAL; THERAPY; PLASMA C1 [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20817 USA. [Ito, Tetsuhide; Igarashi, Hisato] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 812, Japan. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20817 USA. EM robertj@bdg10.niddk.nih.gov FU Intramural NIH HHS [ZIA DK053200-19, Z99 DK999999] NR 21 TC 16 Z9 19 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAY PY 2012 VL 41 IS 4 BP 505 EP 507 DI 10.1097/MPA.0b013e318249a92a PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 928VD UT WOS:000303014100001 PM 22504376 ER PT J AU Zhang, YH Miura, K Li, J Tullo, G Zhu, F Hong, LX Lin, TL Su, XZ Long, C AF Zhang, Yanhui Miura, Kazutoyo Li, Jian Tullo, Gregory Zhu, Feng Hong, Lingxian Lin, Tianlong Su, Xin-zhuan Long, Carole TI Macrophage migration inhibitory factor homolog from Plasmodium yoelii modulates monocyte recruitment and activation in spleen during infection SO PARASITOLOGY RESEARCH LA English DT Article ID FACTOR MIF; FALCIPARUM-MALARIA; INDUCED ARTHRITIS; EXPRESSION; HEMOZOIN; ANTIGEN; ANEMIA; CELLS; GLUCOCORTICOIDS; PHAGOCYTOSIS AB Macrophage migration inhibitory factor (MIF) has been shown to be involved in the pathogenesis of severe malaria. Malaria parasites express an MIF homolog that may play a role in regulating host immune responses, and a recent study showed that overexpression of MIF reduced parasitemia in a mouse malaria model. Another recent study showed migration of monocytes to the spleen contributed to the control of blood stage infection. However, there are few papers describing the effect of MIF on monocyte recruitment/activation during the infection. We generated recombinant Plasmodium yoelii MIF (rPyMIF) and investigated its function on purified mouse CD11b(+) cells in vitro and monocyte responses in vivo. The result shows that rPyMIF protein bound to mouse CD11b(+) cells and inhibited their random migration in vitro. On the other hand, rPyMIF did not induce cytokine release from the cells directly or modulate lipopolysaccharide-induced cytokine release. Mice immunized with rPyMIF showed transient but significantly lower parasitemia than the control mice at day 3 after lethal Py17XL challenge. The total number of CD11b(+) cells in the spleens was significantly higher in rPyMIF-immunized group. Further investigation revealed that there were significantly higher numbers of recruited and activated monocytes in the spleens of rPyMIF immunization group on day 3. These results indicate that PyMIF potentially modulates monocyte recruitment and activation during infection of P. yoelii erythrocytic stages. C1 [Zhang, Yanhui; Miura, Kazutoyo; Li, Jian; Tullo, Gregory; Su, Xin-zhuan; Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Zhang, Yanhui; Li, Jian; Zhu, Feng; Hong, Lingxian; Su, Xin-zhuan] Xiamen Univ, State Key Lab Stress Cell Biol, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China. [Lin, Tianlong] Fujian Acad Agr Sci, Fuzhou 350002, Fujian, Peoples R China. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kmiura@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Basic Research Program of China (973 Program) [2007CB513103]; Science Planning Program of Fujian Province [2010 J1008]; 111 Project of Education of China [B06016] FX We thank Lubin Jiang and Cecilia Huaman for their technical help and the animal facility in NIH Twinbrook 3 for taking care of the mice. We also thank intramural editor Brenda Rae Marshall for editorial assistance. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by grants from the National Basic Research Program of China (973 Program) 2007CB513103, from the Science Planning Program of Fujian Province (2010 J1008), and from 111 Project of Education of China (no. B06016). NR 31 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-0113 J9 PARASITOL RES JI Parasitol. Res. PD MAY PY 2012 VL 110 IS 5 BP 1755 EP 1763 DI 10.1007/s00436-011-2696-6 PG 9 WC Parasitology SC Parasitology GA 926ES UT WOS:000302814700021 PM 22015474 ER PT J AU Diesner, SC Forster-Waldl, E Olivera, A Pollak, A Jensen-Jarolim, E Untersmayr, E AF Diesner, Susanne C. Foerster-Waldl, Elisabeth Olivera, Ana Pollak, Arnold Jensen-Jarolim, Erika Untersmayr, Eva TI Perspectives on immunomodulation early in life SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Review DE food allergy; immunomodulation; infection; newborns; sphingolipid; Th2; Toll-like receptor ID RESPIRATORY SYNCYTIAL VIRUS; INTESTINAL EPITHELIAL-CELLS; NEONATAL DENDRITIC CELLS; SPHINGOSINE KINASE 1; CPG OLIGODEOXYNUCLEOTIDES; IMMUNE-RESPONSES; ALLERGIC DISEASE; INNATE IMMUNITY; AIRWAY INFLAMMATION; CORD BLOOD AB The immune system early in life is characterized by immature activation and function of immune cells and a preponderance of Th2 cytokines. Together with other factors such as genetics and epigenetics, these immature immune responses might prone newborns susceptible to severe infections as well as allergic diseases. Immunomodulation therapy may have potential as therapeutic strategy against those disorders and might have implication in early-life interventions in the future. In this review, we will focus on two immunomodulatory substance classes, Toll-like receptor (TLR) ligands and sphingolipids, which are the focus of extensive research to date. Both TLRs and sphingolipid receptors have a very distinct distribution pattern and function on immune cells. Therefore, they can potentially modulate and balance immune responses, which might be in particular beneficial for the immaturity of the immune response early in life. C1 [Diesner, Susanne C.; Jensen-Jarolim, Erika; Untersmayr, Eva] Med Univ Vienna, Dept Pathophysiol & Allergy Res, Ctr Pathophysiol Infectiol & Immunol, A-1090 Vienna, Austria. [Diesner, Susanne C.; Foerster-Waldl, Elisabeth; Pollak, Arnold] Med Univ Vienna, Dept Pediat & Adolescent Med, A-1090 Vienna, Austria. [Olivera, Ana] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD USA. [Jensen-Jarolim, Erika] Med Univ Vienna, Messerli Res Inst, Vet Univ Vienna, A-1090 Vienna, Austria. [Jensen-Jarolim, Erika] Univ Vienna, Vienna, Austria. RP Untersmayr, E (reprint author), Med Univ Vienna, Dept Pathophysiol & Allergy Res, Ctr Pathophysiol Infectiol & Immunol, Waehringer Guertel 18-20,E3Q, A-1090 Vienna, Austria. EM eva.untersmayr@meduniwien.ac.at FU Austrian Science fund [P21884, P21577]; OeNB [13071] FX This work is supported by the Austrian Science fund projects P21884 and P21577 and the OeNB project 13071. NR 111 TC 12 Z9 13 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0905-6157 EI 1399-3038 J9 PEDIAT ALLERG IMM-UK JI Pediatr. Allergy Immunol. PD MAY PY 2012 VL 23 IS 3 BP 210 EP 223 DI 10.1111/j.1399-3038.2011.01259.x PG 14 WC Allergy; Immunology; Pediatrics SC Allergy; Immunology; Pediatrics GA 927UA UT WOS:000302934400002 PM 22299601 ER PT J AU Tildesley, MJ Smith, G Keeling, MJ AF Tildesley, Michael J. Smith, Gary Keeling, Matt J. TI Modeling the spread and control of foot-and-mouth disease in Pennsylvania following its discovery and options for control SO PREVENTIVE VETERINARY MEDICINE LA English DT Article DE Foot and mouth disease; Spatial model; USA; Culling; Vaccination ID H5N1 AVIAN INFLUENZA; 2001 UK FOOT; GREAT-BRITAIN; VACCINATION STRATEGIES; NATURAL AEROSOLS; POULTRY FLOCK; FMD EPIDEMIC; OUTBREAK; TRANSMISSION; VIRUS AB In this paper, we simulate outbreaks of foot-and-mouth disease in the Commonwealth of Pennsylvania, USA - after the introduction of a state-wide movement ban - as they might unfold in the presence of mitigation strategies. We have adapted a model previously used to investigate FMD control policies in the UK to examine the potential for disease spread given an infection seeded in each county in Pennsylvania. The results are highly dependent upon the county of introduction and the spatial scale of transmission. Should the transmission kernel be identical to that for the UK, the epidemic impact is limited to fewer than 20 premises, regardless of the county of introduction. However, for wider kernels where infection can spread further, outbreaks seeded in or near the county with highest density of premises and animals result in large epidemics (>150 premises). Ring culling and vaccination reduce epidemic size, with the optimal radius of the rings being dependent upon the county of introduction. Should the kernel width exceed a given county-dependent threshold, ring culling is unable to control the epidemic. We find that a vaccinate-to-live policy is generally preferred to ring culling (in terms of reducing the overall number of premises culled), indicating that well-targeted control can dramatically reduce the risk of large scale outbreaks of foot-and-mouth disease occurring in Pennsylvania. (c) 2011 Elsevier B.V. All rights reserved. C1 [Tildesley, Michael J.] Univ Warwick, Ctr Complex Sci, Coventry CV4 7AL, W Midlands, England. [Tildesley, Michael J.] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, Gary] Univ Penn, Sch Vet Med, New Bolton Ctr, Kennett Sq, PA 19348 USA. [Keeling, Matt J.] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. RP Tildesley, MJ (reprint author), Univ Warwick, Ctr Complex Sci, Zeeman Bldg, Coventry CV4 7AL, W Midlands, England. EM M.J.Tildesley@warwick.ac.uk RI Keeling, Matt/J-9280-2012; OI Keeling, Matt/0000-0003-4639-4765 FU Directorate of Science and Technology, U.S. Department of Homeland Security, Chemical/Biological Division; National Institute of General Medical Sciences [5U01GM-076426]; Science and Technology Directorate, Department of Homeland Security [ST-108-000017] FX This work was made possible by funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) Program, Directorate of Science and Technology, U.S. Department of Homeland Security, Chemical/Biological Division, by award number 5U01GM-076426 from the National Institute of General Medical Sciences and by the Foreign Animal Disease Modeling program of the Science and Technology Directorate, Department of Homeland Security (grant ST-108-000017). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, the National Institutes of Health or the Department of Homeland Security. NR 61 TC 6 Z9 7 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 EI 1873-1716 J9 PREV VET MED JI Prev. Vet. Med. PD MAY 1 PY 2012 VL 104 IS 3-4 BP 224 EP 239 DI 10.1016/j.prevetmed.2011.11.007 PG 16 WC Veterinary Sciences SC Veterinary Sciences GA 929AF UT WOS:000303032900005 PM 22169708 ER PT J AU Knowles, MR Leigh, MW Carson, JL Davis, SD Dell, SD Ferkol, TW Olivier, KN Sagel, SD Rosenfeld, M Burns, KA Minnix, SL Armstrong, MC Lori, A Hazucha, MJ Loges, NT Olbrich, H Becker-Heck, A Schmidts, M Werner, C Omran, H Zariwala, MA AF Knowles, Michael R. Leigh, Margaret W. Carson, Johnny L. Davis, Stephanie D. Dell, Sharon D. Ferkol, Thomas W. Olivier, Kenneth N. Sagel, Scott D. Rosenfeld, Margaret Burns, Kimberlie A. Minnix, Susan L. Armstrong, Michael C. Lori, Adriana Hazucha, Milan J. Loges, Niki T. Olbrich, Heike Becker-Heck, Anita Schmidts, Miriam Werner, Claudius Omran, Heymut Zariwala, Maimoona A. CA Genetic Disorders Mucociliary TI Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure SO THORAX LA English DT Article ID DYNEIN ARM DEFECTS; HEAVY-CHAIN; CHLAMYDOMONAS FLAGELLA; SITUS-INVERSUS; GENE; ASYMMETRY; DOMAIN; DNAI1; MUTANT; INNER AB Rationale Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients. C1 [Knowles, Michael R.; Burns, Kimberlie A.; Minnix, Susan L.; Armstrong, Michael C.; Lori, Adriana; Hazucha, Milan J.] UNC Sch Med, Dept Med, Chapel Hill, NC USA. [Leigh, Margaret W.; Carson, Johnny L.; Davis, Stephanie D.] UNC Sch Med, Dept Pediat, Chapel Hill, NC USA. [Dell, Sharon D.] Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Rosenfeld, Margaret] Childrens Hosp & Reg Med Ctr, Seattle, WA USA. [Loges, Niki T.; Becker-Heck, Anita; Schmidts, Miriam; Omran, Heymut] Univ Hosp, Dept Pediat & Adolescent Med, Freiburg, Germany. [Loges, Niki T.; Olbrich, Heike; Becker-Heck, Anita; Werner, Claudius; Omran, Heymut] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed Allgemeine Pad, Munster, Germany. [Loges, Niki T.; Becker-Heck, Anita] Univ Freiburg, Fac Biol, D-79106 Freiburg, Germany. [Zariwala, Maimoona A.] UNC Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. RP Knowles, MR (reprint author), Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Sch Med, CB 7248,7123 Thurston Bowles Bldg, Chapel Hill, NC 27599 USA. EM knowles@med.unc.edu RI Schmidts, Miriam/A-3777-2012; OI Schmidts, Miriam/0000-0002-1714-6749; Milla, Carlos/0000-0001-5515-3053 FU National Institute of Health [5 U54 HL096458-06]; Office of the Director; ORDR; NHLBI; National Institutes of Health [5 R01HL071798]; Children's Discovery Institute; National Institute of Allergy and Infectious Diseases; Flight Attendant Medical Research Institute; Deutsche Forschungsgemeinschaft (DFG) [Om 6/4, GRK1104, SFB592]; US Federal government from National Heart, Lung, and Blood Institute [N01-HV-48194]; National Center of Research Resources [RR00046, UL1 RR025747, UL1 RR025780]; NHLBI [5 U54 HL096458-06, P01 HL034322]; CFF [R026-CR07]; NIH Office of Rare Diseases Research (ORDR); [R01 HL08265] FX MRK, MWL, JLC, MJH, SLM, SDD, TWF, KNO, SDS, MR, KEB, MCA, AL and MAZ are supported by National Institute of Health research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by ORDR and NHLBI, NIH. MRK and MAZ are supported by National Institutes of Health grant 5 R01HL071798. TWF is supported by R01 HL08265 and Children's Discovery Institute. KNO is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. JLC is supported by Clinical Innovator Award by Flight Attendant Medical Research Institute. HO is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Om 6/4, GRK1104, SFB592). Resequencing was provided by the University of Washington, Department of Genome Sciences, under US Federal government contract number N01-HV-48194 from National Heart, Lung, and Blood Institute. This work was supported in part by grants RR00046, UL1 RR025747 and UL1 RR025780 from the National Center of Research Resources, NHLBI P01 HL034322, NIH and CFF R026-CR07. This consortium, Genetic Disorders of Mucociliary Clearance is part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project was provided by grant 5 U54 HL096458-06 from the NHLBI and the NIH Office of Rare Diseases Research (ORDR). The views expressed do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organisations imply endorsement by the U.S government. NR 42 TC 51 Z9 54 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD MAY PY 2012 VL 67 IS 5 BP 433 EP 441 DI 10.1136/thoraxjnl-2011-200301 PG 9 WC Respiratory System SC Respiratory System GA 928CX UT WOS:000302959000014 PM 22184204 ER PT J AU Consonni, D De Matteis, S Pesatori, AC Cattaneo, A Cavallo, DM Lubin, JH Tucker, M Bertazzi, PA Caporaso, NE Wacholder, S Landi, MT AF Consonni, Dario De Matteis, Sara 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 SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE epidemiology; occupational health; case-control study; pulmonary neoplasms; construction industry ID CONSTRUCTION-INDUSTRY; OCCUPATIONAL EXPOSURES; MORTALITY; SILICA; HEALTH; WORK; CARCINOGENS; PREVENTION; COMMUNITY; UK AB Background Bricklayers may be at increased risk of lung cancer, although a firm association has not been established. We examined this association within the EAGLE (Environment And Genetics in Lung cancer Etiology) study, a population-based casecontrol study conducted in Italy between 2002 and 2005. Methods For men in selected occupations in the construction sector we calculated smoking-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). For bricklayers we estimated the population attributable fraction (PAF) and the attributable community risk (ACR). Results We found increased lung cancer risk for bricklayers (OR 1.57, 95% CI 1.12-2.21; 147 cases, 81 controls). The PAF was 3.9% (95% CI 0.7-7.0), corresponding to an ACR of 4.1 cases annually per 100,000 men (95% CI 0.7-7.3) in the whole community. Among bricklayers, there were increased risks for squamous cell (OR 2.03, 95% CI 1.32-3.13, 56 exposed cases) and small cell carcinomas (OR 2.29, 95% CI 1.29-4.07, 21 exposed cases), while no excess (OR 1.06, 95% CI 0.68-1.65, 41 exposed cases) was found for adenocarcinoma. Conclusions Our findings provide additional evidence of increased lung cancer risk in Italian bricklayers. The association is plausible because they are exposed to several carcinogens, notably crystalline silica. Am. J. Ind. Med. 55: 423-428, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Consonni, Dario; De Matteis, Sara; Pesatori, Angela C.; Bertazzi, Pier Alberto] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Dept Prevent Med, Epidemiol Unit, I-20122 Milan, Italy. [De Matteis, Sara; Pesatori, Angela C.; Cavallo, Domenico M.; Bertazzi, Pier Alberto] Univ Milan, Dept Occupat & Environm Hlth, Milan, Italy. [Cattaneo, Andrea; Cavallo, Domenico M.] Univ Insubria, Dept Chem & Environm Sci, Como, Italy. [De Matteis, Sara; Lubin, Jay H.; Tucker, Margaret; Caporaso, Neil E.; Wacholder, Sholom; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Consonni, D (reprint author), Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Dept Prevent Med, Epidemiol Unit, Via San Barnaba, I-20122 Milan, Italy. EM dario.consonni@unimi.it RI Cavallo, Domenico Maria/F-9881-2013; Tucker, Margaret/B-4297-2015; Cattaneo, Andrea/J-4791-2013; Consonni, Dario/K-7943-2016; bertazzi, pietro alberto/D-5039-2017; OI Cavallo, Domenico Maria/0000-0003-1853-2999; Cattaneo, Andrea/0000-0002-2962-7259; Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449; pesatori, angela/0000-0002-0261-3252 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; Lombardy Region (Environmental Epidemiology Program), Milan, Italy; CARIPLO Foundation, Milan, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL, Rome, Italy FX The authors wish to thank Dr. Ester Bramati for helping to code occupational histories. They also express their gratitude to all the EAGLE study participants and collaborators (listed on the EAGLE website at http://eagle.cancer.gov/), whose contribution made this study possible. This work was supported by: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; Lombardy Region (Environmental Epidemiology Program), Milan, Italy; CARIPLO Foundation, Milan, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL, Rome, Italy. NR 30 TC 4 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2012 VL 55 IS 5 BP 423 EP 428 DI 10.1002/ajim.22017 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 925XD UT WOS:000302794500003 PM 22298231 ER PT J AU Epstein, DH Preston, KL AF Epstein, David H. Preston, Kenzie L. TI TGI Monday?: Drug-Dependent Outpatients Report Lower Stress and More Happiness at Work than Elsewhere SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID DAILY-LIFE; NEGATIVE AFFECT; FOLLOW-UP; COCAINE; MOOD; SMOKING; CONTRASTS; RESPONSES; PATTERNS; EXERCISE AB In the general population, experience-sampling studies show that work is the aspect of daily life most associated with momentary unhappiness and a desire to be elsewhere. We assessed whether this holds true for urban outpatients in treatment for heroin and cocaine dependence. In a 25-week natural-history study, 79 employed methadone-maintained misusers of heroin and cocaine carried electronic diaries on which mood and behavior were assessed up to five times per day. Being at work was associated with lower stress, greater happiness, and lower drug craving. Work accounted for 14% of the variance in stress, 30% of the variance in happiness, and 50% of the variance in cocaine craving. Participants with skilled jobs reported more positive and less negative mood states (and lower cocaine craving) at all times compared to participants with semi/unskilled jobs, although the latter reported greater mood improvement at work. In all participants, mood improvements occurred specifically in the presence of coworkers (not other companions). Our seemingly unusual findings might be specific to substance-disorder patients (for whom work may be a respite from drug-using companions), but might also hold for other urban dwellers of similar socioeconomic backgrounds (for whom work may be a respite from environmental stressors). (Am J Addict 2012;21:189198) C1 [Epstein, David H.; Preston, Kenzie L.] NIDA, Treatment Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Epstein, DH (reprint author), NIDA, Intramural Res Program, Treatment Sect, Clin Pharmacol & Therapeut Branch, Room 01B-606,251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM depstein@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS [Z99 DA999999] NR 34 TC 6 Z9 6 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD MAY-JUN PY 2012 VL 21 IS 3 BP 189 EP 198 DI 10.1111/j.1521-0391.2012.00230.x PG 10 WC Substance Abuse SC Substance Abuse GA 923IL UT WOS:000302612900003 PM 22494220 ER PT J AU Stewart, PA Vermeulen, R Coble, JB Blair, A Schleiff, P Lubin, JH Attfield, M Silverman, DT AF Stewart, Patricia A. Vermeulen, Roel Coble, Joseph B. Blair, Aaron Schleiff, Patricia Lubin, Jay H. Attfield, Mike Silverman, Debra T. TI The Diesel Exhaust in Miners Study: V. Evaluation of the Exposure Assessment Methods SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE diesel exhaust; elemental carbon; exposure assessment; mining ID NONMETAL MINING FACILITIES; PARTICULATE MATTER; ELEMENTAL CARBON AB Exposure to respirable elemental carbon (REC), a component of diesel exhaust (DE), was assessed for an epidemiologic study investigating the association between DE and mortality, particularly from lung cancer, among miners at eight mining facilities from the date of dieselization (1947-1967) through 1997. To provide insight into the quality of the estimates for use in the epidemiologic analyses, several approaches were taken to evaluate the exposure assessment process and the quality of the estimates. An analysis of variance was conducted to evaluate the variability of 1998-2001 REC measurements within and between exposure groups of underground jobs. Estimates for the surface exposure groups were evaluated to determine if the arithmetic means (AMs) of the REC measurements increased with increased proximity to, or use of, diesel-powered equipment, which was the basis on which the surface groups were formed. Estimates of carbon monoxide (CO) (another component of DE) air concentrations in 1976-1977, derived from models developed to predict estimated historical exposures, were compared to 1976-1977 CO measurement data that had not been used in the model development. Alternative sets of estimates were developed to investigate the robustness of various model assumptions. These estimates were based on prediction models using: (i) REC medians rather AMs, (ii) a different CO:REC proportionality than a 1:1 relation, and (iii) 5-year averages of historical CO measurements rather than modeled historical CO measurements and DE-related determinants. The analysis of variance found that in three of the facilities, most of the between-group variability in the underground measurements was explained by the use of job titles. There was relatively little between-group variability in the other facilities. The estimated REC AMs for the surface exposure groups rose overall from 1 to 5 mu g m(-3) as proximity to, and use of, diesel equipment increased. The alternative estimates overall were highly correlated (similar to 0.9) with the primary set of estimates. The median of the relative differences between the 1976-1977 CO measurement means and the 1976-1977 estimates for six facilities was 29%. Comparison of estimated CO air concentrations from the facility-specific prediction models with historical CO measurement data found an overall agreement similar to that observed in other epidemiologic studies. Other evaluations of components of the exposure assessment process found moderate to excellent agreement. Thus, the overall evidence suggests that the estimates were likely accurate representations of historical personal exposure levels to DE and are useful for epidemiologic analyses. C1 [Stewart, Patricia A.; Vermeulen, Roel; Coble, Joseph B.; Blair, Aaron; Lubin, Jay H.; Silverman, Debra T.] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schleiff, Patricia; Attfield, Mike] US Natl Inst Occupat Safety & Hlth, Surveillance Branch, Div Resp Dis Studies, Morgantown, WV 26505 USA. RP Silverman, DT (reprint author), US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM silvermd@mail.nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute FX Division of Cancer Epidemiology and Genetics of the National Cancer Institute. NR 15 TC 13 Z9 13 U1 1 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD MAY PY 2012 VL 56 IS 4 BP 389 EP 400 DI 10.1093/annhyg/mes020 PG 12 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 926BP UT WOS:000302806600003 ER PT J AU Nichols, JH Loeb, S Metter, EJ Ferrucci, L Carter, HB AF Nichols, John H. Loeb, Stacy Metter, E. Jeffrey Ferrucci, Luigi Carter, H. Ballentine TI The relationship between prostate volume and prostate-specific antigen variability: data from the Baltimore Longitudinal Study of Aging and the Johns Hopkins Active Surveillance Program SO BJU INTERNATIONAL LA English DT Article DE PSA; prostate volume; PSA variability ID CANCER; SERUM; MORTALITY; VELOCITY; MEN; MRI AB OBJECTIVE To clarify the relationship between serial prostate-specific antigen (PSA) variability and prostate volume in both cancer-free participants from the Baltimore Longitudinal Study of Aging (BLSA) and patients with low-risk prostate cancer from the Johns Hopkins Active Surveillance Program (AS). MATERIALS AND METHODS In all, 287 men from the BLSA and 131 patients from the AS were included in the analysis, all with at least two PSA measurements and concurrent prostate volume measurements. PSA variability was calculated in ng/mL per year, and a linear mixed-effects model was used to determine the relative effects of prostate volume, baseline PSA and age on PSA change over time. RESULTS In a model with prostate volume, age and baseline PSA, there was no significant relationship between prostate volume and PSA variability (BLSA, P = 0.57; AS, P = 0.49). Only baseline PSA showed a significant relationship to PSA yearly variability (PSAYV) (P < 0.001). Specifically, a one unit higher baseline PSA (ng/mL) corresponded on average to 0.09 and 0.06 ng/mL per year higher PSAYV in the BLSA and AS populations, respectively. CONCLUSIONS The results of the present study suggest that the primary driver of PSA variability is the baseline PSA level, rather than prostate volume. Clinicians might consider the baseline PSA level to help predict the expected variability in serial PSA measurements. C1 [Nichols, John H.] Johns Hopkins Univ Hosp, Sch Med, Baltimore, MD 21287 USA. [Loeb, Stacy; Carter, H. Ballentine] Johns Hopkins Univ Hosp, Dept Urol, Baltimore, MD 21287 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Nichols, JH (reprint author), Johns Hopkins Univ Hosp, Sch Med, Urol Marburg 145,600 N Wolfe St, Baltimore, MD 21287 USA. EM jnicho22@jhmi.edu OI Loeb, Stacy/0000-0003-3933-9207 FU National Institutes of Health, the National Institute on Aging; James Buchanan Brady Urological Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute on Aging, and the James Buchanan Brady Urological Institute. NR 15 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD MAY PY 2012 VL 109 IS 9 BP 1304 EP 1308 DI 10.1111/j.1464-410X.2011.10663.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 923JR UT WOS:000302616100009 PM 22093443 ER PT J AU Oz, M Isaev, D Lorke, DE Hasan, M Petroianu, G Shippenberg, TS AF Oz, Murat Isaev, Dmytro Lorke, Dietrich E. Hasan, Muhammed Petroianu, Georg Shippenberg, Toni S. TI Methylene blue inhibits function of the 5-HT transporter SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE 5-HT transporter; methylene blue; HEK-293 cells ID SPATIALLY-RESOLVED ANALYSIS; SEROTONIN TOXICITY; NITRIC-OXIDE; FLUORESCENT SUBSTRATE; REAL-TIME; RECEPTORS; MICE; PARATHYROIDECTOMY; ENCEPHALOPATHY; LOCALIZATION AB BACKGROUND AND PURPOSE Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP+), [ 3H] 5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP+ accumulation (IC50: 1.4 +/- 0.3 mM). A similar effect was observed in N2A cells. Uptake of [ 3H] 5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca2+ levels remained unchanged during MB application. Further experiments revealed that ASP+ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 mM; 10 min) did not alter surface binding of the SERT ligand [ 125I] RTI-55. CONCLUSIONS AND IMPLICATIONS MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity. C1 [Oz, Murat; Isaev, Dmytro; Hasan, Muhammed] UAE Univ, Fac Med & Hlth Sci, Dept Pharmacol, Funct Lipid Branch, Al Ain, U Arab Emirates. [Lorke, Dietrich E.] UAE Univ, Fac Med & Hlth Sci, Dept Anat, Al Ain, U Arab Emirates. [Lorke, Dietrich E.; Petroianu, Georg] Florida Int Univ, Coll Med, Dept Cellular Biol & Pharmacol, Miami, FL 33199 USA. [Shippenberg, Toni S.] Natl Inst Drug Abuse, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD USA. RP Oz, M (reprint author), United Arab Emirates Univ, Dept Pharmacol, Funct Lipid Branch, Fac Med & Hlth Sci, Abu Dhabi, U Arab Emirates. EM Murat_Oz@uaeu.ac.ae RI Oz, Murat/E-2148-2012 FU NIH/NIDA; UAE University FX This research was supported by the NIH/NIDA Intramural Research Program and grants from the individual grants from UAE University. Authors would like to thank Dr Harald Sitte of Medical University of Vienna for kindly supplying hSERT cDNA. NR 43 TC 7 Z9 8 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2012 VL 166 IS 1 SI SI BP 168 EP 176 DI 10.1111/j.1476-5381.2011.01462.x PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 923FZ UT WOS:000302606200015 PM 21542830 ER PT J AU Winkler, EAH Gardiner, PA Clark, BK Matthews, CE Owen, N Healy, GN AF Winkler, Elisabeth A. H. Gardiner, Paul A. Clark, Bronwyn K. Matthews, Charles E. Owen, Neville Healy, Genevieve N. TI Identifying sedentary time using automated estimates of accelerometer wear time SO BRITISH JOURNAL OF SPORTS MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; UNITED-STATES; CALIBRATION; ADULTS; OUTPUT AB Purpose The authors evaluated the accuracy of three automated accelerometer wear-time estimation algorithms against self-report. Direct effects on sedentary time (<100 cpm) and indirect effects on moderate-to-vigorous physical activity (MVPA, >= 1952 cpm) time were examined. Methods A subsample from the 2004/2005 Australian Diabetes, Obesity and Lifestyle Study (n=148) completed activity logs and wore accelerometers for a total of 987 days. A published algorithm that allows movement within non-wear periods (Algorithm 1) was compared with one that allows less movement (Algorithm 2) or no movement (Algorithm 3). Implications for population estimates were examined using 2003/2004 US National Health and Nutrition Examination Survey data. Results Mean difference per day between the criterion and estimated wear time was negligible for all three algorithms (<= 11 min), but 95% limits of agreement (LOA) were wide (+/->= 2 h). Respectively, the algorithms (1, 2 and 3) misclassified sedentary time as non-wear on 31.9%, 19.4% and 18% of days and misclassified non-wear time as sedentary on 42.8%, 43.7% and 51.3% of days. Use of Algorithm 2 (compared with Algorithm 1) affected population estimates of sedentary time (higher by 20 min/day) but not MVPA time. Agreement between Algorithms 1 and 2 was good for MVPA time (mean difference -0.08, LOA: -2.08, 1.91 min), but not for wear time or sedentary time. Conclusion Accelerometer wear time can be estimated accurately on average; however, misclassification can be substantial for individuals. Algorithm choice affects estimates of sedentary time. Allowing very limited movement within non-wear periods can improve accuracy. C1 [Winkler, Elisabeth A. H.; Gardiner, Paul A.; Clark, Bronwyn K.; Owen, Neville; Healy, Genevieve N.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Owen, Neville; Healy, Genevieve N.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. RP Winkler, EAH (reprint author), Univ Queensland, Canc Prevent Res Ctr, Sch Populat Hlth, Herston Rd, Herston, Qld 4006, Australia. EM e.winkler@uq.edu.au RI Clark, Bronwyn/F-8028-2010; Healy, Genevieve/A-7408-2008; Gardiner, Paul/F-2751-2010; Owen, Neville/K-5986-2012; matthews, Charles/E-8073-2015 OI Clark, Bronwyn/0000-0001-7527-4311; Owen, Neville/0000-0003-2784-4820; Healy, Genevieve/0000-0001-7093-7892; Gardiner, Paul/0000-0002-8072-2673; matthews, Charles/0000-0001-8037-3103 FU Queensland Health Core Research Infrastructure grant; NHMRC [569940, 569861]; Heart Foundation of Australia [PP 06B 2889]; Australian Post-graduate Award; NHMRC/National Heart Foundation of Australia [PH 374 08B 3905] FX BKC, PAG, GNH, EAHW and NO are supported by a Queensland Health Core Research Infrastructure grant and by NHMRC Program Grant funding (#569940). PAG is supported by a Heart Foundation of Australia (# PP 06B 2889). BKC is supported by an Australian Post-graduate Award. GNH is also supported by a NHMRC (#569861)/National Heart Foundation of Australia (PH 374 08B 3905) Postdoctoral Fellowship. NR 20 TC 39 Z9 39 U1 2 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-3674 J9 BRIT J SPORT MED JI Br. J. Sports Med. PD MAY PY 2012 VL 46 IS 6 BP 436 EP 442 DI 10.1136/bjsm.2010.079699 PG 7 WC Sport Sciences SC Sport Sciences GA 925CC UT WOS:000302737100013 PM 21504965 ER PT J AU Riggs, ER Church, DM Hanson, K Horner, VL Kaminsky, EB Kuhn, RM Wain, KE Williams, ES Aradhya, S Kearney, HM Ledbetter, DH South, ST Thorland, EC Martin, CL AF Riggs, E. R. Church, D. M. Hanson, K. Horner, V. L. Kaminsky, E. B. Kuhn, R. M. Wain, K. E. Williams, E. S. Aradhya, S. Kearney, H. M. Ledbetter, D. H. South, S. T. Thorland, E. C. Martin, C. L. TI Towards an evidence-based process for the clinical interpretation of copy number variation SO CLINICAL GENETICS LA English DT Article DE Cytogenetics; DNA copy number variation; evidence-based practice; gene dosage; oligonucleotide array sequence analysis ID EVIDENCE-BASED MEDICINE; MOWAT-WILSON-SYNDROME; EGAPP WORKING GROUP; RET PROTOONCOGENE; HUMAN GENOME; HIRSCHSPRUNG DISEASE; DEVELOPMENTAL-DISABILITIES; HEREDITARY NEUROPATHY; STRUCTURAL VARIATION; PRESSURE PALSIES AB The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design. C1 [Riggs, E. R.; Horner, V. L.; Kaminsky, E. B.; Williams, E. S.; Martin, C. L.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Church, D. M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hanson, K.] Sequenom Inc, San Diego, CA USA. [Kuhn, R. M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Wain, K. E.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Aradhya, S.] GeneDx, Gaithersburg, MD USA. [Kearney, H. M.; Thorland, E. C.] Mission Hlth Syst, Fullerton Genet Ctr, Asheville, NC USA. [Ledbetter, D. H.] Geisinger Hlth Syst, Danville, PA USA. [South, S. T.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [South, S. T.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [South, S. T.] ARUP Labs, Salt Lake City, UT USA. RP Martin, CL (reprint author), Emory Univ, Sch Med, Dept Human Genet, 615 Michael St,Suite 301, Atlanta, GA 30322 USA. EM christa.martin@emory.edu FU NIH [HD064525]; NIH, National Library of Medicine FX This work was supported, in part, by NIH Grant HD064525 ( D. H. L. and C. L. M.) and by the Intramural Research Program of the NIH, National Library of Medicine. NR 53 TC 34 Z9 36 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD MAY PY 2012 VL 81 IS 5 BP 403 EP 412 DI 10.1111/j.1399-0004.2011.01818.x PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 923KH UT WOS:000302617700001 PM 22097934 ER PT J AU Ali, RA Rehman, AU Khan, SN Husnain, T Riazuddin, S Friedman, TB Ahmed, ZM Riazuddin, S AF Ali, R. A. Rehman, A. U. Khan, S. N. Husnain, T. Riazuddin, S. Friedman, T. B. Ahmed, Z. M. Riazuddin, S. TI DFNB86, a novel autosomal recessive non-syndromic deafness locus on chromosome 16p13.3 SO CLINICAL GENETICS LA English DT Letter ID MUTATIONS; MICE C1 [Riazuddin, S.] Cincinnati Childrens Hosp, Med Ctr, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab,Childrens Hosp Res Fdn, Cincinnati, OH USA. [Ali, R. A.; Khan, S. N.; Husnain, T.; Ahmed, Z. M.; Riazuddin, S.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Rehman, A. U.; Friedman, T. B.] NIDOCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD USA. [Khan, S. N.; Riazuddin, S.] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Ahmed, Z. M.; Riazuddin, S.] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH 45221 USA. [Ahmed, Z. M.; Riazuddin, S.] Univ Cincinnati, Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45221 USA. [Ahmed, Z. M.; Riazuddin, S.] Univ Cincinnati, Coll Med, Dept Ophthalmol, Cincinnati, OH 45221 USA. RP Riazuddin, S (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab,Childrens Hosp Res Fdn, Cincinnati, OH USA. EM saima.riazuddin@cchmc.org; saima.riazuddin@cchmc.org RI Nasim Khan, Shaheen/F-2135-2015; Husnain, Tayyab/G-3805-2015 FU Cincinnati Children's Hospital Research Foundation; National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R00-DC009287-03]; RPB; Higher Education Commission, Islamabad; EMRO/WHO-COMSTECH; Ministry of Science and Technology, Islamabad; International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01, 08/009]; NIDCD/NIH [DC00039-14] FX The authors are grateful to the family for contributing to this study. We thank Alejandro Schaffer for suggestions regarding statistical analysis of our linkage data. We also thank Dennis Drayna and Changsoo Kang for their critiques. This study was supported by the Cincinnati Children's Hospital Research Foundation intramural research funds to Si. R. and Z. M. A., the National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grant R00-DC009287-03 to Z. A. Z. A. is also a recipient of RPB Career Development Award. Work in Pakistan was supported by the Higher Education Commission, Islamabad, EMRO/WHO-COMSTECH, Ministry of Science and Technology, Islamabad and the International Center for Genetic Engineering and Biotechnology, Trieste, Italy, under project CRP/PAK08-01 Contract no. 08/009 to Sh. R. This study was also supported by intramural funds from the NIDCD/NIH DC00039-14 to T. B. F. NR 9 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD MAY PY 2012 VL 81 IS 5 BP 498 EP 500 DI 10.1111/j.1399-0004.2011.01729.x PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 923KH UT WOS:000302617700016 PM 22211675 ER PT J AU Nelson, EL Konidaris, GD Berthier, NE Braun, MC Novak, MFSX Suomi, SJ Novak, MA AF Nelson, Eliza L. Konidaris, George D. Berthier, Neil E. Braun, Maurine C. Novak, Matthew F. S. X. Suomi, Stephen J. Novak, Melinda A. TI Kinematics of reaching and implications for handedness in rhesus monkey infants SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE handedness; reaching; kinematics; primate; infant ID MACAQUES MACACA-MULATTA; CAPUCHINS CEBUS-APELLA; HAND PREFERENCES; PREHENSION MOVEMENTS; NONHUMAN-PRIMATES; OBJECT SIZE; LOCATION; TASK AB Kinematic studies of reaching in human infants using two-dimensional (2-D) and three-dimensional (3-D) recordings have complemented behavioral studies of infant handedness by providing additional evidence of early right asymmetries. Right hand reaches have been reported to be straighter and smoother than left hand reaches during the first year. Although reaching has been a popular measure of handedness in primates, there has been no systematic comparison of left and right hand reach kinematics. We investigated reaching in infant rhesus monkeys using the 2-D motion analysis software MaxTRAQ Lite+ (Innovision Systems). Linear mixed-effects models revealed that left hand reaches were smoother, but not straighter, than right hand reaches. An early left bias matches previous findings of a left hand preference for reaching in adult rhesus monkeys. Additional work using this kind of kinematic approach will extend our understanding of primate handedness beyond traditional studies measuring only frequency or bouts of hand use. (c) 2011 Wiley Periodicals, Inc. Dev Psychobiol 54:460467, 2012. C1 [Konidaris, George D.] Univ Massachusetts, Dept Comp Sci, Amherst, MA 01003 USA. [Novak, Matthew F. S. X.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Dept Hlth & Human Serv, NIH, Poolesville, MD USA. [Nelson, Eliza L.; Berthier, Neil E.; Braun, Maurine C.; Novak, Melinda A.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. RP Nelson, EL (reprint author), Univ N Carolina Chapel Hill, Ctr Dev Sci, 100 E Franklin St,Suite 200,CB 8115, Chapel Hill, NC 27599 USA. EM eliza_nelson@unc.edu OI Nelson, Eliza/0000-0003-0058-8409 FU Division of Intramural Research, NICHD FX Contract grant sponsor: Division of Intramural Research, NICHD. NR 44 TC 1 Z9 1 U1 2 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD MAY PY 2012 VL 54 IS 4 BP 460 EP 467 DI 10.1002/dev.20604 PG 8 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 919VM UT WOS:000302358800010 PM 22031459 ER PT J AU Stang, A Trabert, B Wentzensen, N Cook, MB Rusner, C Oosterhuis, JW McGlynn, KA AF Stang, A. Trabert, B. Wentzensen, N. Cook, M. B. Rusner, C. Oosterhuis, J. W. McGlynn, K. A. TI Burden of extragonadal germ cell tumours in Europe and the United States SO EUROPEAN JOURNAL OF CANCER LA English DT Letter C1 [Stang, A.; Rusner, C.] Univ Halle Wittenberg, Inst Clin Epidemiol, Fac Med, D-06097 Halle, Saale, Germany. [Trabert, B.; Wentzensen, N.; Cook, M. B.; McGlynn, K. A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Oosterhuis, J. W.] Erasmus MC, Dept Pathol, Josephine Nefkens Inst, Rotterdam, Netherlands. RP Stang, A (reprint author), Univ Halle Wittenberg, Inst Clin Epidemiol, Fac Med, Magdeburger Str 8, D-06097 Halle, Saale, Germany. EM andreas.stang@medizin.uni-halle.de RI Cook, Michael/A-5641-2009; Trabert, Britton/F-8051-2015 OI Cook, Michael/0000-0002-0533-7302; FU Intramural NIH HHS [Z01 CP010126-13] NR 4 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAY PY 2012 VL 48 IS 7 BP 1116 EP 1117 DI 10.1016/j.ejca.2012.02.061 PG 2 WC Oncology SC Oncology GA 925RU UT WOS:000302779700020 PM 22425262 ER PT J AU Goedert, JJ Pfeiffer, R Zhu, MZ Yang, XHR Garcia-Closas, M Lissowska, J Kopp, WC AF Goedert, James J. Pfeiffer, Ruth Zhu, Mingzhu Yang, Xiaohong R. Garcia-Closas, Montserrat Lissowska, Jolanta Kopp, William C. TI Peripheral blood immunologic phenotype of population-based breast cancer cases and matched controls SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Letter ID REGULATORY T-CELLS; RISK; CD4 C1 [Goedert, James J.; Pfeiffer, Ruth; Yang, Xiaohong R.; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Zhu, Mingzhu; Kopp, William C.] SAIC Frederick Inc, Clin Support Lab, Frederick, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Lissowska, Jolanta] Ctr Canc, Warsaw, Poland. RP Goedert, JJ (reprint author), 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS [ZIA CP010214-01] NR 10 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAY PY 2012 VL 42 IS 5 BP 572 EP 574 DI 10.1111/j.1365-2362.2011.02610.x PG 3 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 923KT UT WOS:000302618900015 PM 22073930 ER PT J AU Prabakaran, P Chen, WZ Singarayan, MG Stewart, CC Streaker, E Feng, Y Dimitrov, DS AF Prabakaran, Ponraj Chen, Weizao Singarayan, Maria G. Stewart, Claudia C. Streaker, Emily Feng, Yang Dimitrov, Dimiter S. TI Expressed antibody repertoires in human cord blood cells: 454 sequencing and IMGT/HighV-QUEST analysis of germline gene usage, junctional diversity, and somatic mutations SO IMMUNOGENETICS LA English DT Article DE 454 Sequencing; IMGT/HighV-QUEST; Antibodyome; Human cord blood; Antibody repertoire; IgM; Immunoglobulin; Antibody library ID VARIABLE-REGION GENES; IMMUNOGLOBULIN REPERTOIRE; B-CELLS; IGM ANTIBODIES; V-H; CHAIN; CDR-H3; LIBRARY; IDENTIFICATION; CONSTRUCTION AB Human cord blood cell-derived IgM antibodies are important for the neonate immune responses and construction of germline-based immunoglobulin libraries. Several previous studies of a relatively small number of sequences found that they exhibit restrictions in the usage of germline genes and in the diversity of the variable heavy chain complementarity determining region 3 compared to adults. To further characterize such restrictions on a larger scale and to compare the early B-cell diversity to adult IgM repertoires, we performed 454 sequencing and IMGT/HighV-QUEST analysis of cord blood IG libraries from two babies and determined germline gene usage, V-D-J rearrangement, VHCDR3 diversity, and somatic mutations to characterize human neonate repertoire. Most of the germline subgroups were identified with frequencies comparable to those present in the adult IgM repertoire except for the IGHV1-2 gene that was preferentially expressed in the cord blood cells. The gene usage diversity contributed to 1,430 unique IGH V-D-J rearrangement patterns while the exonuclease trimming and N region addition at the V-D-J junctions along with gene diversity created a wide range of VHCDR3 with different lengths and sequence variability. We observed a lower degree of somatic mutations in the CDR and framework regions of antibodies from cord blood cells compared to adults. These results provide insights into the characteristics of human cord blood antibody repertoires, which have gene usage diversity and VHCDR3 lengths similar to that of the adult IgM repertoire but differ significantly in some of the gene usages, V-D-J rearrangements, junctional diversity, and somatic mutations. C1 [Prabakaran, Ponraj; Chen, Weizao; Streaker, Emily; Feng, Yang; Dimitrov, Dimiter S.] Natl Canc Inst NCI Frederick, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,NIH, Frederick, MD 21702 USA. [Prabakaran, Ponraj; Streaker, Emily] NCI Frederick, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Stewart, Claudia C.] NCI Frederick, Lab Mol Technol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), Natl Canc Inst NCI Frederick, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimiter.dimitrov@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIH, National Cancer Institute [NO1-CO-12400] FX We thank the Laboratory of Molecular Technology of SAIC-Frederick Inc. for providing Roche 454 sequencing service. We are grateful to Eltaf Alamyar and to the IMGT (R) team for providing access to IMGT/HighV-QUEST. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by Federal funds from the NIH, National Cancer Institute, under contract no. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 61 TC 21 Z9 23 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD MAY PY 2012 VL 64 IS 5 BP 337 EP 350 DI 10.1007/s00251-011-0595-8 PG 14 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 925HC UT WOS:000302750800001 PM 22200891 ER PT J AU Ayele, FT Doumatey, A Huang, HX Zhou, J Charles, B Erdos, M Adeleye, J Balogun, W Fasanmade, O Johnson, T Oli, J Okafor, G Amoah, A Eghan, BA Agyenim-Boateng, K Acheampong, J Adebamowo, CA Herbert, A Gerry, N Christman, M Chen, GJ Shriner, D Adeyemo, A Rotimi, CN AF Ayele, Fasil Tekola Doumatey, Ayo Huang, Hanxia Zhou, Jie Charles, Bashira Erdos, Michael Adeleye, Jokotade Balogun, Williams Fasanmade, Olufemi Johnson, Thomas Oli, Johnnie Okafor, Godfrey Amoah, Albert Eghan, Benjamin A., Jr. Agyenim-Boateng, Kofi Acheampong, Joseph Adebamowo, Clement A. Herbert, Alan Gerry, Norman Christman, Michael Chen, Guanjie Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles N. TI Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans SO IMMUNOGENETICS LA English DT Article DE Interleukin; Interleukin-10; Interleukin-1Ra; Interleukin-6; Genome-wide association study; African American ID C-REACTIVE PROTEIN; RECEPTOR ANTAGONIST GENE; PLASMA-LEVELS; PROMOTER POLYMORPHISMS; INSULIN-RESISTANCE; CIRCULATING LEVELS; DIABETES-MELLITUS; ADIPOSE-TISSUE; BLOOD-PRESSURE; WEST AFRICANS AB Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 x 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 x 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 x 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 x 10(-6) to 1.75 x 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 x 10(-6) to 1.63 x 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 x 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases. C1 [Ayele, Fasil Tekola; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Charles, Bashira; Chen, Guanjie; Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Erdos, Michael] NHGRI, Genome Technol Branch, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. [Adeleye, Jokotade; Balogun, Williams] Univ Ibadan, Dept Med, Ibadan, Nigeria. [Fasanmade, Olufemi; Johnson, Thomas] Univ Lagos, Lagos, Nigeria. [Oli, Johnnie; Okafor, Godfrey] Univ Nigeria, Teaching Hosp, Enugu, Nigeria. [Amoah, Albert] Univ Ghana, Sch Med, Dept Med, Accra, Ghana. [Eghan, Benjamin A., Jr.; Agyenim-Boateng, Kofi; Acheampong, Joseph] Univ Sci & Technol, Dept Med, Kumasi, Ghana. [Adebamowo, Clement A.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Herbert, Alan] Boston Univ, Dept Genet & Genom, Boston, MA 02215 USA. [Gerry, Norman; Christman, Michael] Coriell Inst Med Res, Camden, NJ USA. RP Ayele, FT (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM ayeleft@mail.nih.gov; rotimic@mail.nih.gov RI e-, a/F-9947-2012; OI Adebamowo, Clement/0000-0002-6571-2880; Adeyemo, Adebowale/0000-0002-3105-3231; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU NIGMS/MBRS/SCORE [S06GM008016-320107, S06GM008016-380111]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [2M01RR010284]; National Human Genome Research Institute, National Institutes of Health, in the Center for Research in Genomics and Global Health [Z01HG200362]; Coriell Institute for Biomedical Sciences FX The study was supported by grants S06GM008016-320107 to CR and S06GM008016-380111 to AA, both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center (GCRC), which is supported by grant number 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Additional support was provided by the Coriell Institute for Biomedical Sciences. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research in Genomics and Global Health (Z01HG200362). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 11 Z9 11 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 EI 1432-1211 J9 IMMUNOGENETICS JI Immunogenetics PD MAY PY 2012 VL 64 IS 5 BP 351 EP 359 DI 10.1007/s00251-011-0596-7 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 925HC UT WOS:000302750800002 ER PT J AU Pai, VM Kozlowski, M Donahue, D Miller, E Xiao, XH Chen, MY Yu, ZX Connelly, P Jeffries, K Wen, H AF Pai, Vinay M. Kozlowski, Megan Donahue, Danielle Miller, Elishiah Xiao, Xianghui Chen, Marcus Y. Yu, Zu-Xi Connelly, Patricia Jeffries, Kenneth Wen, Han TI Coronary artery wall imaging in mice using osmium tetroxide and micro-computed tomography (micro-CT) SO JOURNAL OF ANATOMY LA English DT Article DE apolipoprotein E; atherosclerosis; coronary artery wall; micro-computed tomography; osmium ID X-RAY MICROTOMOGRAPHY; KNOCKOUT MICE; APOLIPOPROTEIN-E; MOUSE EMBRYOS; HYPERCHOLESTEROLEMIA; LESIONS AB The high spatial resolution of micro-computed tomography (micro-CT) is ideal for 3D imaging of coronary arteries in intact mouse heart specimens. Previously, micro-CT of mouse heart specimens utilized intravascular contrast agents that hardened within the vessel lumen and allowed a vascular cast to be made. However, for mouse coronary artery disease models, it is highly desirable to image coronary artery walls and highlight plaques. For this purpose, we describe an ex vivo contrast-enhanced micro-CT imaging technique based on tissue staining with osmium tetroxide (OsO4) solution. As a tissue-staining contrast agent, OsO4 is retained in the vessel wall and surrounding tissue during the fixation process and cleared from the vessel lumens. Its high X-ray attenuation makes the artery wall visible in CT. Additionally, since OsO4 preferentially binds to lipids, it highlights lipid deposition in the artery wall. We performed micro-CT of heart specimens of 5- to 25-week-old C57BL/6 wild-type mice and 5- to 13-week-old apolipoprotein E knockout (apoE-/-) mice at 10 mu m resolution. The results show that walls of coronary arteries as small as 45 mu m in diameter are visible using a table-top micro-CT scanner. Similar image clarity was achieved with 1/2000th the scan time using a synchrotron CT scanner. In 13-week-old apoE mice, lipid-rich plaques are visible in the aorta. Our study shows that the combination of OsO4 and micro-CT permits the visualization of the coronary artery wall in intact mouse hearts. C1 [Pai, Vinay M.; Kozlowski, Megan; Miller, Elishiah; Wen, Han] NHLBI, Imaging Phys Grp, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Chen, Marcus Y.] NHLBI, Adv Cardiovasc Imaging Grp, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Connelly, Patricia] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Jeffries, Kenneth] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Donahue, Danielle] NINDS, MIF, NIH, Bethesda, MD 20892 USA. [Xiao, Xianghui] Argonne Natl Lab, Adv Photon Source, Argonne, IL 60439 USA. [Miller, Elishiah] Univ Texas El Paso, Dept Comp Sci, El Paso, TX 79968 USA. RP Wen, H (reprint author), Room B1D416,Bldg 10,MSC 1061,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Division of Intramural Research of the National Institutes of Health [HL006142-01]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX This research was funded by the Division of Intramural Research of the National Institutes of Health (Project Number HL006142-01 to H.W.). Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. No conflicts of interest, financial or otherwise, are declared by the author(s). NR 23 TC 13 Z9 13 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-8782 J9 J ANAT JI J. Anat. PD MAY PY 2012 VL 220 IS 5 BP 514 EP 524 DI 10.1111/j.1469-7580.2012.01483.x PG 11 WC Anatomy & Morphology SC Anatomy & Morphology GA 922GX UT WOS:000302536500009 PM 22360411 ER PT J AU Maglinte, GA Hays, RD Kaplan, RM AF Maglinte, Gregory A. Hays, Ron D. Kaplan, Robert M. TI US general population norms for telephone administration of the SF-36v2 SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE SF-36; Health-related quality of life; General population norms; Population survey; Factor analysis; Factor scoring coefficients ID QUALITY-OF-LIFE; HEALTH SURVEY; SCORES; MODE AB Objective: US general population norms for mail administration of the Medical Outcomes Study 36-item Short Form Version 2 (SF-36v2) were established in 1998. This article reports SF-36v2 telephone-administered norms collected in 2005-2006 for adults aged 35-89 years. Study Design and Setting: The SF-36v2 was administered to 3,844 adults in the National Health Measurement Study (NHMS), a random-digit dial telephone survey. Scale scores and physical and mental component summary (PCS and MCS) scores were computed. Results: When compared with 1998 norms (mean = 50.00, standard deviation [SD] = 10.00), SF-36v2 scores for the 2005-2006 general population tended to be higher: physical functioning (mean = 50.68, SD = 14.48); role limitations due to physical health problems (mean = 49.47, SD = 14.71); bodily pain (mean = 50.66, SD = 16.28); general health perceptions (mean = 50.10, SD = 16.87); vitality (mean = 53.71, SD = 15.35); social functioning (mean = 51.37, SD = 13.93); role limitations due to emotional problems (mean = 51.44, SD = 13.93); mental health (mean = 54.27, SD = 13.28); PCS (mean = 49.22, SD = 15.13); MCS (mean = 53.78, SD = 13.14). PCS and MCS factor scoring coefficients were similar to those previously reported for the 1998 norms. SF-36v2 norms for telephone administration were created. Conclusion: The higher scores for NHMS data are likely due to the effect of telephone administration. The 2005-2006 norms can be used as a reference to interpret scale and component summary scores for telephone-administered surveys with the SF-36v2. (c) 2012 Elsevier Inc. All rights reserved. C1 [Maglinte, Gregory A.; Hays, Ron D.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90095 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Maglinte, GA (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90095 USA. EM greg.maglinte@ucla.edu RI Hays, Ronald/D-5629-2013 FU National Institute on Aging [P01-AG020679, P30AG021684, P30-AG028748]; NCMHD [P20MD000182] FX This research was supported by a grant from the National Institute on Aging (P01-AG020679). Hays and Kaplan were also supported in part by NIA grants (P30AG021684 and P30-AG028748), and Hays had partial support from NCMHD (P20MD000182). NR 19 TC 23 Z9 24 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD MAY PY 2012 VL 65 IS 5 BP 497 EP 502 DI 10.1016/j.jclinepi.2011.09.008 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 920ZJ UT WOS:000302447500007 PM 22269331 ER PT J AU Eberlein, M Arnaoutakis, GJ Yarmus, L Feller-Kopman, D Dezube, R Chahla, MF Bolukbas, S Reed, RM Klesney-Tait, J Parekh, KR Merlo, CA Shah, AS Orens, JB Brower, RG AF Eberlein, Michael Arnaoutakis, George J. Yarmus, Lonny Feller-Kopman, David Dezube, Rebecca Chahla, Mayy F. Bolukbas, Servet Reed, Robert M. Klesney-Tait, Julia Parekh, Kalpaj R. Merlo, Christian A. Shah, Ashish S. Orens, Jonathan B. Brower, Roy G. TI The effect of lung size mismatch on complications and resource utilization after bilateral lung transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE lung transplantation; lung size mismatch; resource utilization; airway complications ID PRIMARY GRAFT DYSFUNCTION; AIRWAY COMPLICATIONS; PULMONARY-FIBROSIS; UNITED-STATES; CAPACITY; IMPACT; DYSANAPSIS; PRESSURE; STRESS; FLOW AB BACKGROUND: Oversizing the lung allograft, as estimated by a donor-to-recipient predicted total lung capacity (pTLC) ratio > 1.0, was associated with improved long-term survival after lung transplantation (LTx) but could be associated with increased post-operative complications and higher resource utilization. METHODS: The prospectively maintained LTx database at The Johns Hopkins Hospital was retrospectively reviewed for bilateral LTx patients in the post-Lung Allocation Score (LAS) era. Patients were grouped by pTLC ratio 1.0 (undersized) or > 1.0 (oversized). Post-operative complications and hospital charges were analyzed. RESULTS: The pTLC ratio was available for 70 patients: 31 were undersized and 39 oversized. Undersized patients had a higher LAS (40.4 vs 35.8, p = 0.009), were more often in the intensive care unit (ICU) pre-LTx (35% vs 10%, p = 0.01), and had a higher occurrence of primary graft dysfunction (POD; 25% vs 5%, p = 0.013) and tracheostomy (32% vs 10%, p = 0.02), longer index hospitalizations (20 [interquartile range (IQR), 10-46] vs 16 [IQR, 12-251 days, p = 0.048), and higher index; hospitalization charges ($176,247 [IQR, $137,646 $284,0 I 2] vs $158,492 [IQR, $136,250 4191,301], p = 0.04). After adjusting for LAS and pre-LTx ICU stay, a lower pTLC ratio remained associated with higher hospital charges (p = 0.049). Airway complications were more frequent and severe in undersized patients. CONCLUSION: Oversized allografts were not associated with an increase in post-LTx complications. However, LTx recipients of undersized allografts were more likely to experience POD, tracheostomy, and had higner resource utilization. Higher acuity in the undersized group might explain these findings; however, multivariate models suggest an independent association between undersizing, PGD, and resource utilization. J Heart Lung Transplant 2012;31:492-500 (C) Published by Elsevier Inc. on behalf of the International Society for Heart and Lung Transplantation. C1 [Eberlein, Michael; Yarmus, Lonny; Feller-Kopman, David; Merlo, Christian A.; Orens, Jonathan B.; Brower, Roy G.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. [Eberlein, Michael] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Dezube, Rebecca] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Arnaoutakis, George J.; Shah, Ashish S.] Johns Hopkins Univ, Sch Med, Div Cardiac Surg, Baltimore, MD USA. [Chahla, Mayy F.] Johns Hopkins Univ, Sch Med, Div Hosp Med, Baltimore, MD USA. [Bolukbas, Servet] Dr Horst Schmidt Klin, Dept Thorac Surg, Wiesbaden, Germany. [Reed, Robert M.] Univ Maryland, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Klesney-Tait, Julia; Parekh, Kalpaj R.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. RP Eberlein, M (reprint author), Univ Iowa, Carver Coll Med, Div Pulm Crit Care & Occupat Med, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM michael-eberlein@uiowa.edu RI Parekh, Kalpaj/E-4966-2012; OI Shah, Ashish/0000-0002-1821-9110 NR 30 TC 29 Z9 29 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD MAY PY 2012 VL 31 IS 5 BP 492 EP 500 DI 10.1016/j.healun.2011.12.009 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 925JE UT WOS:000302756700009 PM 22325691 ER PT J AU Groninger, H Phillips, JM AF Groninger, Hunter Phillips, Jayne M. TI Gross Hematuria Assessment and Management at the End of Life SO JOURNAL OF HOSPICE & PALLIATIVE NURSING LA English DT Article DE goals of care; gross hematuria; hospice; palliative; pain management; urology ID URETHRAL CATHETERIZATION; FLEXIBLE CYSTOSCOPY; PAIN; EMBOLIZATION; PATIENT; RELIEF AB A distressing complication for patients and families, gross hematuria at the end of life challenges hospice and palliative care clinicians to utilize skills in medical and nursing management, communication and clarification of patient goals, and relief of symptom burden. Massive hemorrhage in the genitourinary tract can radically alter the terminal trajectory for patients and necessitate intensive interventions aimed at promoting comfort. Here, a case of gross hematuria in an adult hospice patient serves to broaching decision-making challenges and management strategies. C1 [Groninger, Hunter; Phillips, Jayne M.] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, Bldg 10,Room 2-1733,MSC 1517, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 19 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1522-2179 J9 J HOSP PALLIAT NURS JI J. Hosp. Palliat. Nurs. PD MAY PY 2012 VL 14 IS 3 BP 184 EP 188 DI 10.1097/NJH.0b013e31824fc169 PG 5 WC Nursing SC Nursing GA 925OH UT WOS:000302770200003 PM 24826082 ER PT J AU Tayo, BO Luke, A McKenzie, CA Kramer, H Cao, G Durazo-Arvizu, R Forrester, T Adeyemo, AA Cooper, RS AF Tayo, B. O. Luke, A. McKenzie, C. A. Kramer, H. Cao, G. Durazo-Arvizu, R. Forrester, T. Adeyemo, A. A. Cooper, R. S. TI Patterns of sodium and potassium excretion and blood pressure in the African Diaspora SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article DE blood pressure; sodium excretion; potassium excretion; African Diaspora ID SALT INTAKE; DIETARY-SODIUM; CARDIOVASCULAR-DISEASE; RACIAL-DIFFERENCES; HYPERTENSION; METAANALYSIS; ASSOCIATION; REDUCTION; CHILDREN; HUMANS AB Habitual levels of dietary sodium and potassium are correlated with age-related increases in blood pressure (BP) and likely have a role in this phenomenon. Although extensive published evidence exists from randomized trials, relatively few large-scale community surveys with multiple 24-h urine collections have been reported. We obtained three 24-h samples from 2704 individuals from Nigeria, Jamaica and the United States to evaluate patterns of intake and within-person relationships with BP. The average (+/- s.d.) age and weight of the participants across all the three sites were 39.9 +/- 8.6 years and 76.1 +/- 21.2 kg, respectively, and 55% of the total participants were females. Sodium excretion increased across the East-West gradient (for example, 123.9 +/- 54.6, 134.1 +/- 48.8, 176.6 +/- 71.0 (+/- s.d.) mmol, Nigeria, Jamaica and US, respectively), whereas potassium was essentially unchanged (for example, 46.3 +/- 22.9, 40.7 +/- 16.1, 44.7 +/- 16.4 (+/- s.d.) mmol, respectively). In multivariate analyses both sodium (positively) and potassium (negatively) were strongly correlated with BP (P<0.001); quantitatively the association was stronger, and more consistent in each site individually, for potassium. The within-population day-to-day variation was also greater for sodium than for potassium. Among each population group, a significant correlation was observed between sodium and urine volume, supporting the prior finding of sodium as a determinant of fluid intake in free-living individuals. These data confirm the consistency with the possible role of dietary electrolytes as hypertension risk factors, reinforcing the relevance of potassium in these populations. Journal of Human Hypertension (2012) 26, 315-324; doi:10.1038/jhh.2011.39; published online 19 May 2011 C1 [Tayo, B. O.; Luke, A.; Kramer, H.; Cao, G.; Durazo-Arvizu, R.; Cooper, R. S.] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [McKenzie, C. A.; Forrester, T.] Univ W Indies, Trop Metab Res Unit, Kingston 7, Jamaica. [Adeyemo, A. A.] Univ Ibadan, Coll Med, Inst Child Hlth, Dept Pediat, Ibadan, Nigeria. [Adeyemo, A. A.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Cooper, RS (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, 2160 S 1st Ave, Maywood, IL 60153 USA. EM rcooper@lumc.edu OI Kramer, Holly/0000-0002-6374-837X; Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [R37HL045508, R01HL 053353] FX This work was supported by the National Institutes of Health, grant numbers R37HL045508 and R01HL 053353. NR 38 TC 12 Z9 12 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD MAY PY 2012 VL 26 IS 5 BP 315 EP 324 DI 10.1038/jhh.2011.39 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 925WD UT WOS:000302791800005 PM 21593783 ER PT J AU Puronen, CE Thompson, WL Imamichi, H Beq, S Hodge, JN Rehm, C Parker, R DerSimonian, R Brenchley, JM Sereti, I AF Puronen, Camille E. Thompson, William L. Imamichi, Hiromi Beq, Stephanie Hodge, Jessica N. Rehm, Catherine Parker, Raphaelle DerSimonian, Rebecca Brenchley, Jason M. Sereti, Irini TI Decreased Interleukin 7 Responsiveness of T Lymphocytes in Patients With Idiopathic CD4 Lymphopenia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CELL HOMEOSTASIS; IL-7 PROMOTES; RECEPTOR; MEMORY; PROLIFERATION; EXPRESSION; INCREASES; SUPPRESSION; MECHANISM; INFECTION AB Background. Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency. Methods. To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/mu L) and healthy controls (median CD4 T-cell count, 582 cells/mu L) were evaluated for expression of IL-7R alpha chain (CD127) and intracellular phosphorylated STAT-5 (a marker of gamma c cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation. Results. The percentage of CD4+CD127+ T cells was lower in patients with ICL, compared with controls (P < .001). Lower levels of STAT-5 phosphorylation after IL-7 stimulation were observed in both CD4 and CD8 T cells from patients with ICL, compared with controls (P < .001 and P = .017, respectively), that inversely correlated in CD4 T cells with serum IL-7 levels (r = -0.734, P = .013). Destabilization of p27(kip1), a critical step for IL-7-induced T-cell cycling, was decreased in patients with ICL, compared with controls (P = .004), after IL-7 stimulation. Conclusions. These data suggest that diminished responsiveness to IL-7 in CD4 and CD8 T cells during ICL may be contributing to the dysregulation of T-cell homeostasis. C1 [Puronen, Camille E.; Thompson, William L.; Imamichi, Hiromi; Hodge, Jessica N.; Rehm, Catherine; Parker, Raphaelle; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [DerSimonian, Rebecca] NIAID, Biostat Branch, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Beq, Stephanie] Cytheris SA, Issy Les Moulineaux, France. RP Sereti, I (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10 Magnuson Clin Ctr,Room 11B07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E]; NIH; Pfizer FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH). Additionally, this project has also been funded in part with federal funds from the National Cancer Institute, NIH (grant HHSN261200800001E). C. E. P. was a participant in the NIH Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer. NR 37 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2012 VL 205 IS 9 BP 1382 EP 1390 DI 10.1093/infdis/jis219 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 921QI UT WOS:000302491800008 PM 22454463 ER PT J AU Hubbard, JJ Greenwell-Wild, T Barrett, L Yang, J Lempicki, RA Wahl, SM Asmuth, DM Murphy, RL Pollard, RB Kottilil, S AF Hubbard, Jonathan J. Greenwell-Wild, Teresa Barrett, Lisa Yang, Jun Lempicki, Richard A. Wahl, Sharon M. Asmuth, David M. Murphy, Robert L. Pollard, Richard B. Kottilil, Shyam TI Host Gene Expression Changes Correlating With Anti-HIV-1 Effects in Human Subjects After Treatment With Peginterferon Alfa-2a SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC HEPATITIS-C; PEGYLATED INTERFERON; RIBAVIRIN; REPLICATION; TRIAL; BETA AB We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = 5 20.7; P < .05) with virological response. The strength of peginterferon alfa-2-ainduced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection. C1 [Hubbard, Jonathan J.; Barrett, Lisa; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Greenwell-Wild, Teresa; Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [Yang, Jun; Lempicki, Richard A.] SAIC Frederick Inc, Frederick, MD USA. [Asmuth, David M.; Pollard, Richard B.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Murphy, Robert L.] Northwestern Univ, Evanston, IL USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Murphy, Robert/0000-0003-3936-2052 FU National Institutes of Health (NIH) [1U01-AI068636, 1U01-AI068634, 1U01-AI069471, 1U01-AI069432, 1U01-AI069484, 201IC001, 204IC006]; NIH; Pfizer Inc FX This work was supported by the National Institutes of Health (NIH) (grant 1U01-AI068636 to the ACTG; grant 1U01-AI068634 to the ACTG Statistical and Data Analysis Center; grant 1U01-AI069471 to Northwestern University; grant 1U01-AI069432 to University of California, San Diego; grant 1U01-AI069484 to Duke University; Immunology Support Laboratory grant 201IC001 to University of California-Davis; and Immunology Support Laboratory grant 204IC006 to University of Pittsburgh, and the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease and the National Institute of Dental and Craniofacial Research). The participation of J. J. H. was made possible by the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the foundation for NIH from Pfizer). NR 15 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2012 VL 205 IS 9 BP 1443 EP 1447 DI 10.1093/infdis/jis211 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 921QI UT WOS:000302491800015 PM 22454462 ER PT J AU Wheless, L Kistner-Griffin, E Jorgensen, TJ Ruczinski, I Berthier-Schaad, Y Kessing, B Hoffman-Bolton, J Francis, L Shugart, YY Strickland, PT Kao, WHL Alani, RM Smith, MW Alberg, AJ AF Wheless, Lee Kistner-Griffin, Emily Jorgensen, Timothy J. Ruczinski, Ingo Berthier-Schaad, Yvette Kessing, Bailey Hoffman-Bolton, Judith Francis, Lesley Shugart, Yin Yao Strickland, Paul T. Kao, W. H. Linda Alani, Rhoda M. Smith, Michael W. Alberg, Anthony J. TI A Community-Based Study of Nucleotide Excision Repair Polymorphisms in Relation to the Risk of Non-Melanoma Skin Cancer SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID BASAL-CELL CARCINOMA; XERODERMA-PIGMENTOSUM; DNA-DAMAGE; MOLECULAR-ORIGINS; COMMON VARIANTS; SUN EXPOSURE; GENE XPD; ASSOCIATION; MELANOMA; PROTEIN AB Nucleotide excision repair (NER) is responsible for protecting DNA in skin cells against UVR-induced damage. Using a candidate pathway approach, a matched case-control study nested within a prospective, community-based cohort was carried out to test the hypothesis that single-nucleotide polymorphisms (SNPs) in NER genes are associated with susceptibility to non-melanoma skin cancer (NMSC). Histologically confirmed cases of NMSC (n = 900) were matched to controls (n = 900) on the basis of age, gender, and skin type. Associations were measured between NMSC and 221 SNPs in 26 NER genes. Using the additive model, two tightly linked functional SNPs in ERCC6 were significantly associated with increased risk of NMSC: rs2228527 (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.20-2.05) and rs2228529 (OR 1.57, 95% CI 1.20-2.05). These associations were confined to basal cell carcinoma (BCC) of the skin (rs2228529, OR 1.78, 95% CI 1.30-2.44; rs2228527, OR 1.78, 95% CI 1.31-2.43). These hypothesis-generating findings suggest that functional variants in ERCC6 may be associated with an increased risk of NMSC that may be specific to BCC. C1 [Kistner-Griffin, Emily; Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Wheless, Lee; Kistner-Griffin, Emily; Francis, Lesley; Alberg, Anthony J.] Med Univ S Carolina, Dept Med, Div Epidemiol & Biostat, Charleston, SC 29425 USA. [Jorgensen, Timothy J.] Georgetown Univ, Sch Med, Dept Radiat Med, Washington, DC USA. [Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Berthier-Schaad, Yvette; Kessing, Bailey] NCI Frederick, Lab Genom Divers, Frederick, MD USA. [Berthier-Schaad, Yvette; Strickland, Paul T.; Kao, W. H. Linda; Alberg, Anthony J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hoffman-Bolton, Judith] George W Comstock Ctr Publ Hlth Res & Prevent, Washington Cty, MD USA. [Shugart, Yin Yao] NIMH, Div Intramural Res Programs, Rockville, MD 20857 USA. [Strickland, Paul T.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Alani, Rhoda M.] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Smith, Michael W.] SAIC Frederick Inc, Genet & Genom Grp, Adv Technol Program, NCI Frederick, Frederick, MD USA. RP Alberg, AJ (reprint author), Med Univ S Carolina, Hollings Canc Ctr, 68 President St,MSC 955, Charleston, SC 29425 USA. EM alberg@musc.edu OI Alani, Rhoda/0000-0003-2741-2665 FU National Cancer Institute [R01 CA105069]; NIH/NCCR [TL1 RR029881]; Abney Family Foundation; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This research was made possible by funding from the National Cancer Institute (R01 CA105069), NIH/NCCR (TL1 RR029881), and the Abney Family Foundation. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The project described in this article has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 42 TC 10 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 IS 5 BP 1354 EP 1362 DI 10.1038/jid.2012.4 PG 9 WC Dermatology SC Dermatology GA 926UA UT WOS:000302856200011 PM 22336945 ER PT J AU Makrogiannis, S Serai, S Fishbein, KW Schreiber, C Ferrucci, L Spencer, RG AF Makrogiannis, Sokratis Serai, Suraj Fishbein, Kenneth W. Schreiber, Catherine Ferrucci, Luigi Spencer, Richard G. TI Automated quantification of muscle and fat in the thigh from water-, fat-, and nonsuppressed MR images SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE body composition; image segmentation; thigh imaging ID INTERMUSCULAR ADIPOSE-TISSUE; MAGNETIC-RESONANCE IMAGES; SEGMENTATION; OBESITY AB Purpose: To introduce and validate an unsupervised muscle and fat quantification algorithm based on joint analysis of water-suppressed (WS), fat-suppressed (FS), and water and fat (nonsuppressed) volumetric magnetic resonance imaging (MRI) of the mid-thigh region. Materials and Methods: We first segmented the subcutaneous fat by use of a parametric deformable model, then applied centroid clustering in the feature domain defined by the voxel intensities in WS and FS images to identify the intermuscular fat and muscle. In the final step we computed volumetric and area measures of fat and muscle. We applied this algorithm on datasets of water-, fat-, and nonsuppressed volumetric MR images acquired from 28 participants. Results: We validated our tissue composition analysis against fat and muscle area measurements obtained from semimanual analysis of single-slice mid-thigh computed tomography (CT) images of the same participants and found very good agreement between the two methods. Furthermore, we compared the proposed approach with a variant that uses nonsuppressed images only and observed that joint analysis of WS and FS images is more accurate than the nonsuppressed only variant. Conclusion: Our MRI algorithm produces accurate tissue quantification, is less labor-intensive, and more reproducible than the original CT-based workflow and can address interparticipant anatomic variability and intensity inhomogeneity effects. C1 [Makrogiannis, Sokratis; Serai, Suraj; Fishbein, Kenneth W.; Schreiber, Catherine; Ferrucci, Luigi; Spencer, Richard G.] NIA, NIH, Baltimore, MD 21225 USA. RP Makrogiannis, S (reprint author), NIA, NIH, 3001 S Hanover St,5th Fl, Baltimore, MD 21225 USA. EM makrogianniss@mail.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS [Z99 AG999999] NR 25 TC 15 Z9 15 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAY PY 2012 VL 35 IS 5 BP 1152 EP 1161 DI 10.1002/jmri.22842 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 924WK UT WOS:000302721800020 PM 22170747 ER PT J AU Madsen, DH Jurgensen, HJ Ingvarsen, S Melander, MC Vainer, B Egerod, KL Hald, A Rono, B Madsen, CA Bugge, TH Engelholm, LH Behrendt, N AF Madsen, Daniel H. Jurgensen, Henrik J. Ingvarsen, Signe Melander, Maria C. Vainer, Ben Egerod, Kristoffer L. Hald, Andreas Rono, Birgitte Madsen, Charlotte A. Bugge, Thomas H. Engelholm, Lars H. Behrendt, Niels TI Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis SO JOURNAL OF PATHOLOGY LA English DT Article DE matrix remodelling; uPARAP; Endo180; knockout mouse; mannose receptor; liver disease model; endocytosis; matrix metalloproteinase; HSC; MRC2 ID MACROPHAGE MANNOSE RECEPTOR; HEPATIC STELLATE CELLS; MATRIX METALLOPROTEINASES; PLASMINOGEN-ACTIVATOR; EXTRACELLULAR-MATRIX; TRANSMEMBRANE GLYCOPROTEIN; PROTEIN UPARAP/ENDO180; DENATURED COLLAGEN; ENDOTHELIAL-CELLS; MEMBRANE-PROTEINS AB Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl4 administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Madsen, Daniel H.; Jurgensen, Henrik J.; Ingvarsen, Signe; Melander, Maria C.; Madsen, Charlotte A.; Engelholm, Lars H.; Behrendt, Niels] Univ Copenhagen, Rigshosp, Finsen Lab, BRIC, DK-1168 Copenhagen, Denmark. [Ingvarsen, Signe] Univ Copenhagen, Dept Biol, DK-1168 Copenhagen, Denmark. [Vainer, Ben] Rigshosp, Dept Pathol, DK-2200 Copenhagen N, Denmark. [Egerod, Kristoffer L.] Univ Copenhagen, Dept Neurosci & Pharmacol, DK-1168 Copenhagen, Denmark. [Hald, Andreas; Rono, Birgitte] Univ Copenhagen, Dept Cellular & Mol Med, DK-1168 Copenhagen, Denmark. [Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Behrendt, N (reprint author), Rigshosp, Copenhagen Bioctr, Finsen Lab BRIC, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark. EM niels.behrendt@finsenlab.dk RI Egerod, Kristoffer/D-9481-2012; OI Egerod, Kristoffer/0000-0003-2781-1594; Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; Lundbeck Foundation; Danish National Research Foundation (Danish-Chinese Centre for Proteases and Cancer); European Community [201279]; Grosserer Alfred Nielsen og Hustrus Foundation; NIDCR; Copenhagen University Hospital; University of Copenhagen, Faculty of Science FX The excellent technical assistance of Suzanne K. Moller, Katharina H. Stegmann, Agnieszka Ingvorsen and Mette M. Andersen and the expert assistance at the Core facility for Integrated Microcopy, Faculty of Health Sciences, University of Copenhagen, is gratefully acknowledged. We thank Dr Marcos Rojkind for generously providing the CFSC-2G cells. This work was supported by the Danish Cancer Society, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Lundbeck Foundation, the Danish National Research Foundation (Danish-Chinese Centre for Proteases and Cancer) and the European Community's Seventh Framework Programme FP7/2007-2011 (under Grant Agreement No. 201279 to NB), by the Lundbeck Foundation and the Grosserer Alfred Nielsen og Hustrus Foundation (to LHE), and by the NIDCR Intramural Research Program (to THB). The work was also supported by personal grants from Copenhagen University Hospital (to DHM and HJJ), the Lundbeck Foundation (to DHM) and the University of Copenhagen, Faculty of Science (to SI). NR 59 TC 16 Z9 17 U1 1 U2 29 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD MAY PY 2012 VL 227 IS 1 BP 94 EP 105 DI 10.1002/path.3981 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA 921IF UT WOS:000302470600011 PM 22294280 ER PT J AU Hautvast, GLTF Salton, CJ Chuang, ML Breeuwer, M O'Donnell, CJ Manning, WJ AF Hautvast, Gilion L. T. F. Salton, Carol J. Chuang, Michael L. Breeuwer, Marcel O'Donnell, Christopher J. Manning, Warren J. TI Accurate computer-aided quantification of left ventricular parameters: Experience in 1555 cardiac magnetic resonance studies from the Framingham Heart Study SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE segmentation; postprocessing; technique development; technical research ID MR-IMAGES; SEGMENTATION; APPEARANCE; PROPAGATION AB Quantitative analysis of short-axis functional cardiac magnetic resonance images can be performed using automatic contour detection methods. The resulting myocardial contours must be reviewed and possibly corrected, which can be time-consuming, particularly when performed across all cardiac phases. We quantified the impact of manual contour corrections on both analysis time and quantitative measurements obtained from left ventricular short-axis cine images acquired from 1555 participants of the Framingham Heart Study Offspring cohort using computer-aided contour detection methods. The total analysis time for a single case was 7.6 +/- 1.7 min for an average of 221 +/- 36 myocardial contours per participant. This included 4.8 +/- 1.6 min for manual contour correction of 2% of all automatically detected endocardial contours and 8% of all automatically detected epicardial contours. However, the impact of these corrections on global left ventricular parameters was limited, introducing differences of 0.4 +/- 4.1 mL for end-diastolic volume, -0.3 +/- 2.9 mL for end-systolic volume, 0.7 +/- 3.1 mL for stroke volume, and 0.3 +/- 1.8% for ejection fraction. We conclude that left ventricular functional parameters can be obtained under 5 min from short-axis functional cardiac magnetic resonance images using automatic contour detection methods. Manual correction more than doubles analysis time, with minimal impact on left ventricular volumes and ejection fraction. Magn Reson Med, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Hautvast, Gilion L. T. F.; Breeuwer, Marcel] Philips Healthcare, Imaging Syst, MR, NL-5680 DA Best, Netherlands. [Salton, Carol J.; Chuang, Michael L.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Salton, Carol J.; Chuang, Michael L.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Chuang, Michael L.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Breeuwer, Marcel] Eindhoven Univ Technol, NL-5600 MB Eindhoven, Netherlands. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Manning, Warren J.] Harvard Univ, Sch Med, Boston, MA USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Hautvast, GLTF (reprint author), Philips Healthcare, Imaging Syst, MR, Veenpluis 4-6, NL-5680 DA Best, Netherlands. EM gilion.hautvast@philips.com; marcel.breeuwer@philips.com FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institutes of Health [N01-HC-25195, RO1 HL70279]; Philips Healthcare FX Grant sponsor: National Heart, Lung and Blood Institute's Framingham Heart Study; Grant number: N01-HC-25195; Grant sponsor: National Institutes of Health; Grant number: N01-HC-25195 is a subcontract of RO1 HL70279; Grant sponsor: unrestricted grant from Philips Healthcare. NR 25 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAY PY 2012 VL 67 IS 5 BP 1478 EP 1486 DI 10.1002/mrm.23127 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 923KY UT WOS:000302619400029 PM 22021128 ER PT J AU Guerreiro, RJ Lohmann, E Kinsella, E Bras, JM Luu, N Gurunlian, N Dursun, B Bilgic, B Santana, I Hanagasi, H Gurvit, H Gibbs, JR Oliveira, C Emre, M Singleton, A AF Guerreiro, Rita Joao Lohmann, Ebba Kinsella, Emma Bras, Jose Miguel Luu, Nga Gurunlian, Nicole Dursun, Burcu Bilgic, Basar Santana, Isabel Hanagasi, Hasmet Gurvit, Hakan Gibbs, Jesse Raphael Oliveira, Catarina Emre, Murat Singleton, Andrew TI Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; NOTCH3; CADASIL; Exome sequencing ID CADASIL PATIENTS; LEUKOENCEPHALOPATHY; DIAGNOSIS; SPECTRUM; STROKE AB Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP. PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Singleton, Andrew] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Guerreiro, Rita Joao; Bras, Jose Miguel; Oliveira, Catarina] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Guerreiro, Rita Joao; Bras, Jose Miguel; Gurunlian, Nicole; Gibbs, Jesse Raphael] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Lohmann, Ebba; Bilgic, Basar; Hanagasi, Hasmet; Gurvit, Hakan; Emre, Murat] Istanbul Univ, Dept Neurol, Istanbul Fac Med, Istanbul, Turkey. [Kinsella, Emma] Cardiff Univ, Sch Med, Cardiff, S Glam, Wales. [Dursun, Burcu] Istanbul Univ, Inst Expt Med, Istanbul, Turkey. [Santana, Isabel; Oliveira, Catarina] Coimbra Univ Hosp, Neurol Serv, Coimbra, Portugal. RP Singleton, A (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A1014,35 Convent Dr, Bethesda, MD 20892 USA. EM Singleta@mail.nih.gov RI bilgic, basar/E-4821-2012; Singleton, Andrew/C-3010-2009; Bras, Jose/A-1428-2011; OI Bras, Jose/0000-0001-8186-0333; Oliveira, Catarina/0000-0001-6942-4328; Santana, Isabel/0000-0002-8114-9434 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000950-06]; National Institute on Aging (NIA) [U24 AG21886] 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 AG000950-06. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors, including the Alzheimer's Disease Centers, who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Samples from the Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org) were also used. NR 25 TC 6 Z9 8 U1 1 U2 7 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 MAY PY 2012 VL 33 IS 5 AR 1008.e17 DI 10.1016/j.neurobiolaging.2011.10.009 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 921OF UT WOS:000302486200033 PM 22153900 ER PT J AU Boyd, AS Rodrigues, NP Lui, KO Fu, XM Xu, Y AF Boyd, Ashleigh S. Rodrigues, Neil P. Lui, Kathy O. Fu, Xuemei Xu, Yang TI Concise Review: Immune Recognition of Induced Pluripotent Stem Cells SO STEM CELLS LA English DT Article DE Stem cells; Embryonic stem cells; Induced pluripotent stem cells; Cell replacement therapy; Immunogenicity; Transplantation; Tolerance; Rejection; Regenerative medicine ID REGULATORY T-CELLS; LONG-TERM ACCEPTANCE; HUMAN SOMATIC-CELLS; DIFFERENTIATED DERIVATIVES; COSTIMULATION BLOCKADE; CARDIAC ALLOGRAFTS; DENDRITIC CELLS; DEFINED FACTORS; BLOCKING CD40; CD28 PATHWAYS AB Autologous-induced pluripotent stem cells (iPSCs) may eventually be used in cell replacement therapies to treat a wide range of diseases and have been touted as a solution to the vexing problem of immune rejection in this context. Emerging evidence suggests, however, that ostensibly histocompatible iPSCs may be rejected following transplantation. Here, we review the mechanisms that contribute to immunogenicity in iPSCs and forward approaches to permit their acceptance in potential cell replacement therapies. STEM CELLS 2012;30:797803 C1 [Boyd, Ashleigh S.; Rodrigues, Neil P.] Boston Univ, NIH, Ctr Biomed Res Excellence COBRE Stem Cell Biol, Roger Williams Canc Med Ctr,Sch Med, Providence, RI 02908 USA. [Boyd, Ashleigh S.; Rodrigues, Neil P.] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Boyd, Ashleigh S.; Rodrigues, Neil P.] Boston Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02118 USA. [Lui, Kathy O.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Fu, Xuemei; Xu, Yang] Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, La Jolla, CA 92093 USA. [Fu, Xuemei] Chengdu Womens & Childrens Cent Hosp, Chengdu, Sichuan, Peoples R China. RP Boyd, AS (reprint author), Boston Univ, NIH, COBRE, Roger Williams Canc Med Ctr,Sch Med,Prior Off 207, 825 Chalkstone Ave, Providence, RI 02908 USA. EM asboyd@bu.edu; yangxu@ucsd.edu RI Lui, Kathy O./E-4883-2015 OI Lui, Kathy O./0000-0002-1616-3643 FU NIH [P20RR018757]; Rhode Island Foundation; BD Biosciences; NSFC [30872346]; California Institute for Regenerative Medicine [TR1-01277]; NIH COBRE at Roger Williams Medical Center FX This work was supported by NIH Grant P20RR018757 (A.S.B. and N.P.R.), Rhode Island Foundation (A.S.B.), BD Biosciences (N.P.R.), a NSFC Grant 30872346 (X.F.), and California Institute for Regenerative Medicine Grant TR1-01277 (Y.X.). Additional support to A.S.B. and N.P.R. laboratories is provided by the administrative and flow cytometry cores within the NIH COBRE at Roger Williams Medical Center. NR 53 TC 26 Z9 27 U1 1 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2012 VL 30 IS 5 BP 797 EP 803 DI 10.1002/stem.1066 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 923KD UT WOS:000302617300001 PM 22419544 ER PT J AU Kele, J Andersson, ER Villaescusa, JC Cajanek, L Parish, CL Bonilla, S Toledo, EM Bryja, V Rubin, JS Shimono, A Arenas, E AF Kele, Julianna Andersson, Emma R. Villaescusa, J. Carlos Cajanek, Lukas Parish, Clare L. Bonilla, Sonia Toledo, Enrique M. Bryja, Vitezslav Rubin, Jeffrey S. Shimono, Akihiko Arenas, Ernest TI SFRP1 and SFRP2 Dose-Dependently Regulate Midbrain Dopamine Neuron Development In Vivo and in Embryonic Stem Cells SO STEM CELLS LA English DT Article DE Embryonic stem cells; Neural differentiation; Developmental biology; Parkinson's disease ID FRIZZLED-RELATED PROTEIN-1; DISHEVELLED PHOSPHORYLATION; INCREASES DIFFERENTIATION; INT-1 PROTOONCOGENE; PARKINSONS-DISEASE; SPEMANN ORGANIZER; WNT/BETA-CATENIN; WNT ANTAGONIST; NERVOUS-SYSTEM; MOUSE AB Secreted Frizzled related proteins (sFRPs) are a family of proteins that modulate Wnt signaling, which in turn regulates multiple aspects of ventral midbrain (VM) and dopamine (DA) neuron development. However, it is not known which Wnt signaling branch and what aspects of midbrain DA neuron development are regulated by sFRPs. Here, we show that sFRP1 and sFRP2 activate the Wnt/planar-cell-polarity/Rac1 pathway in DA cells. In the developing VM, sFRP1 and sFRP2 are expressed at low levels, and sFRP1-/- or sFRP2-/- mice had no detectable phenotype. However, compound sFRP1-/-;sFRP2-/- mutants revealed a Wnt/PCP phenotype similar to that previously described for Wnt5a-/- mice. This included an anteroposterior shortening of the VM, a lateral expansion of the Shh domain and DA lineage markers (Lmx1a and Th), as well as an accumulation of Nurr1+ precursors in the VM. In vitro experiments showed that, while very high concentrations of SFRP1 had a negative effect on cell survival, low/medium concentrations of sFRP1 or sFRP2 promoted the DA differentiation of progenitors derived from primary VM cultures or mouse embryonic stem cells (ESCs), mimicking the effects of Wnt5a. We thus conclude that the main function of sFRP1 and sFRP2 is to enhance Wnt/PCP signaling in DA cells and to regulate Wnt/PCP-dependent functions in midbrain development. Moreover, we suggest that lowmedium concentrations of sFRPs may be used to enhance the DA differentiation of ESCs and improve their therapeutic application. STEM CELLS 2012;30:865875 C1 [Kele, Julianna; Andersson, Emma R.; Villaescusa, J. Carlos; Cajanek, Lukas; Bonilla, Sonia; Toledo, Enrique M.; Bryja, Vitezslav; Arenas, Ernest] Karolinska Inst, Lab Mol Neurobiol Med Biochem & Biophys, S-17177 Stockholm, Sweden. [Parish, Clare L.] Univ Melbourne, Florey Neurosci Inst, Parkville, Vic 3052, Australia. [Parish, Clare L.] Univ Melbourne, Ctr Neurosci, Parkville, Vic 3052, Australia. [Rubin, Jeffrey S.] NCI CCR LCMB, MSC 4255, Bethesda, MD USA. [Shimono, Akihiko] Natl Univ Singapore, Ctr Life Sci 02 07, Canc Sci Inst Singapore, Singapore, Singapore. RP Arenas, E (reprint author), Karolinska Inst, Lab Mol Neurobiol Med Biochem & Biophys, Scheelevag 1, S-17177 Stockholm, Sweden. EM Ernest.Arenas@ki.se RI Parish, Clare/A-3380-2014; Toledo, Enrique/E-8860-2010; Bryja, Vit?zslav/H-1925-2014; Andersson, Emma/J-4236-2012 OI Villaescusa, J. Carlos/0000-0001-9456-9828; Cajanek, Lukas/0000-0003-2914-8589; Arenas, Ernest/0000-0003-0197-6577; Toledo, Enrique/0000-0002-1460-4708; Bryja, Vit?zslav/0000-0002-9136-5085; Andersson, Emma/0000-0002-8608-625X FU Swedish Research Council (DBRM) [VR2008:2811, 3287]; European Union; Swedish Foundation for Strategic Research (INGVAR and DBRM); Norwegian Research Council; Karolinska Institute; National Health and Medical Research Council (NHMRC), Australia; Swedish National Neuroscience Network; FEBS; EMBO; Ministry of Education, Youth and Sports of the Czech Republic [MSM0021622430]; NHMRC FX We thank Carmen Ramirez-Castillejo, Helena Mira, and Carmen Salto, for support and assistance; Alessandra Nanni for secretarial help; Johan Glad for help with statistical analysis; Johnny Soderlund and Lottie Jansson-Sjostrand for additional assistance. This work was supported by grants from the Swedish Research Council (DBRM, VR2008:2811 and 3287), European Union (Neurostemcell and Eurostemcell), Swedish Foundation for Strategic Research (INGVAR and DBRM), Norwegian Research Council, and Karolinska Institute, National Health and Medical Research Council (NHMRC), Australia. J.K. was supported by the Swedish National Neuroscience Network. J.C.V. was supported by a FEBS Long-Term Fellowship. V. B. was supported by EMBO Installation Grant and Ministry of Education, Youth and Sports of the Czech Republic (MSM0021622430). C.L.P was supported by an NHMRC Career development Fellowship, Australia. J.K. is currently affiliated with Ludwig Institute for Cancer Research Ltd., Stockholm, Sweden; E.R.A. is currently affiliated with Department of Cellular and Molecular Biology, Karolinska Institute, Stockholm, Sweden; S.B. is currently affiliated with Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocio, Sevilla, Spain; V.B. is currently affiliated with Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic, and Institute of Biophysics, Brno, Czech Republic. NR 56 TC 23 Z9 24 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2012 VL 30 IS 5 BP 865 EP 875 DI 10.1002/stem.1049 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 923KD UT WOS:000302617300008 PM 22290867 ER PT J AU Zheng, XF Dumitru, R Lackford, BL Freudenberg, JM Singh, AP Archer, TK Jothi, R Hu, G AF Zheng, Xiaofeng Dumitru, Raluca Lackford, Brad L. Freudenberg, Johannes M. Singh, Ajeet P. Archer, Trevor K. Jothi, Raja Hu, Guang TI Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation SO STEM CELLS LA English DT Article DE Ccr4-Not; Embryonic stem cell; Self-renewal; Pluripotency; Extraembryonic differentiation ID EMBRYONIC STEM-CELLS; MESSENGER-RNA METABOLISM; SELF-RENEWAL; CCR4-NOT COMPLEX; TRANSCRIPTIONAL NETWORK; REGULATORY NETWORKS; SIGNALING PATHWAYS; PLURIPOTENCY; SCREEN; BIOLOGY AB Embryonic stem cell (ESC) identity and self-renewal is maintained by extrinsic signaling pathways and intrinsic gene regulatory networks. Here, we show that three members of the Ccr4-Not complex, Cnot1, Cnot2, and Cnot3, play critical roles in maintaining mouse and human ESC identity as a protein complex and inhibit differentiation into the extraembryonic lineages. Enriched in the inner cell mass of blastocysts, these Cnot genes are highly expressed in ESC and downregulated during differentiation. In mouse ESCs, Cnot1, Cnot2, and Cnot3 are important for maintenance in both normal conditions and the 2i/LIF medium that supports the ground state pluripotency. Genetic analysis indicated that they do not act through known self-renewal pathways or core transcription factors. Instead, they repress the expression of early trophectoderm (TE) transcription factors such as Cdx2. Importantly, these Cnot genes are also necessary for the maintenance of human ESCs, and silencing them mainly lead to TE and primitive endoderm differentiation. Together, our results indicate that Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs. STEM CELLS 2012;30:910922 C1 [Zheng, Xiaofeng; Dumitru, Raluca; Lackford, Brad L.; Singh, Ajeet P.; Archer, Trevor K.; Hu, Guang] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Freudenberg, Johannes M.; Jothi, Raja] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Hu, G (reprint author), NIEHS, Mol Carcinogenesis Lab, Bldg 101,Rm D-416,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov RI Singh, Ajeet/G-3935-2013; Jothi, Raja/G-3780-2015; Hu, Guang/E-7474-2016 OI Hu, Guang/0000-0003-0437-4723 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES102745, Z01ES071006-11, 1ZIAES102625-02] FX We thank Drs. Thomas Kunkel, Paul Wade, Carmen Williams (NIEHS), Rene Maehr (UMass Med), and Guokai Chen (NHLBI) for providing insightful comments and suggestions on the manuscript. We thank Dr. Austin Smith for providing the Oct4GiP cells, Dr. Hitoshi Niwa for providing the Cdx2-/- ESCs, Dr. Janet Rossant for providing the mouse TS cells, Dr. G. Sebastiaan Winkler (University of Nottingham) and Dr. H. Th. Marc Timmers (University Medical Centre, Utrecht) for providing the Cnot1 antibody and technical guidance on detecting the Cnot proteins. We thank the FACS, microarray, and animal facilities at NIEHS for assistance with the experiments. This research was supported by the National Institute of Environmental Health Sciences, National Institutes of Health Intramural Research Program Z01ES102745 (to G.H.), Z01ES071006-11 (to T.K.A.), and 1ZIAES102625-02 (to R.J.). NR 66 TC 24 Z9 34 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD MAY PY 2012 VL 30 IS 5 BP 910 EP 922 DI 10.1002/stem.1070 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 923KD UT WOS:000302617300012 PM 22367759 ER PT J AU Lee, SB Seo, D Choi, D Park, KY Holczbauer, A Marquardt, JU Conner, EA Factor, VM Thorgeirsson, SS AF Lee, Seung Bum Seo, Daekwan Choi, Dongho Park, Kye-Yoon Holczbauer, Agnes Marquardt, Jens U. Conner, Elizabeth A. Factor, Valentina M. Thorgeirsson, Snorri S. TI Contribution of Hepatic Lineage Stage-Specific Donor Memory to the Differential Potential of Induced Mouse Pluripotent Stem Cells SO STEM CELLS LA English DT Article DE Induced pluripotent stem cells; Donor memory; Hepatocyte lineage cells; Hepatic differentiation ID LIVER DEVELOPMENT; IPS CELLS; HEPATOCYTE DIFFERENTIATION; EPIGENETIC MEMORY; GENE-EXPRESSION; DEFINED FACTORS; ONCOSTATIN-M; GENERATION; SWI/SNF; METHYLATION AB Recent studies suggested that induced pluripotent stem cells (iPSCs) retain a residual donor cell gene expression, which may impact their capacity to differentiate into cell of origin. Here, we addressed a contribution of a lineage stage-specific donor cell memory in modulating the functional properties of iPSCs. iPSCs were generated from hepatic lineage cells at an early (hepatoblast-derived, HB-iPSCs) and end stage (adult hepatocyte, AH-iPSCs) of hepatocyte differentiation as well as from mouse embryonic fibroblasts (MEFs-iPSCs) using a lentiviral vector encoding four pluripotency-inducing factors Oct4, Sox2, Klf4, and c-Myc. All resulting iPSC lines acquired iPSCs phenotype as judged by the accepted criteria including morphology, expression of pluripotency markers, silencing of transducing factors, capacity of multilineage differentiation in teratoma assay, and normal diploid karyotype. However, HB-iPSCs were more efficient in directed differentiation toward hepatocytic lineage as compared to AH-iPSCs, MEF-iPSCs, or mouse embryonic stem cells (mESCs). Extensive comparative transcriptome analyses of the early passage iPSCs, donor cells, and mESCs revealed that despite global similarities in gene expression patterns between generated iPSCs and mESCs, HB-iPSCs retained a transcriptional memory (seven upregulated and 17 downregulated genes) typical of the original cells. Continuous passaging of HB-iPSCs erased most of these differences including a superior capacity for hepatic redifferentiation. These results suggest that retention of lineage stage-specific donor memory in iPSCs may facilitate differentiation into donor cell type. The identified gene set may help to improve hepatic differentiation for therapeutic applications and contribute to the better understanding of liver development. STEM CELLS 2012;30:9971007 C1 [Lee, Seung Bum; Seo, Daekwan; Choi, Dongho; Holczbauer, Agnes; Marquardt, Jens U.; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] Natl Canc Inst, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Kye-Yoon] Natl Inst Neurol Disorders & Stroke, Stem Cell Unit, NIH, Bethesda, MD 20892 USA. [Choi, Dongho] Soonchunhyang Univ, Coll Med, Dept Surg, Seoul, South Korea. RP Thorgeirsson, SS (reprint author), Natl Canc Inst, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Susan Garfiled and Langston Lim for the assistance with confocal imaging and Barbara Taylor for the help with fluorescence-activated cell sorting analysis. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 55 TC 29 Z9 29 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2012 VL 30 IS 5 BP 997 EP 1007 DI 10.1002/stem.1074 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 923KD UT WOS:000302617300020 PM 22378611 ER PT J AU Masedunskas, A Porat-Shliom, N Weigert, R AF Masedunskas, Andrius Porat-Shliom, Natalie Weigert, Roberto TI Regulated Exocytosis: Novel Insights from Intravital Microscopy SO TRAFFIC LA English DT Review DE actin; cytoskeleton; exocrine secretion; in vivo imaging; intravital microscopy; light microscopy; regulated exocytosis ID REFLECTION FLUORESCENCE MICROSCOPY; ACINAR EPITHELIAL-CELLS; RAT SUBMANDIBULAR-GLAND; FUSION PORE; 2-PHOTON MICROSCOPY; COMPOUND EXOCYTOSIS; SECRETORY GRANULES; MULTIPHOTON MICROSCOPY; DIRECT VISUALIZATION; VESICLE EXOCYTOSIS AB Regulated exocytosis is a fundamental process that every secretory cell uses to deliver molecules to the cell surface and the extracellular space by virtue of membranous carriers. This process has been extensively studied using various approaches such as biochemistry, electrophysiology and electron microscopy. However, recent developments in time-lapse light microscopy have made possible imaging individual exocytic events, hence, advancing our understanding of this process at a molecular level. In this review, we focus on intravital microscopy (IVM), a light microscopy-based approach that enables imaging subcellular structures in live animals, and discuss its recent application to study regulated exocytosis. IVM has revealed differences in regulation and modality of regulated exocytosis between in vitro and in vivo model systems, unraveled novel aspects of this process that can be appreciated only in in vivo settings and provided valuable and novel information on its molecular machinery. In conclusion, we make the case for IVM being a mature technique that can be used to investigate the molecular machinery of several intracellular events under physiological conditions. C1 [Masedunskas, Andrius; Porat-Shliom, Natalie; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Masedunskas, Andrius] Univ N Carolina, Dept Biol, Chapel Hill, NC 27514 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr 303A, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU NIH, National Institute of Dental and Craniofacial Research (NIDCR) FX This research was supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research (NIDCR). We apologize to those whose work could not be cited because of space limitations. NR 69 TC 12 Z9 12 U1 3 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD MAY PY 2012 VL 13 IS 5 BP 627 EP 634 DI 10.1111/j.1600-0854.2012.01328.x PG 8 WC Cell Biology SC Cell Biology GA 923LR UT WOS:000302621300001 PM 22243493 ER PT J AU Lazny, R Wolosewicz, K Dauter, Z Brzezinski, K AF Lazny, Ryszard Wolosewicz, Karol Dauter, Zbigniew Brzezinski, Krzysztof TI (1RS, 2SR, 5SR)-9-Benzyl-2-[(1RS)-1-hydroxybenzyl]-9-azabicyclo[3.3.1]nonan-3-one from synchrotron data SO ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS LA English DT Article AB In the crystal structure of the racemic title compound, C22H25NO2, solved and refined against sychrotron diffraction data, the hydroxy group and the carbonyl O atom participate in the formation of O-H center dot center dot center dot O hydrogen bonds between pairs of enantiomers related by a crystallographic centre of symmetry. C1 [Lazny, Ryszard; Wolosewicz, Karol; Brzezinski, Krzysztof] Univ Bialystok, Inst Chem, Hurtowa 1, PL-15399 Bialystok, Poland. [Dauter, Zbigniew; Brzezinski, Krzysztof] NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab,Biosci Div, Argonne, IL 60439 USA. RP Lazny, R (reprint author), Univ Bialystok, Inst Chem, Hurtowa 1, PL-15399 Bialystok, Poland. EM lazny@uwb.edu.pl FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 12 TC 5 Z9 5 U1 0 U2 6 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2056-9890 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Crystallogr. Commun. PD MAY PY 2012 VL 68 BP O1367 EP + DI 10.1107/S1600536812014754 PN 5 PG 8 WC Crystallography SC Crystallography GA V46AT UT WOS:000209857800216 PM 22590261 ER PT J AU Lieberman, AP Puertollano, R Raben, N Slaugenhaupt, S Walkley, SU Ballabio, A AF Lieberman, Andrew P. Puertollano, Rosa Raben, Nina Slaugenhaupt, Susan Walkley, Steven U. Ballabio, Andrea TI Autophagy in lysosomal storage disorders SO AUTOPHAGY LA English DT Review DE autophagy; glycogenosis; Mucolipidosis Type IV; lysosomal storage disorders; mucopolysaccharidoses; lysosomes; sphingolipidoses ID MUCOLIPIDOSIS TYPE-IV; MULTIPLE SULFATASE DEFICIENCY; PICK-C DISEASE; PHOSPHOTRANSFERASE ALPHA/BETA-SUBUNITS; NEURONAL CEROID-LIPOFUSCINOSIS; ENZYME REPLACEMENT THERAPY; SINGLE MUSCLE-FIBERS; POMPE-DISEASE; MOUSE MODEL; GAUCHER-DISEASE AB Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. As a consequence, many tissues and organ systems are affected, including brain, viscera, bone and cartilage. The progressive nature of phenotype development is one of the hallmarks of LSDs. In recent years biochemical and cell biology studies of LSDs have revealed an ample spectrum of abnormalities in a variety of cellular functions. These include defects in signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking. Lysosomes also play a fundamental role in the autophagic pathway by fusing with autophagosomes and digesting their content. Considering the highly integrated function of lysosomes and autophagosomes it was reasonable to expect that lysosomal storage in LSDs would have an impact upon autophagy. The goal of this review is to provide readers with an overview of recent findings that have been obtained through analysis of the autophagic pathway in several types of LSDs, supporting the idea that LSDs could be seen primarily as "autophagy disorders." C1 [Ballabio, Andrea] Telethon Inst Genet & Med TIGEM, Naples, Italy. [Ballabio, Andrea] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Ballabio, Andrea] Univ Naples Federico II, Dept Pediat, Naples, Italy. [Lieberman, Andrew P.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [Puertollano, Rosa; Raben, Nina] NIH, Bethesda, MD 20892 USA. [Puertollano, Rosa] NHLBI, Cell Biol Lab, Bethesda, MD USA. [Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD USA. [Slaugenhaupt, Susan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Walkley, Steven U.] Albert Einstein Coll Med, Rose F Kennedy Ctr, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 USA. RP Ballabio, A (reprint author), Telethon Inst Genet & Med TIGEM, Naples, Italy. EM ballabio@tigem.it OI BALLABIO, Andrea/0000-0003-1381-4604 FU NIH [R01 NS063967, HD045561]; NIH, National Heart, Lung, and Blood Institute (NHLBI); Beyond Batten Disease Foundation; Telethon Foundation; European Research Council (ERC) [250154] FX We thank Dr. G. Diez-Roux for manuscript preparation, helpful discussions and critical reading of the manuscript and C. Settembre for critical reading of the manuscript. A. P. L. is supported by the NIH grant R01 NS063967; R. P. is supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI); S. U. W. is supported by NIH grant HD045561; A. B. is supported by the Beyond Batten Disease Foundation, the Telethon Foundation and the European Research Council (ERC) grant #250154. NR 132 TC 115 Z9 119 U1 3 U2 21 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD MAY PY 2012 VL 8 IS 5 BP 719 EP 730 DI 10.4161/auto.19469 PG 12 WC Cell Biology SC Cell Biology GA 960QU UT WOS:000305403800002 PM 22647656 ER PT J AU Codispoti, KET Beason-Held, LL Kraut, MA O'Brien, RJ Rudow, G Pletnikova, O Crain, B Troncoso, JC Resnick, SM AF Codispoti, Kari-Elise T. Beason-Held, Lori L. Kraut, Michael A. O'Brien, Richard J. Rudow, Gay Pletnikova, Olga Crain, Barbara Troncoso, Juan C. Resnick, Susan M. TI Longitudinal brain activity changes in asymptomatic Alzheimer disease SO BRAIN AND BEHAVIOR LA English DT Article DE Amyloid; dementia; fMRI; neuropathology; PET; resting state; tau AB Asymptomatic Alzheimer disease (ASYMAD) is characterized by normal cognition despite substantial AD pathology. To identify factors contributing to cognitive resilience, we compared early changes in regional cerebral blood flow (rCBF) in individuals subsequently diagnosed as ASYMAD with changes in cognitively impaired (CI) and normal older participants from the Baltimore Longitudinal Study of Aging. Participants underwent annual positron emission tomography (PET) rCBF measurements beginning 10.0 (SD 3.6) years before death and while cognitively intact. Based on clinical and autopsy information, subjects were grouped as cognitively normal (CN = 7), ASYMAD (n = 6), and CI (= 6). Autopsy material was analyzed using CERAD and Braak scores and quantitative stereologic measures of tau and amyloid. ASYMAD and CI groups had similar CERAD and Braak scores, similar amounts of beta-amyloid and tau in middle frontal (MFG), middle temporal (MTG), and inferior parietal (IP) regions, and more beta-amyloid than CN in precuneus, MFG, and IP areas. Voxel-based PET analysis identified similarities and differences in longitudinal rCBF change among groups across a 7.2-year interval. Both ASYMAD and CI groups showed similar longitudinal rCBF declines in precuneus, lingual, and MTG regions relative to CN. The CI also showed greater rCBF decreases in anterior and posterior cingulate, cuneus, and brainstem regions relative to ASYMAD and CN, whereas ASYMAD showed greater relative rCBF increases over time in medial temporal and thalamic regions relative to CI and CN. Our findings provide evidence of early functional alterations that may contribute to cognitive resilience in those who accumulate AD pathology but maintain normal cognition. C1 [Codispoti, Kari-Elise T.; Rudow, Gay; Pletnikova, Olga; Crain, Barbara; Troncoso, Juan C.] Johns Hopkins Univ, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. [Beason-Held, Lori L.] NIA, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. [Kraut, Michael A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21205 USA. [O'Brien, Richard J.; Troncoso, Juan C.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA. RP Codispoti, KET (reprint author), Johns Hopkins Univ, Dept Pathol, Div Neuropathol, 720 Rutland Ave,558 Ross Res Bldg, Baltimore, MD 21205 USA. EM kcodisp1@jhmi.edu FU Intramural Research Program of the NIH, National Institute on Aging; Johns Hopkins Alzheimer Disease Research Center [P50AG05146]; Alzheimer's Association [IIRG-09134090]; Ruth L. Kirschstein National Research Service Award [T32EB006351-05]; Research and Development [N01-AG-3-2124] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, the Johns Hopkins Alzheimer Disease Research Center (P50AG05146), the Alzheimer's Association (IIRG-09134090), the Ruth L. Kirschstein National Research Service Award (T32EB006351-05), and by Research and Development Contract N01-AG-3-2124. We are grateful to the BLSA participants and staff for their dedication to these studies, the staff of the Johns Hopkins PET facility for their assistance, and to Dr. Mony de Leon for his thoughtful review of the manuscript. NR 36 TC 6 Z9 6 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD MAY PY 2012 VL 2 IS 3 BP 221 EP 230 DI 10.1002/brb3.47 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V35UR UT WOS:000209174000003 PM 22741095 ER PT J AU Bekker, LG Beyrer, C Quinn, TC AF Bekker, Linda-Gail Beyrer, Chris Quinn, Thomas C. TI Behavioral and Biomedical Combination Strategies for HIV Prevention SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; SUB-SAHARAN AFRICA; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; FEMALE SEX WORKERS; HOMOSEXUAL BISEXUAL MEN; HERPES-SIMPLEX-VIRUS; MALE CIRCUMCISION; HETEROSEXUAL TRANSMISSION AB Around 2.5 million people become infected with HIV each year. This extraordinary toll on human life and public health worldwide will only be reversed with effective prevention. What's more, in the next few years, it is likely at least, that no single prevention strategy will be sufficient to contain the spread of the disease. There is a need for combination prevention as there is for combination treatment, including biomedical, behavioral, and structural interventions. Expanded HIV prevention must be grounded in a systematic analysis of the epidemic's dynamics in local contexts. Although 85% of HIV is transmitted sexually, effective combinations of prevention have been shown for people who inject drugs. Combination prevention should be based on scientifically derived evidence, with input and engagement from local communities that fosters the successful integration of care and treatment. C1 [Bekker, Linda-Gail] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [Beyrer, Chris] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Sect Int HIV STD Res, NIH, Bethesda, MD 20892 USA. RP Bekker, LG (reprint author), Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. EM Linda-gail.bekker@hiv-research.org.za NR 146 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD MAY PY 2012 VL 4 IS 5 AR a007435 DI 10.1101/cshperspect.a007435 PG 23 WC Cell Biology SC Cell Biology GA 995PV UT WOS:000308024100007 ER PT J AU Ribeiro-Gomes, FL Sacks, D AF Ribeiro-Gomes, Flavia L. Sacks, David TI The influence of early neutrophil-Leishmania interactions on the host immune response to infection SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE neutrophils; Leishmania; inflammation; immune response; sand fly; apoptosis; dendritic cells; macrophages ID MAJOR INFECTION; CUTANEOUS LEISHMANIASIS; POLYMORPHONUCLEAR LEUKOCYTES; DONOVANI PROMASTIGOTES; EXTRACELLULAR TRAPS; MONOCLONAL-ANTIBODY; SUSCEPTIBLE MICE; PARASITE BURDEN; LYMPH-NODES; IN-VIVO AB Neutrophils are the first cells recruited to the dermal site of Leishrnania infection following injection by needle or sand fly bite. The role of neutrophils in either promoting or suppressing host immunity remains controversial. We discuss the events driving neutrophil recruitment, their interaction with the parasite and apoptotic fate, and the nature of their encounters with other innate cells. We suggest that the influence of the neutrophil response on infection outcome critically depends on the timing of their recruitment and the tissue environment in which it occurs. C1 [Ribeiro-Gomes, Flavia L.; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov RI Ribeiro-Gomes, Flavia/F-7609-2015 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 59 TC 28 Z9 28 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD MAY PY 2012 VL 2 AR UNSP 59 DI 10.3389/fcimb.2012.00059 PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 220ZU UT WOS:000324627400005 PM 22919650 ER PT J AU Zheng, XF Hu, G AF Zheng, Xiaofeng Hu, Guang TI Oct4GiP Reporter Assay to Study Genes that Regulate Mouse Embryonic Stem Cell Maintenance and Self-renewal SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Stem Cell Biology; Issue 63; Molecular Biology; Genetics; Embryonic stem cell; ESC; self-renewal; differentiation; Oct4; GFP; reporter assay; RNAi AB Pluripotency and self-renewal are two defining characteristics of embryonic stem cells (ES cells). Understanding the underlying molecular mechanism will greatly facilitate the use of ES cells for developmental biology studies, disease modeling, drug discovery, and regenerative medicine (reviewed in(1,2)). To expedite the identification and characterization of novel regulators of ES cell maintenance and self-renewal, we developed a fluorescence reporter-based assay to quantitatively measure the self-renewal status in mouse ES cells using the Oct4GiP cells(3). The Oct4GiP cells express the green fluorescent protein (GFP) under the control of the Oct4 gene promoter region(4,5). Oct4 is required for ES cell self-renewal, and is highly expressed in ES cells and quickly down-regulated during differentiation(6,7). As a result, GFP expression and fluorescence in the reporter cells correlates faithfully with the ES cell identity(5), and fluorescence-activated cell sorting (FACS) analysis can be used to closely monitor the self-renewal status of the cells at the single cell level(3,8). Coupled with RNAi, the Oct4GiP reporter assay can be used to quickly identify and study regulators of ES cell maintenance and self-renewal(3,8). Compared to other methods for assaying self-renewal, it is more convenient, sensitive, quantitative, and of lower cost. It can be carried out in 96-or 384-well plates for large-scale studies such as high-throughput screens or genetic epistasis analysis. Finally, by using other lineage-specific reporter ES cell lines, the assay we describe here can also be modified to study fate specification during ES cell differentiation. C1 [Zheng, Xiaofeng; Hu, Guang] Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, Res Triangle Pk, NC 27709 USA. RP Hu, G (reprint author), Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health Intramural Research Program [Z01ES102745] FX We thank Brad Lackford for reading and editing the manuscript. This research was supported by the National Institute of Environmental Health Sciences, National Institutes of Health Intramural Research Program Z01ES102745 (to G. H.). NR 19 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2012 IS 63 AR UNSP e3987 DI 10.3791/3987 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36PH UT WOS:000209223000043 ER PT J AU Campos, NG Castle, PE Schiffman, M Kim, JJ AF Campos, Nicole G. Castle, Philip E. Schiffman, Mark Kim, Jane J. TI Policy Implications of Adjusting Randomized Trial Data for Economic Evaluations: A Demonstration from the ASCUS-LSIL Triage Study SO MEDICAL DECISION MAKING LA English DT Article DE economic evaluation; randomized trial; bias; cervical cancer; human papillomavirus ID ATYPICAL SQUAMOUS-CELLS; INTRAEPITHELIAL LESION TRIAGE; UNDETERMINED SIGNIFICANCE; HUMAN-PAPILLOMAVIRUS; COST-EFFECTIVENESS; CERVICAL CYTOLOGY; RESEARCH DESIGNS; STRATEGIES; MANAGEMENT; ALTS AB Background. Although the randomized controlled trial (RCT) is widely considered the most reliable method for evaluation of health care interventions, challenges to both internal and external validity exist. Thus, the efficacy of an intervention in a trial setting does not necessarily represent the real-world performance that decision makers seek to inform comparative effectiveness studies and economic evaluations. Methods. Using data from the ASCUS-LSIL Triage Study (ALTS), we performed a simplified economic evaluation of age-based management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3) among women who were referred to the study with low-grade squamous intraepithelial lesions (LSIL). We used data from the trial itself to adjust for 1) potential lead time bias and random error that led to variation in the observed prevalence of CIN3 by study arm and 2) potential ascertainment bias among providers in the most aggressive management arm. Results. We found that using unadjusted RCT data may result in counterintuitive cost-effectiveness results when random error and/or bias are present. Following adjustment, the rank order of management strategies changed for 2 of the 3 age groups we considered. Conclusions. Decision analysts need to examine study design, available trial data, and cost-effectiveness results closely in order to detect evidence of potential bias. Adjustment for random error and bias in RCTs may yield different policy conclusions relative to unadjusted trial data. C1 [Campos, Nicole G.; Kim, Jane J.] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Campos, Nicole G.] Univ Miami, Ctr Excellence Hlth Dispar Res El Ctr, Sch Nursing & Hlth Studies, Coral Gables, FL 33124 USA. [Castle, Philip E.] Amer Soc Clin Pathol Inst, Washington, DC USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Campos, NG (reprint author), POB 248153, Coral Gables, FL 33124 USA. EM gastin@post.harvard.edu FU National Cancer Institute [R01 CA93435]; National Institutes of Health/National Cancer Institute; National Cancer Institute, National Institutes of Health, Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105] FX Received 5 November 2010 from the Center for Health Decision Science, Harvard School of Public Health, Boston, MA (NGC, JJK); Center of Excellence for Health Disparities Research-El Centro, School of Nursing and Health Studies, University of Miami, Coral Gables, FL (NGC); American Society for Clinical Pathology Institute, Washington, DC (PEC); and Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (MS). This work was supported by the National Cancer Institute (R01 CA93435), the National Institutes of Health/National Cancer Institute Intramural Research Program, and the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (contract no. CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105). PEC has received donations of HPV tests from Qiagen and serves on a data safety and monitoring committee for Merck, the manufacturer of Gardasil, for which he receives compensation. Revision accepted for publication 31 August 2011. NR 36 TC 4 Z9 4 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD MAY-JUN PY 2012 VL 32 IS 3 BP 400 EP 427 DI 10.1177/0272989X11428516 PG 28 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 951ET UT WOS:000304704300005 PM 22147881 ER PT J AU Fang, F Umbach, DM Xu, ZL Ye, WM Sandler, DP Taylor, JA Kamel, F AF Fang, Fang Umbach, David M. Xu, Zongli Ye, Weimin Sandler, Dale P. Taylor, Jack A. Kamel, Freya TI No association between DNA repair gene XRCC1 and amyotrophic lateral sclerosis SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; DNA repair; XRCC1 ID POPULATION AB Reduced DNA repair capacity may play a role in amyotrophic lateral sclerosis (ALS) etiology. We examined the association between ALS risk and single nucleotide polymorphisms (SNPs) in the gene x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) utilizing data from a case-control study and 2 genome-wide association studies the study of Irish Amyotrophic Lateral Sclerosis and the National Institute of Neurological Disorders and Stroke (NINDS,) genome-wide study in Amyotrophic Lateral Sclerosis and Neurologically Normal Controls). Our results did not show any differences in the frequency of XRCC1 gene polymorphisms between ALS patients and controls free of any neurological disease. Published by Elsevier Inc. C1 [Fang, Fang; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Fang, Fang; Xu, Zongli; Sandler, Dale P.; Taylor, Jack A.; Kamel, Freya] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Fang, F (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, POB 281, S-17177 Stockholm, Sweden. EM fang.fang@ki.se OI Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01 ES49005-15] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES49005-15). NR 5 TC 1 Z9 1 U1 1 U2 3 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 MAY PY 2012 VL 33 IS 5 AR 1015.e25 DI 10.1016/j.neurobiolaging.2010.07.004 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 921OF UT WOS:000302486200049 PM 20719408 ER PT J AU Huey, ED Ferrari, R Moreno, JH Jensen, C Morris, CM Potocnik, F Kalaria, RN Tierney, M Wassermann, EM Hardy, J Grafman, J Momeni, P AF Huey, Edward D. Ferrari, Raffaele Moreno, Jorge H. Jensen, Christopher Morris, Christopher M. Potocnik, Felix Kalaria, Rajesh N. Tierney, Michael Wassermann, Eric M. Hardy, John Grafman, Jordan Momeni, Parastoo TI FUS and TDP43 genetic variability in FTD and CBS SO NEUROBIOLOGY OF AGING LA English DT Article DE Frontotemporal dementia; Corticobasal syndrome; Genetics; FUS; TDP-43 ID FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; TARDBP MUTATIONS; TDP-43; DEMENTIA; DISEASE AB This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ferrari, Raffaele; Moreno, Jorge H.; Jensen, Christopher; Momeni, Parastoo] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Neurogenet Lab, Lubbock, TX 79430 USA. [Huey, Edward D.] Columbia Univ, Med Ctr, Taub Inst, New York, NY USA. [Huey, Edward D.] Columbia Univ, Gertrude H Sergievsky Ctr, Med Ctr, New York, NY 10027 USA. [Huey, Edward D.; Tierney, Michael; Wassermann, Eric M.; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Ferrari, Raffaele; Hardy, John] UCL, Inst Neurol, London, England. [Morris, Christopher M.; Kalaria, Rajesh N.] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Potocnik, Felix] Univ Stellenbosch, Dept Psychiat, Cape Town, South Africa. [Hardy, John] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Grafman, Jordan] Kessler Fdn, Res Ctr, Traumat Brain Injury Res Lab, W Orange, NJ USA. RP Momeni, P (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Neurogenet Lab, 4C101-4C160-4C127,3601 4th St,STOP 9410, Lubbock, TX 79430 USA. EM parastoo.momeni@ttuhsc.edu RI Hardy, John/C-2451-2009; OI Grafman, Jordan H./0000-0001-8645-4457 FU office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech Health Sciences Center; South Plains Foundation; NIH NINDS [5R00NS060766]; NINDS FX Molecular genetics work was funded by the office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech Health Sciences Center and a grant from South Plains Foundation (PM). This work was also supported by NIH NINDS grant 5R00NS060766 (EDH), and the NINDS Intramural Research Program (JG). The authors thank Cynthia Crews, Anne Leopold, and Karen DeTucci for the study coordination, Dr Susan Bergeson for sharing her control DNA samples with PM for genetic screening, Poorna Dharmasri for proofreading of the manuscript, and Stephanie Cosentino for comments. NR 26 TC 8 Z9 8 U1 1 U2 3 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 MAY PY 2012 VL 33 IS 5 AR 1016.e9 DI 10.1016/j.neurobiolaging.2011.08.004 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 921OF UT WOS:000302486200051 PM 21943958 ER PT J AU Takekoshi, T Fang, L Paragh, G Hwang, ST AF Takekoshi, T. Fang, L. Paragh, G. Hwang, S. T. TI CCR7-expressing B16 melanoma cells downregulate interferon-gamma-mediated inflammation and increase lymphangiogenesis in the tumor microenvironment SO ONCOGENESIS LA English DT Article DE melanoma; CCR7; IFN-gamma; lymphangiogenesis AB The expression of the CC chemokine receptor-7 (CCR7) by cancers, including melanoma, augments lymph node (LN) metastasis, but little is known about its role in lymphangiogenesis and anti-tumor immunity. We injected control B16 murine melanoma cells (pLNCX2-B16) and CCR7-overexpressing B16 cells (CCR7-B16) in murine footpads and compared resulting tumors at the protein and mRNA level using immunostaining, Affymetrix gene microarray and quantitative reverse-transcriptase PCR. Although control and CCR7-B16 primary tumors were of similar size, LN metastasis was dramatically enhanced in CCR7-B16 tumors. Microarray analysis of leukocyte-depleted pLNCX2-B16 and CCR7-B16 tumor cell suspensions showed that three major groups of genes linked to interferon (IFN)-gamma signaling pathways (for example, STAT1, CXCR 9-11, CCL5 and CXCL10, major histocompatibility complex (MHC) I and MHC II) were downregulated in the CCR7-B16 tumor microenvironment, suggesting activation through CCR7 can downregulate pathways critical for host anti-tumor immunity. In addition, mRNA expression of the lymphatic marker podoplanin was upregulated in CCR7-B16 tumors by 3.35-fold versus control tumors. Anti-podoplanin monoclonal antibody staining revealed a three-fold increase in intratumoral CCL21-expressing lymphatic vessels, as well as a two-fold increase in the number of invading tumor cells per lymphatic vessel in CCR7-B16 versus control tumors. Enhanced anti-vascular endothelial growth factor C (VEGF-C) staining was present in CCR7-B16 versus control tumors, suggesting that VEGF-C may have a role in the CCR7-mediated lymphangiogenesis. In summary, CCR7-B16 tumors show a striking decrease in IFN-gamma-mediated inflammatory gene expression in contrast to increased expression of VEGF-C, CCL21 and podoplanin by lymphatic vessels. Enhanced lymphangiogenesis may contribute to the dramatic increase in LN metastasis that is observed in the CCR7-expressing tumors. C1 [Takekoshi, T.; Paragh, G.; Hwang, S. T.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA. [Takekoshi, T.; Paragh, G.; Hwang, S. T.] Froedtert Hosp, Milwaukee, WI 53226 USA. [Fang, L.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), Med Coll Wisconsin, Dept Dermatol, FEC 4100,9200W Wisconsin Ave, Milwaukee, WI 53226 USA. EM sthwang@mcw.edu FU Advancing Healthier Wisconsin Research Funds; Advancing Healthier Wisconsin Endowment of the Medical College of Wisconsin; Ann's Hope Foundation for Melanoma; MCW/Froedtert Cancer Center Collaborative Research Fellowship; Intramural Research Program of the National Cancer Institute FX We thank Dr Ryan E Sells, Dr Xuesong Wu, Mr Nathan Duncan and Dr Tomotaka Mabuchi (Department of Dermatology, MCW) for their advice and technical support. This study was supported by the Advancing Healthier Wisconsin Research Funds, Advancing Healthier Wisconsin Endowment of the Medical College of Wisconsin and The Ann's Hope Foundation for Melanoma (to STH), an MCW/Froedtert Cancer Center Collaborative Research Fellowship (to TT) and the Intramural Research Program of the National Cancer Institute (STH and LF). NR 24 TC 5 Z9 5 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2157-9024 J9 ONCOGENESIS JI Oncogenesis PD MAY PY 2012 VL 1 AR UNSP e9 DI 10.1038/oncsis.2012.9 PG 9 WC Oncology SC Oncology GA V36NR UT WOS:000209219000001 PM 23552640 ER PT J AU Malachowa, N Kobayashi, SD DeLeo, FR AF Malachowa, Natalia Kobayashi, Scott D. DeLeo, Frank R. TI Community-Associated Methicillin-Resistant Staphylococcus aureus and Athletes SO PHYSICIAN AND SPORTSMEDICINE LA English DT Article DE antibiotics; CA-MRSA; hygiene; infection; innate immunity; MRSA; resistance; Staphylococcus aureus ID SOFT-TISSUE INFECTIONS; PANTON-VALENTINE LEUKOCIDIN; CASSETTE CHROMOSOME MEC; INDUCIBLE CLINDAMYCIN RESISTANCE; MUPIROCIN RESISTANCE; VIRULENCE DETERMINANTS; ALPHA-TOXIN; CUTANEOUS INFECTIONS; NASAL COLONIZATION; DISK DIFFUSION AB The remarkable ability of Staphylococcus aureus to develop antibiotic resistance in conjunction with the emergence of highly virulent and/or transmissible strains has established the pathogen as a leading cause of human bacterial infections worldwide. Historically, methicillin-resistant S aureus (MRSA) was found almost exclusively in hospitals and/or health care-related facilities. However, in the late 1990s, community-associated MRSA strains emerged in the United States and rapidly became the leading cause of community-associated bacterial infections. An enhanced understanding of the pathogenesis and epidemiology of this bacterium is fundamental for the prevention and/or treatment of community-associated MRSA infections. This review highlights salient features of S aureus biology that contribute to the exceptional ability of this pathogen to cause human disease, as well as discusses, in brief, the established approaches for treatment and prevention of infection. C1 [Malachowa, Natalia; Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Austin Athman (Visual and Medical Arts, NIAID) for photography assistance. NR 103 TC 4 Z9 4 U1 1 U2 16 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0091-3847 J9 PHYSICIAN SPORTSMED JI Physician Sportsmed. PD MAY PY 2012 VL 40 IS 2 BP 13 EP 21 DI 10.3810/psm.2012.05.1960 PG 9 WC Primary Health Care; Orthopedics; Sport Sciences SC General & Internal Medicine; Orthopedics; Sport Sciences GA 107DU UT WOS:000316195800001 PM 22759601 ER PT J AU Murcia, PR Hughes, J Battista, P Lloyd, L Baillie, GJ Ramirez-Gonzalez, RH Ormond, D Oliver, K Elton, D Mumford, JA Caccamo, M Kellam, P Grenfell, BT Holmes, EC Wood, JLN AF Murcia, Pablo R. Hughes, Joseph Battista, Patrizia Lloyd, Lucy Baillie, Gregory J. Ramirez-Gonzalez, Ricardo H. Ormond, Doug Oliver, Karen Elton, Debra Mumford, Jennifer A. Caccamo, Mario Kellam, Paul Grenfell, Bryan T. Holmes, Edward C. Wood, James L. N. TI Evolution of an Eurasian Avian-like Influenza Virus in Naive and Vaccinated Pigs SO PLOS PATHOGENS LA English DT Article ID A VIRUS; HOST-RANGE; HEMAGGLUTININ; SWINE; TRANSMISSION; ORIGIN; DYNAMICS; SPECIFICITY; PHYLOGENIES; PROGRAM AB Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in naive and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies. C1 [Murcia, Pablo R.; Battista, Patrizia; Mumford, Jennifer A.; Wood, James L. N.] Univ Cambridge, Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge, England. [Murcia, Pablo R.; Hughes, Joseph] Univ Glasgow, MRC, Coll Med Vet & Life Sci, Ctr Virus Res,Inst Infect Inflammat & Immun, Glasgow, Lanark, Scotland. [Lloyd, Lucy; Elton, Debra] Ctr Prevent Med, Anim Hlth Trust, Newmarket, Suffolk, England. [Baillie, Gregory J.; Ormond, Doug; Oliver, Karen; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge, England. [Ramirez-Gonzalez, Ricardo H.; Caccamo, Mario] Genome Anal Ctr, Norwich, Norfolk, England. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.; Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Murcia, PR (reprint author), Univ Cambridge, Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge, England. EM jlnw2@cam.ac.uk RI Wood, James/A-1626-2008; Baillie, Gregory/F-9478-2013; Hughes, Joseph/B-7711-2009; OI Wood, James/0000-0002-0258-3188; Holmes, Edward/0000-0001-9596-3552; Baillie, Gregory/0000-0002-6130-250X; Hughes, Joseph/0000-0003-2556-2563; Ramirez Gonzalez, Ricardo Humberto/0000-0001-5745-7085 FU Wellcome Trust; Veterinary Training and Research Initiative; Defra [VT0105]; Alborada Trust; RAPIDD of the Science & Technology Directorate, Department of Homeland Security; National Institutes of Health [R01 GM080533-05]; Fogarty International Center, National Institutes of Health FX PRM was supported by the Wellcome Trust. LL and PB were funded by a Veterinary Training and Research Initiative grant provided through Defra (VT0105). The sequencing was funded by a programme grant from the Wellcome Trust. JLNW is supported by the Alborada Trust. BTG and JLNW were supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. ECH was supported by grant R01 GM080533-05 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 32 TC 29 Z9 29 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2012 VL 8 IS 5 AR e1002730 DI 10.1371/journal.ppat.1002730 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 959OS UT WOS:000305322900058 PM 22693449 ER PT J AU Ferrer, RA Shmueli, D Bergman, HE Harris, PR Klein, WMP AF Ferrer, Rebecca A. Shmueli, Dikla Bergman, Hannah E. Harris, Peter R. Klein, William M. P. TI Effects of Self-Affirmation on Implementation Intentions and the Moderating Role of Affect SO SOCIAL PSYCHOLOGICAL AND PERSONALITY SCIENCE LA English DT Article DE self-affirmation; implementation intentions; positive affect; alcohol; health behavior change AB Self-affirmation may offset defensiveness to threatening messages, increase intentions to engage in protective behaviors, and facilitate actual change. Relatively little is known about the conditions under which self-affirmation is most beneficial. The authors examined whether self-affirmation facilitates the forming of implementation intentions-plans to engage in specific steps that facilitate behavior change-and whether effects differ by affective state. Undergraduate female drinkers (N = 265) were self-affirmed or not prior to reading an article linking excessive alcohol consumption to breast cancer susceptibility. They then had the opportunity to report implementation intentions, by listing specific steps they planned to take to reduce consumption. Consistent with predictions, self-affirmation promoted formation of implementation intentions, an effect found only among individuals manifesting positive (as opposed to negative) affect following receipt of the message. Self-affirmation may facilitate behavior change by encouraging development of implementation intentions, an effect that is likely enhanced among those experiencing positive affect. C1 [Ferrer, Rebecca A.; Shmueli, Dikla; Bergman, Hannah E.; Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Harris, Peter R.] Univ Sheffield, Dept Psychol, Sheffield S10 2TN, S Yorkshire, England. RP Ferrer, RA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4083, Rockville, MD 20852 USA. EM ferrerra@mail.nih.gov NR 63 TC 12 Z9 13 U1 4 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1948-5506 EI 1948-5514 J9 SOC PSYCHOL PERS SCI JI Soc. Psychol. Personal Sci. PD MAY PY 2012 VL 3 IS 3 BP 300 EP 307 DI 10.1177/1948550611419265 PG 8 WC Psychology, Social SC Psychology GA V32FF UT WOS:000208936400007 ER PT J AU Simons-Morton, B Kuntsche, E AF Simons-Morton, Bruce Kuntsche, Emmanuel TI ADOLESCENT ESTIMATION OF PEER SUBSTANCE USE: WHY IT MATTERS SO ADDICTION LA English DT Editorial Material DE Drinking; overestimation; peers ID BEHAVIOR; NORMS C1 [Simons-Morton, Bruce] NICHHD, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. [Kuntsche, Emmanuel] Res Inst, Lausanne, Switzerland. [Kuntsche, Emmanuel] Radboud Univ Nijmegen, Inst Behav Sci, NL-6525 ED Nijmegen, Netherlands. RP Simons-Morton, B (reprint author), NICHHD, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. EM mortonb@exchange.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD002110-18] NR 10 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD MAY PY 2012 VL 107 IS 5 BP 885 EP 886 DI 10.1111/j.1360-0443.2011.03744.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 919QW UT WOS:000302344500009 PM 22471569 ER PT J AU Evans-Lacko, SE Baum, N Danis, M Biddle, A Goold, S AF Evans-Lacko, Sara E. Baum, Nancy Danis, Marion Biddle, Andrea Goold, Susan TI Laypersons' Choices and Deliberations for Mental Health Coverage SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Mental health; Insurance; Health policy; Consumer preference ID COMORBIDITY SURVEY REPLICATION; SOCIAL DISTANCE; ILLNESS; CARE; SERVICES; PARITY; STIGMA; PREFERENCES; RESOURCES; ATTITUDES AB Insurance coverage for mental health services has historically lagged behind other types of health services. We used a simulation exercise in which groups of laypersons deliberate about healthcare tradeoffs. Groups deciding for their "community" were more likely to select mental health coverage than individuals. Individual prioritization of mental health coverage, however, increased after group discussion. Participants discussed: value, cost and perceived need for mental health coverage, moral hazard and community benefit. A deliberative exercise in priority-setting led a significant proportion of persons to reconsider decisions about coverage for mental health services. Deliberations illustrated public-spiritedness, stigma and significant polarity of views. C1 [Evans-Lacko, Sara E.] Kings Coll London, Inst Psychiat, Hlth Serv & Populat Res Dept, London SE5 8AF, England. [Baum, Nancy; Goold, Susan] Univ Michigan, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Danis, Marion] NIH, Sect Eth & Hlth Policy, Dept Clin Bioeth, Bethesda, MD 20892 USA. [Danis, Marion] NIH, Bioeth Consultat Serv, Ctr Clin, Bethesda, MD 20892 USA. [Biddle, Andrea] Univ N Carolina, Chapel Hill, NC USA. [Goold, Susan] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Goold, Susan] Univ Michigan, Bioeth Program, Ann Arbor, MI 48109 USA. RP Evans-Lacko, SE (reprint author), Kings Coll London, Inst Psychiat, Hlth Serv & Populat Res Dept, De Crespigny Pk, London SE5 8AF, England. EM Sara.Evans-Lacko@iop.kcl.ac.uk RI Evans-Lacko, Sara/A-8768-2011; Evans-Lacko, Sara/F-8489-2014; OI Evans-Lacko, Sara/0000-0003-4691-2630; Evans-Lacko, Sara/0000-0003-4691-2630; Biddle, Andrea/0000-0003-0273-7439; Goold, Susan Dorr/0000-0002-0258-9774 FU Intramural NIH HHS [ZIA CL010529-04] NR 49 TC 6 Z9 6 U1 0 U2 7 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD MAY PY 2012 VL 39 IS 3 BP 158 EP 169 DI 10.1007/s10488-011-0341-4 PG 12 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 919KC UT WOS:000302323200002 PM 21452017 ER PT J AU Wei, Z Range, R Angerer, R Angerer, L AF Wei, Zheng Range, Ryan Angerer, Robert Angerer, Lynne TI Axial patterning interactions in the sea urchin embryo: suppression of nodal by Wnt1 signaling SO DEVELOPMENT LA English DT Article DE Strongylocentrotus purpuratus; Wnt1; Embryonic axes; Nodal; Sea urchin ID GENE REGULATORY NETWORK; NUCLEAR BETA-CATENIN; ORAL-ABORAL AXIS; STRONGYLOCENTROTUS-PURPURATUS; ANIMAL-VEGETAL; ENDODERM; SPECIFICATION; GASTRULATION; EXPRESSION; ECTODERM AB Wnt and Nodal signaling pathways are required for initial patterning of cell fates along anterior-posterior (AP) and dorsal-ventral (DV) axes, respectively, of sea urchin embryos during cleavage and early blastula stages. These mechanisms are connected because expression of nodal depends on early Wnt/beta-catenin signaling. Here, we show that an important subsequent function of Wnt signaling is to control the shape of the nodal expression domain and maintain correct specification of different cell types along the axes of the embryo. In the absence of Wnt1, the posterior-ventral region of the embryo is severely altered during early gastrulation. Strikingly, at this time, nodal and its downstream target genes gsc and bra are expressed ectopically, extending posteriorly to the blastopore. They override the initial specification of posterior-ventral ectoderm and endoderm fates, eliminating the ventral contribution to the gut and displacing the ciliary band dorsally towards, and occasionally beyond, the blastopore. Consequently, in Wnt1 morphants, the blastopore is located at the border of the re-specified posterior-ventral oral ectoderm and by larval stages it is in the same plane near the stomodeum on the ventral side. In normal embryos, a Nodal-dependent process downregulates wnt1 expression in dorsal posterior cells during early gastrulation, focusing Wnt1 signaling to the posterior-ventral region where it suppresses nodal expression. These subsequent interactions between Wnt and Nodal signaling are thus mutually antagonistic, each limiting the range of the other's activity, in order to maintain and stabilize the body plan initially established by those same signaling pathways in the early embryo. C1 [Wei, Zheng; Range, Ryan; Angerer, Robert; Angerer, Lynne] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20891 USA. RP Angerer, L (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20891 USA. EM langerer@mail.nih.gov FU Division of Intramural Research in the National Institute for Dental and Craniofacial Research of the National Institutes of Health [ZO1 DE000712] FX This work was supported by the Division of Intramural Research in the National Institute for Dental and Craniofacial Research of the National Institutes of Health [ZO1 DE000712]. Deposited in PMC for release after 12 months. NR 51 TC 9 Z9 9 U1 0 U2 17 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY 1 PY 2012 VL 139 IS 9 BP 1662 EP 1669 DI 10.1242/dev.075051 PG 8 WC Developmental Biology SC Developmental Biology GA 919XV UT WOS:000302366400013 PM 22438568 ER PT J AU Linehan, WM AF Linehan, W. Marston TI The Genetic Basis of Kidney Cancer: Implications for Management and Use of Targeted Therapeutic Approaches SO EUROPEAN UROLOGY LA English DT Editorial Material ID DISEASE; IDENTIFICATION; CARCINOMA C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Bldg 10,CRC Rm 1-5940, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural NIH HHS [ZIA BC011043-05, ZIA BC011028-05, ZIA BC011038-05]; NCI NIH HHS [Z01 BC011089-01, Z01 BC011043-01, Z01 BC011028-01, Z01 BC011038-01] NR 11 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAY PY 2012 VL 61 IS 5 BP 896 EP 898 DI 10.1016/j.eururo.2012.02.022 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 918RJ UT WOS:000302267900017 PM 22386837 ER PT J AU Ribeiro, JMC Labruna, MB Mans, BJ Maruyama, SR Francischetti, IMB Barizon, GC Santos, IKFD AF Ribeiro, Jose Marcos C. Labruna, Marcelo B. Mans, Ben J. Maruyama, Sandra Regina Francischetti, Ivo M. B. Barizon, Gustavo Canavaci de Miranda Santos, Isabel K. F. TI The sialotranscriptome of Antricola delacruzi female ticks is compatible with non-hematophagous behavior and an alternative source of food SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Antricola delacruzi; Hematophagy; Scavenging; Transcriptome; Salivary glands; Bat guano ID SERUM-AMYLOID-A; BAT-GUANO; IXODES-SCAPULARIS; SALIVARY-GLAND; SOFT TICK; BOOPHILUS-MICROPLUS; INSECTIVOROUS BATS; SEQUENCE ALIGNMENT; ANOPHELES-GAMBIAE; FEEDING-BEHAVIOR AB The hosts for Antricola delacruzi ticks are insectivorous, cave-dwelling bats on which only larvae are found. The mouthparts of nymphal and adult A. delacruzi are compatible with scavenging feeding because the hypostome is small and toothless. How a single blood meal of a larva provides energy for several molts as well as for oviposition by females is not known. Adults of A. delacruzi possibly feed upon an unknown food source in bat guano, a substrate on which nymphal and adult stages are always found. Guano produced by insectivorous bats contains twice the amount of protein and 60 times the amount of iron as beef. In addition, bacteria and chitin-rich fungi proliferate on guano. Comparative data on the transcriptome of the salivary glands of A. delacruzi is nonexistent and would help to understand the physiological adaptations of salivary glands that accompany different sources of food as well as the steps taken by the Acari toward haematophagy, believed to have evolved from scavenging dead animals. Annotation of the transcriptome of salivary glands from female instars of A. delacruzi collected on guano categorized 5.7% of the clusters of expressed genes as putative secreted proteins. They included abundantly expressed TIL-domain-containing proteins (possible anti-microbials), an abundantly expressed protein similar to a serum amyloid found in the sialotranscriptomes of Ornithodoros spp., a savignygrin, a family of mucin/peritrophin/cuticle-like proteins, anti-microbials and an HIV envelope-like glycoprotein also found in soft ticks. When comparing the transcriptome of A. delacruzi with those of blood-feeding female soft and hard ticks some notable differences were observed; they consisted of the following transcripts over- or under-represented or absent in the sialotranscriptome of A. delacruzi that may reflect its source of food: ferritin, mucins with chitin-binding domains and TIL-domain-containing proteins versus lipocalins, basic tail proteins, metalloproteases, glycine-rich proteins and Kunitz protease inhibitors, respectively. (C) 2012 Elsevier Ltd. All rights reserved. C1 [de Miranda Santos, Isabel K. F.] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto Sch Med, BR-14049900 Ribeirao Preto, SP, Brazil. [Ribeiro, Jose Marcos C.; Francischetti, Ivo M. B.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Labruna, Marcelo B.] Univ Sao Paulo, Sch Vet Med, Dept Prevent Vet Med & Anim Hlth, Sao Paulo, Brazil. [Mans, Ben J.] Onderstepoort Vet Inst, Agr Res Council, Onderstepoort, South Africa. [Mans, Ben J.] Univ Pretoria, Dept Vet Trop Dis, ZA-0002 Pretoria, South Africa. RP Santos, IKFD (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto Sch Med, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM imsantos@fmrp.usp.br RI Maruyama, Sandra/G-1171-2012; Labruna, Marcelo/B-6241-2013; de Miranda Santos, Isabel/B-7597-2012; Ghartouchent, malek/B-9088-2012; Ribeiro, Jose/J-7011-2015; de Miranda Santos, Isabel/D-5261-2016; OI Labruna, Marcelo/0000-0002-9675-3132; de Miranda Santos, Isabel/0000-0002-0438-4430; Mans, Ben/0000-0002-0177-0029; Maruyama, Sandra/0000-0001-6807-1452; Ribeiro, Jose/0000-0002-9107-0818 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP [2009/53645-3, 2007/59357-4]; Brazilian National Science Foundation-CNPq [559603/2009-6, 302832/2007-6]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP through a grant. No 2009/53645-3 to IKFMS, and a scholarship to SRM (No 2007/59357-4): by the Brazilian National Science Foundation-CNPq through grants No 559603/2009-6 and No 47194612010-9 to IKFMS, and No 302832/2007-6 to MBL, and the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 83 TC 21 Z9 23 U1 2 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD MAY PY 2012 VL 42 IS 5 BP 332 EP 342 DI 10.1016/j.ibmb.2012.01.003 PG 11 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 921ZE UT WOS:000302515800003 PM 22306723 ER PT J AU Hwang, SK Minai-Tehrani, A Yu, KN Chang, SH Kim, JE Lee, KH Park, J Beck, GR Cho, MH AF Hwang, Soon-Kyung Minai-Tehrani, Arash Yu, Kyeong-Nam Chang, Seung-Hee Kim, Ji-Eun Lee, Kee-Ho Park, Jongsun Beck, George R., Jr. Cho, Myung-Haing TI Carboxyl-terminal modulator protein induces apoptosis by regulating mitochondrial function in lung cancer cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE CTMP; apoptosis; mitochondria; lung cancer cells ID CYTOCHROME-C; OPA1; DYNAMICS; AKT; PROLIFERATION; MORPHOLOGY; MEMBRANE; PKB/AKT; RELEASE; PATHWAY AB Serine/threonine protein kinase 13 (PKB/Akt) is involved in cell survival and growth. Carboxyl-terminal modulator protein (CTMP), a novel Akt binding partner, prevents Akt activation at the plasma membrane in response to various stimuli, and thus possesses a tumor suppressor-like function. In a previous study, we have demonstrated that CTMP inhibits tumor progression by facilitating apoptosis in a mouse lung cancer model. However, the precise mechanism of CTMP-induced apoptosis remains to be elucidated. The present study was performed to examine the role of CTMP in mitochondrial-mediated apoptosis and regulation of mitochondrial function in human lung carcinoma cells. Our results showed that CTMP altered mitochondrial morphology and caused the release of cytochrome c by inhibiting OPA1 expression. Additionally, CTMP facilitated mitochondrial-mediated apoptosis by inhibiting heat-shock protein 27 and preventing cytochrome c interaction with Apaf-1. Our data suggest that CTMP may therefore play a critical role in mitochondrial-mediated apoptosis in lung cancer cells. C1 [Hwang, Soon-Kyung; Minai-Tehrani, Arash; Yu, Kyeong-Nam; Chang, Seung-Hee; Kim, Ji-Eun; Cho, Myung-Haing] Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea. [Hwang, Soon-Kyung] NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Kim, Ji-Eun; Cho, Myung-Haing] Seoul Natl Univ, Dept Nano Fus Technol, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Grad Grp Tumor Biol, Seoul 151742, South Korea. [Lee, Kee-Ho] Korea Inst Radiol & Med Sci, Div Radiat Canc Res, Mol Oncol Lab, Seoul 139240, South Korea. [Park, Jongsun] Chungnam Natl Univ, Dept Pharmacol, Res Inst Med Sci, Coll Med,Canc Res Inst,Daejeon Reg Canc Ctr, Taejon 301131, South Korea. [Beck, George R., Jr.] Emory Univ, Sch Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. RP Cho, MH (reprint author), Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea. EM mchotox@snu.ac.kr RI CHO, Myung-Haing/B-7362-2014; Park, Jongsun/E-7465-2010 OI Park, Jongsun/0000-0002-4690-1854 FU National Research Foundation of the Ministry of Education, Science and Technology in South Korea [NRF-2010-0000784, 2011-0019175, NRF-2011-0000380]; Research Institute for Veterinary Science of Seoul National University FX This work was supported partially by a research grant (NRF-2010-0000784, 2011-0019175 and NRF-2011-0000380) from the National Research Foundation of the Ministry of Education, Science and Technology in South Korea. This study was also partially supported by the Research Institute for Veterinary Science of Seoul National University. NR 27 TC 4 Z9 4 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 MAY PY 2012 VL 40 IS 5 BP 1515 EP 1524 DI 10.3892/ijo.2011.1319 PG 10 WC Oncology SC Oncology GA 918TG UT WOS:000302273400022 PM 22200884 ER PT J AU Newhauser, WD Scheurer, ME Faupel-Badger, JM Clague, J Weitzel, J Woods, KV AF Newhauser, Wayne D. Scheurer, Michael E. Faupel-Badger, Jessica M. Clague, Jessica Weitzel, Jeffrey Woods, Kendra V. TI The Future Workforce in Cancer Prevention: Advancing Discovery, Research, and Technology SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer prevention; Training; Workforce; Technology; Research ID CLINICAL-ONCOLOGY; AMERICAN-SOCIETY; PROTON-BEAMS; HEALTH-CARE; RISK; PROGRAM; RADIOTHERAPY; IRRADIATION; STUDENTS; COST AB As part of a 2-day conference on October 15 and 16, 2009, a nine-member task force composed of scientists, clinicians, educators, administrators, and students from across the USA was formed to discuss research, discovery, and technology obstacles to progress in cancer prevention and control, specifically those related to the cancer prevention workforce. This article summarizes the task force's findings on the current state of the cancer prevention workforce in this area and its needs for the future. The task force identified two types of barriers impeding the current cancer prevention workforce in research, discovery, and technology from reaching its fullest potential: (1) limited cross-disciplinary research opportunities with underutilization of some disciplines is hampering discovery and research in cancer prevention, and (2) new research avenues are not being investigated because technology development and implementation are lagging. Examples of impediments and desired outcomes are provided in each of these areas. Recommended solutions to these problems are based on the goals of enhancing the current cancer prevention workforce and accelerating the pace of discovery and clinical translation. C1 [Newhauser, Wayne D.] Louisiana State Univ, Dept Phys & Astron, Med Phys Program, Baton Rouge, LA 70803 USA. [Newhauser, Wayne D.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Scheurer, Michael E.] Baylor Coll Med, Dept Pediat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Faupel-Badger, Jessica M.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH, Bethesda, MD 20892 USA. [Clague, Jessica; Weitzel, Jeffrey] City Hope Natl Med Ctr, Div Clin Canc Genet, Dept Populat Sci, Duarte, CA 91010 USA. [Woods, Kendra V.] Univ Texas MD Anderson Canc Ctr, Off Acad Affairs, Houston, TX 77030 USA. RP Newhauser, WD (reprint author), Louisiana State Univ, Dept Phys & Astron, Med Phys Program, 202 Nicholson Hall, Baton Rouge, LA 70803 USA. EM newhauser@lsu.edu OI Scheurer, Michael/0000-0002-8379-6088 FU National Cancer Institute [1 R01 CA131463-01A1, R25T CA57730, R25T CA085771]; National Institute of Health [K07CA131505] FX We thank Drs. E. Grubbs, M. Hildebrandt, S. Chang, and S. Tomasovic for the helpful discussions and Ms. K. Carnes and Ms. S. Wilson for the assistance in preparing this manuscript. This work was funded in part by a grant from the National Cancer Institute (awards 1 R01 CA131463-01A1, R25T CA57730 and R25T CA085771) and by the National Institute of Health (award K07CA131505). NR 49 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD MAY PY 2012 VL 27 SU 2 BP 128 EP 135 DI 10.1007/s13187-012-0328-1 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 919QZ UT WOS:000302344800003 ER PT J AU Harrop, JP Nelson, DE Kuratani, DG Mullen, PD Paskett, ED AF Harrop, J. Phil Nelson, David E. Kuratani, Darrah Goo Mullen, Patricia Dolan Paskett, Electra D. TI Translating Cancer Prevention and Control Research into the Community Setting: Workforce Implications SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer prevention; Cancer control; Community-based participatory research; Dissemination; Cancer workforce ID HEALTH-PROMOTION RESEARCH; OF-THE-LITERATURE; PARTICIPATORY RESEARCH; UNITED-STATES; IMPLEMENTATION RESEARCH; DISSEMINATION; RECOMMENDATIONS; INTERVENTIONS; DISPARITIES; SHORTAGE AB A gap exists between cancer prevention research and its translation into community practice. Two strategies to reduce this gap are community-based participatory research (CBPR) and dissemination research. CBPR offers an avenue to engage academic and community partners, thereby providing mechanisms for joint learning and application of knowledge. Dissemination research examines the movement of evidence-based public health and clinical innovations to practice settings. While applying these approaches may reduce the gap between research and practice, the cancer prevention workforce may be inadequate in size, insufficiently trained, lack resources and incentives, or face structural barriers to effectively participate in CBPR and disseminate evidence-based research findings into practice. Information on translating cancer prevention information to communities and workforce implications was obtained from a panel of experts and through a review of the literature on CBPR and dissemination research. The expert panel and literature review identified major barriers to successfully conducting CBPR and dissemination research in community settings. Barriers included inadequate policies; insufficient networking and communication infrastructures; unsupportive research cultures, climates, and mindsets; inadequate researcher and practitioner education; and limited CBPR and dissemination research with adequate study designs. No specific estimates of the cancer prevention workforce were found; however, indirect evidence for a shortfall were identified. We recommend expanding CBPR training for academic and community partners; increasing funding for dissemination research and practice; supporting proven partnerships; and providing strategic coordination for government agencies, research institutions, nongovernmental organizations, and the private sector to foster better dissemination of information and integration of community-based cancer prevention and control programs and practices. Specific challenges and needs that must be addressed to improve the translation of cancer prevention research into community settings were identified. C1 [Paskett, Electra D.] Ohio State Univ, Ctr Comprehens Canc, Coll Publ Hlth, Coll Med, Columbus, OH 43201 USA. [Harrop, J. Phil] Ohio State Univ, Ctr Comprehens Canc, Div Hlth Serv Management & Policy, Coll Publ Hlth, Columbus, OH 43201 USA. [Nelson, David E.] NCI, Rockville, MD 20852 USA. [Kuratani, Darrah Goo] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Mullen, Patricia Dolan] Univ Texas Sch Publ Hlth, Div Hlth Promot & Behav Sci, Houston, TX 77030 USA. RP Paskett, ED (reprint author), Ohio State Univ, Ctr Comprehens Canc, Coll Publ Hlth, Coll Med, 1590 N High St,Suite 525, Columbus, OH 43201 USA. EM Electra.Paskett@osumc.edu NR 42 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD MAY PY 2012 VL 27 SU 2 BP 157 EP 164 DI 10.1007/s13187-012-0329-0 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 919QZ UT WOS:000302344800007 ER PT J AU Leckman, JF Pine, DS AF Leckman, James F. Pine, Daniel S. TI Editorial Commentary: Challenges and potential of DSM-5 and ICD-11 revisions SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Editorial Material ID DISORDERS; CHILDREN; PSYCHOPATHOLOGY; ADOLESCENTS; PREVALENCE C1 [Leckman, James F.] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Leckman, James F.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Leckman, James F.] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Leckman, James F.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Leckman, JF (reprint author), Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. NR 27 TC 3 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD MAY PY 2012 VL 53 IS 5 BP 449 EP 453 DI 10.1111/j.1469-7610.2012.02548.x PG 5 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 921FF UT WOS:000302462800001 PM 22486485 ER PT J AU Addington, AM Rapoport, JL AF Addington, Anjene M. Rapoport, Judith L. TI Annual Research Review: Impact of advances in genetics in understanding developmental psychopathology SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Review DE Developmental psychopathology; genetics; copy number variants; pre-natal diagnosis; nosology; prevention ID AUTISM SPECTRUM DISORDERS; GENOME-WIDE ASSOCIATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CHILDHOOD-ONSET SCHIZOPHRENIA; SCAFFOLDING PROTEIN SHANK3; FRAGILE-X-SYNDROME; PSYCHIATRIC-DISORDERS; MENTAL-RETARDATION; COMMON VARIANTS; MUTATIONS AB It was hoped that diagnostic guidelines for, and treatment of, child psychiatric disorders in DSM-5 would be informed by the wealth of clinical genetic research related to neurodevelopmental disorders. In spite of remarkable advances in genetic technology, this has not been the case. Candidate gene, genome-wide association, and rare copy number variant (CNV) studies have been carried out for attention-deficit/hyperactivity disorder (ADHD), Autism, Tourettes Syndrome, and schizophrenia, with intriguing results, but environmental factors, incomplete penetrance, pleiotropy, and genetic heterogeneity, underlying any given phenotype have limited clinical translation. One promising approach may be the use of developmental brain imaging measures as more relevant phenotypes. This is particularly important, as subtle abnormalities in timing and expression of gene pathways underlying brain development may well link these disorders and be the ultimate target of treatments. C1 [Addington, Anjene M.; Rapoport, Judith L.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), 10 Ctr Dr,Room 3N202, Bethesda, MD 20892 USA. EM rapoporj@mail.nih.gov FU NIH FX This manuscript is based on material funded by the NIH. NR 96 TC 19 Z9 19 U1 2 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD MAY PY 2012 VL 53 IS 5 BP 510 EP 518 DI 10.1111/j.1469-7610.2011.02478.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 921FF UT WOS:000302462800005 PM 22067053 ER PT J AU Ferrari, PF Vanderwert, RE Paukner, A Bower, S Suomi, SJ Fox, NA AF Ferrari, Pier Francesco Vanderwert, Ross E. Paukner, Annika Bower, Seth Suomi, Stephen J. Fox, Nathan A. TI Distinct EEG Amplitude Suppression to Facial Gestures as Evidence for a Mirror Mechanism in Newborn Monkeys SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID INFERIOR PARIETAL; PREMOTOR CORTEX; MOTOR CORTEX; MU-RHYTHMS; IMITATION; EXECUTION; NEURONS; SYSTEM; OSCILLATIONS; PERCEPTION AB At birth, human infants and newborns of other primate species demonstrate the capacity to attend and to respond to facial stimuli provided by a caregiver. Newborn infants are also capable of exhibiting a range of facial expressions. Identification of the neural underpinnings of these capacities represents a formidable challenge in understanding social development. One possible neuronal substrate is the mirror-neuron system assumed to activate shared motor cortical representations for both observation and production of actions. We tested this hypothesis by recording scalp EEG from 1- to 7-day-old newborn rhesus macaques who were observing and producing facial gestures. We found that 5-6 Hz EEG activity was suppressed both when the infants produced facial gestures and while they were observing facial gestures of a human experimenter, but not when they were observing nonbiological stimuli. These findings demonstrate the presence of neural reactivity for biological, communicatively relevant stimuli, which may be a likely signature of neuronal mirroring. The basic elements of the mirror-neuron system appear to operate from the very first days of life and contribute to the encoding of socially relevant stimuli. C1 [Ferrari, Pier Francesco] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Vanderwert, Ross E.; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Paukner, Annika; Bower, Seth; Suomi, Stephen J.] NIH, Poolesville, MD USA. RP Ferrari, PF (reprint author), Univ Parma, Dipartimento Neurosci, Via Volturno 39, I-43100 Parma, Italy. EM pierfrancesco.ferrari@unipr.it OI Vanderwert, Ross/0000-0002-2280-8401 FU NIH [P01HD064653-01]; Division of Intramural Research, NICHD FX We thank Giacomo Rizzolatti, Leonardo Fogassi, and Riitta Hari for useful comments on an earlier version of the manuscript. This research was supported by P01HD064653-01 NIH grant to F. P. F. and N. A. F. and the Division of Intramural Research, NICHD. NR 37 TC 34 Z9 36 U1 1 U2 15 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD MAY PY 2012 VL 24 IS 5 BP 1165 EP 1172 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 918NI UT WOS:000302256300011 PM 22288390 ER PT J AU Baird, K Booher, S Comis, L Joe, G Steinberg, SM Figg, WD Spencer, SD Takebe, N Pavletic, S Cowen, EW AF Baird, K. Booher, S. Comis, L. Joe, G. Steinberg, S. M. Figg, W. D. Spencer, S. D. Takebe, N. Pavletic, S. Cowen, E. W. TI Imatinib mesylate for the treatment of sclerotic skin chronic graft-versus-host disease SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Baird, K.; Booher, S.; Comis, L.; Joe, G.; Steinberg, S. M.; Figg, W. D.; Spencer, S. D.; Takebe, N.; Pavletic, S.; Cowen, E. W.] NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 518 BP S88 EP S88 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900520 ER PT J AU Colmont, CS Ben Ketah, A Errington, R Yee, CL Udey, M Vogel, JC Patel, GK AF Colmont, C. S. Ben Ketah, A. Errington, R. Yee, C. L. Udey, M. Vogel, J. C. Patel, G. K. TI Human basal cell carcinoma tumor initiating cells express MDR1 and are resistant to etoposide killing SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Errington, R.] Cardiff Univ, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Yee, C. L.; Udey, M.; Vogel, J. C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 124 BP S21 EP S21 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900123 ER PT J AU Cui, C Childress, V Piao, Y Michel, M Johnson, AA Kunisada, M Ko, MS Kaestner, KH Marmorstein, AD Schlessinger, D AF Cui, C. Childress, V. Piao, Y. Michel, M. Johnson, A. A. Kunisada, M. Ko, M. S. Kaestner, K. H. Marmorstein, A. D. Schlessinger, D. TI Forkhead transcription factor FoxA1 regulates sweat secretion through Best2 and Nkcc1 ion transporters SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Cui, C.; Childress, V.; Piao, Y.; Michel, M.; Ko, M. S.; Schlessinger, D.] NIA, Genet Lab, Baltimore, MD 21224 USA. [Johnson, A. A.; Marmorstein, A. D.] Univ Arizona, Dept Ophthalmol & Vis Sci, Tucson, AZ USA. [Kunisada, M.] Kobe Univ, Div Dermatol, Kobe, Hyogo 657, Japan. [Kaestner, K. H.] Univ Penn, Dept Genet, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 472 BP S80 EP S80 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900474 ER PT J AU Daily, K Patel, VR Rigor, P Xie, X Baldi, P AF Daily, K. Patel, V. R. Rigor, P. Xie, X. Baldi, P. TI MotifMap: Integrative genome-wide maps of regulatory motif sites for model species SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Daily, K.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Daily, K.; Patel, V. R.; Rigor, P.; Xie, X.; Baldi, P.] UC Irvine, Dept Comp Sci, Irvine, CA USA. [Daily, K.; Patel, V. R.; Rigor, P.; Xie, X.; Baldi, P.] UC Irvine, Inst Genom & Bioinformat, Irvine, CA USA. [Baldi, P.] UC Irvine, Dept Dev & Cell Biol, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 417 BP S71 EP S71 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900420 ER PT J AU Duverger, O Zah, A Isaac, J Sun, H Lian, JB Berdal, A Hwang, J Morasso, MI AF Duverger, O. Zah, A. Isaac, J. Sun, H. Lian, J. B. Berdal, A. Hwang, J. Morasso, M. I. TI Dissection of Dlx3 function in ectodermal appendage development: Impacts of mesenchymal and epithelial-specific deletions on tooth development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Duverger, O.; Zah, A.; Isaac, J.; Hwang, J.; Morasso, M. I.] NIAMS, NIH, Dev Skin Biol Sect, Bethesda, MD USA. [Sun, H.] NIAMS, NIH, Biodata Min & Discovery Sect, Bethesda, MD USA. [Lian, J. B.] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. [Lian, J. B.] Univ Massachusetts, Sch Med, Dept Orthoped Surg, Worcester, MA 01655 USA. [Berdal, A.] INSERM, Lab Mol Oral Physiopathol, UMRS 872, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 398 BP S68 EP S68 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900399 ER PT J AU Gaiser, MR Lammermann, T Feng, X Igyarto, BZ Kaplan, DH Tessarollo, L Germain, RN Udey, MC AF Gaiser, M. R. Laemmermann, T. Feng, X. Igyarto, B. Z. Kaplan, D. H. Tessarollo, L. Germain, R. N. Udey, M. C. TI EpCAM (CD326) enables epidermal Langerhans cell motility and migration SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Gaiser, M. R.; Feng, X.; Udey, M. C.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Gaiser, M. R.] Univ Heidelberg, Dept Dermatol, D-6900 Heidelberg, Germany. [Laemmermann, T.; Germain, R. N.] NIAID, Lab Syst Biol, Bethesda, MD 20892 USA. [Igyarto, B. Z.; Kaplan, D. H.] Univ Minnesota, Dept Dermatol, Ctr Immunol, Minneapolis, MN 55455 USA. [Tessarollo, L.] NCI, Mouse Canc Genet Programm, Ctr Canc Res, Frederick, MD 21701 USA. RI Kaplan, Daniel/N-2779-2013 OI Kaplan, Daniel/0000-0002-7851-7320 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 578 BP S98 EP S98 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900577 ER PT J AU Inozume, T Furuta, J Hanada, K Shimada, S AF Inozume, T. Furuta, J. Hanada, K. Shimada, S. TI Enhanced NGFR signal in melanoma cells suppresses the tumor recognition by melanoma specific T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Inozume, T.; Furuta, J.; Shimada, S.] Univ Yamanashi, Tamaho, Yamanashi, Japan. [Hanada, K.] NCI, Surg Branch, Bethesda, MD 20892 USA. RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 571 BP S97 EP S97 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900573 ER PT J AU Khan, SG Tamura, D Rao, T Zein, WM Brooks, BP Boyle, J Ueda, T DiGiovanna, JJ Kraemer, KH AF Khan, S. G. Tamura, D. Rao, T. Zein, W. M. Brooks, B. P. Boyle, J. Ueda, T. DiGiovanna, J. J. Kraemer, K. H. TI Patients with the rare DNA repair disease overlap syndrome xeroderma pigmentosum and trichothiodystrophy (XP/TTD) are at high risk for skin and internal cancers SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Khan, S. G.; Tamura, D.; Rao, T.; Boyle, J.; Ueda, T.; DiGiovanna, J. J.; Kraemer, K. H.] NCI, Derm Branch, Bethesda, MD 20892 USA. [Zein, W. M.; Brooks, B. P.] NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 412 BP S70 EP S70 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900412 ER PT J AU Kim, J Hwang, J Morasso, MI AF Kim, J. Hwang, J. Morasso, M. I. TI Dlx3 is a critical regulator on hair follicle differentiation and development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Kim, J.; Morasso, M. I.] NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 449 BP S76 EP S76 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900448 ER PT J AU Kiss, A Koppel, AC Anders, J Cataisson, C Yuspa, SH Efimova, T AF Kiss, A. Koppel, A. C. Anders, J. Cataisson, C. Yuspa, S. H. Efimova, T. TI Keratinocyte-specific p38 delta mitogen-activated protein kinase (MAPK) deletion reveals a context and gender dependent regulation of skin carcinogenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Kiss, A.; Koppel, A. C.; Efimova, T.] Washington Univ, Sch Med, St Louis, MO USA. [Anders, J.; Cataisson, C.; Yuspa, S. H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 130 BP S22 EP S22 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900129 ER PT J AU Kong, HH Oh, J Conlan, S Deming, C Grice, EA Turner, ML Segre, JA AF Kong, H. H. Oh, J. Conlan, S. Deming, C. Grice, E. A. Turner, M. L. Segre, J. A. TI Temporal shifts in the skin microbiome associated with atopic dermatitis disease flares and treatment SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Kong, H. H.; Turner, M. L.] NIH, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Oh, J.; Conlan, S.; Deming, C.; Grice, E. A.; Segre, J. A.] NHGRI, GMBB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 665 BP S113 EP S113 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900668 ER PT J AU Kuschal, C DiGiovanna, JJ Khan, SG Kraemer, KH AF Kuschal, C. DiGiovanna, J. J. Khan, S. G. Kraemer, K. H. TI Restoration of XPC protein and induction of DNA repair in homozygous and heterozygous xeroderma pigmentosum group C cells by readthrough of stop codons using aminoglycoside compounds SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Kuschal, C.; DiGiovanna, J. J.; Khan, S. G.; Kraemer, K. H.] NCI, Derm Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 411 BP S70 EP S70 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900414 ER PT J AU Li, L Ansbro, M Shukla, S Ambudkar, S Blumberg, P Yuspa, SH AF Li, L. Ansbro, M. Shukla, S. Ambudkar, S. Blumberg, P. Yuspa, S. H. TI Identification of protein kinase C activating phorbol ester and ingenol derivatives as candidates for cutaneous P-glycoprotein absorptive transport across the epidermis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Li, L.; Ansbro, M.; Shukla, S.; Ambudkar, S.; Blumberg, P.; Yuspa, S. H.] NCI, LCBG, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 139 BP S24 EP S24 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900142 ER PT J AU Li, S Liu, Y Wang, J Moss, J Darling, TN AF Li, S. Liu, Y. Wang, J. Moss, J. Darling, T. N. TI Tuberous sclerosis skin tumor cells express high levels of cathepsins B, K, and L SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Li, S.; Liu, Y.; Wang, J.; Darling, T. N.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Moss, J.] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 196 BP S33 EP S33 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900195 ER PT J AU Mabuchi, T Singh, T Takekoshi, T Farber, J Hwang, S AF Mabuchi, T. Singh, T. Takekoshi, T. Farber, J. Hwang, S. TI CCR6 is required for epidermal trafficking of (and IL22 production by) gamma delta-low T cells in an IL23-induced model of psoriasiform dermatitis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Mabuchi, T.; Takekoshi, T.; Hwang, S.] Med Coll WI, Milwaukee, WI USA. [Singh, T.; Farber, J.] NIAID, Inflammat Biol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 583 BP S99 EP S99 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900585 ER PT J AU Masaki, T DiGiovanna, JJ Wang, Y Khan, SG Hornyak, T Lee, C Kraemer, KH AF Masaki, T. DiGiovanna, J. J. Wang, Y. Khan, S. G. Hornyak, T. Lee, C. Kraemer, K. H. TI Mutation analysis of pre-malignant and malignant pigmented lesions in xeroderma pigmentosum: The role of UV damage in melanoma induction SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Masaki, T.; DiGiovanna, J. J.; Wang, Y.; Khan, S. G.; Hornyak, T.; Kraemer, K. H.] NCI, Derm Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 732 BP S125 EP S125 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900731 ER PT J AU Miyagawa, F Tagaya, Y Ozato, K Katz, SI AF Miyagawa, F. Tagaya, Y. Ozato, K. Katz, S. I. TI IRF8 controls activation-induced cell death on CD8 T cells by regulating Bcl2 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Miyagawa, F.; Tagaya, Y.; Ozato, K.; Katz, S. I.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 572 BP S97 EP S97 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900571 ER PT J AU Mohammed, J Gunderson, A Khong, L Koubek, R Udey, M Glick, A AF Mohammed, J. Gunderson, A. Khong, L. Koubek, R. Udey, M. Glick, A. TI Overexpression of TGF beta 1 in murine epidermis alters skin dendritic cell homeostasis and enhances adaptive immunity SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Mohammed, J.; Gunderson, A.; Khong, L.; Koubek, R.; Glick, A.] Penn State Univ, University Pk, PA 16802 USA. [Udey, M.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 609 BP S103 EP S103 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900610 ER PT J AU Motegi, S Ishikawa, O Udey, MC AF Motegi, S. Ishikawa, O. Udey, M. C. TI Expression of MFG-E8 in murine and human skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Motegi, S.; Udey, M. C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Motegi, S.; Ishikawa, O.] Gunma Univ, Grad Sch Med, Dept Dermatol, Maebashi, Gumma 371, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 184 BP S31 EP S31 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900183 ER PT J AU Nagao, K Kobayashi, T Moro, K Kabashima, K Ohyama, M Cho, Y Clausen, BE Udey, MC Amagai, M AF Nagao, K. Kobayashi, T. Moro, K. Kabashima, K. Ohyama, M. Cho, Y. Clausen, B. E. Udey, M. C. Amagai, M. TI Dendritic cell trafficking in skin is regulated by hair follicles via chemokine production SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Nagao, K.; Kobayashi, T.; Moro, K.; Ohyama, M.; Amagai, M.] Keio Univ, Sch Med, Tokyo, Japan. [Kabashima, K.] Kyoto Univ, Kyoto, Japan. [Clausen, B. E.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Cho, Y.; Udey, M. C.] NCI, CCR, NIH, Bethesda, MD 20892 USA. RI Kabashima, Kenji/G-2521-2014; Moro, Kazuyo/A-5987-2016 OI Kabashima, Kenji/0000-0002-0773-0554; NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 585 BP S99 EP S99 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900586 ER PT J AU Okano, J Lichti, U Mamiya, S Aronova, M Zhang, G Yuspa, SH Hamada, H Sakai, Y Morasso, MI AF Okano, J. Lichti, U. Mamiya, S. Aronova, M. Zhang, G. Yuspa, S. H. Hamada, H. Sakai, Y. Morasso, M. I. TI Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Okano, J.; Morasso, M. I.] NIAMS, Dev Skin Biol Sect, NIH, Bethesda, MD USA. [Lichti, U.; Yuspa, S. H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mamiya, S.; Hamada, H.] Osaka Univ, Dev Genet Grp, Grad Sch Frontier Biosci, Osaka, Japan. [Aronova, M.; Zhang, G.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Sakai, Y.] Osaka Univ, Sch Med, Dept Plast Surg, Osaka, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 313 BP S53 EP S53 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900312 ER PT J AU Okiyama, N Furumoto, Y Villarroel, V Gutermuth, J Ghoreschi, K Gadina, M Katz, SI AF Okiyama, N. Furumoto, Y. Villarroel, V. Gutermuth, J. Ghoreschi, K. Gadina, M. Katz, S. I. TI Effective prevention and treatment of CD8 T cell-mediated Graft-versus-host-like disease (GvHD) using a JAK inhibitor SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Okiyama, N.; Villarroel, V.; Gutermuth, J.; Katz, S. I.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Furumoto, Y.; Gutermuth, J.; Ghoreschi, K.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 040 BP S7 EP S7 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900042 ER PT J AU Qian, Y Jeong, JS Maldonado, M Evangelista, F Qaqish, BF Aoki, V Hans, G Rivitti, EA Valenzuela, JG Diaz, LA AF Qian, Y. Jeong, J. S. Maldonado, M. Evangelista, F. Qaqish, B. F. Aoki, V. Hans-Filhio, G. Rivitti, E. A. Valenzuela, J. G. Diaz, L. A. TI Anti-Desmoglein 1 autoantibodies from Fogo Selvagem recognize LJM11, a member of the "yellow" family of salivary proteins from Lutzomyia longipalpis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Qian, Y.; Jeong, J. S.; Maldonado, M.; Evangelista, F.; Qaqish, B. F.; Diaz, L. A.] Univ N Carolina, Chapel Hill, NC USA. [Aoki, V.; Rivitti, E. A.] Univ Sao Paulo, Sao Paulo, Brazil. [Hans-Filhio, G.] Univ Mato Grosso do Sul, Mato Grosso, Brazil. [Valenzuela, J. G.] NIAID, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 054 BP S9 EP S9 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900055 ER PT J AU Richardson, BS Anderson, WF Barnholtz-Sloan, JS Tucker, MA Gerstenblith, MR AF Richardson, B. S. Anderson, W. F. Barnholtz-Sloan, J. S. Tucker, M. A. Gerstenblith, M. R. TI Gender is an age-specific effect modifier for ulcerated malignant melanomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Barnholtz-Sloan, J. S.] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. [Anderson, W. F.] NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. [Tucker, M. A.] NCI, Human Genet Program, NIH, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 282 BP S48 EP S48 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900285 ER PT J AU Sekulic, A Zismann, V Froman, R Allen, A Huentleman, M Paoloni, M Neff, M Davis, B Cox, A Duesbery, N Xu, J Bittner, M Webb, C Brown, K LoRusso, P Trent, J AF Sekulic, A. Zismann, V. Froman, R. Allen, A. Huentleman, M. Paoloni, M. Neff, M. Davis, B. Cox, A. Duesbery, N. Xu, J. Bittner, M. Webb, C. Brown, K. LoRusso, P. Trent, J. TI Efforts to provide a comprehensive overview of genetic changes in canine melanoma as a means to identify genetic correlates for drug response SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Sekulic, A.; Zismann, V.; Allen, A.; Huentleman, M.; Bittner, M.; Trent, J.] Tgen, Phoenix, AZ USA. [Sekulic, A.] Mayo Clin, Scottsdale, AZ USA. [Froman, R.; Neff, M.; Cox, A.; Duesbery, N.; Webb, C.] Van Andel Res Inst, Grand Rapids, MI USA. [Paoloni, M.; Brown, K.] NCI, Bethesda, MD 20892 USA. [Davis, B.] Tufts Univ, Medford, MA 02155 USA. [Xu, J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [LoRusso, P.] Karmanos Canc Inst, Detroit, MI USA. RI Webb, Craig/I-8123-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 781 BP S133 EP S133 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900782 ER PT J AU Singh, A Trempus, CS Morris, RJ AF Singh, A. Trempus, C. S. Morris, R. J. TI Identification of novel mutations in the candidate keratinocyte stem cell regulatory gene, Bone Morphogenetic Protein 5 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Singh, A.; Morris, R. J.] Univ Minnesota, Hormel Inst, Lab Stem Cells & Canc, Austin, MN 55912 USA. [Trempus, C. S.] NIEHS, Matrix Biol Grp, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 830 BP S142 EP S142 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900830 ER PT J AU Tan, X Anzick, S Khan, SG Ueda, T Stone, G DiGiovanna, JJ Tamura, D Wattendorf, D Walker, R Meltzer, P Kraemer, KH AF Tan, X. Anzick, S. Khan, S. G. Ueda, T. Stone, G. DiGiovanna, J. J. Tamura, D. Wattendorf, D. Walker, R. Meltzer, P. Kraemer, K. H. TI Chimeric 9p-22q transcript in a patient with melanoma and DNA repair deficiency acts as a negative regulator of p14ARF SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Tan, X.; Khan, S. G.; Ueda, T.; DiGiovanna, J. J.; Tamura, D.; Kraemer, K. H.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Anzick, S.; Stone, G.; Walker, R.; Meltzer, P.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Wattendorf, D.] USAF, Off Surgeon Gen, Washington, DC 20330 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 741 BP S127 EP S127 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900744 ER PT J AU Tomita, T Putney, JW AF Tomita, T. Putney, J. W. TI STIM1 and Orai1-mediated store-operated Ca2+ entry is critical for Ca2+-switch-induced keratinocyte differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Tomita, T.; Putney, J. W.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 370 BP S63 EP S63 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900373 ER PT J AU Totonchy, MB Tamura, D Zalewski, C Bradford, PT DiGiovanna, JJ Kraemer, KH Brewer, CC AF Totonchy, M. B. Tamura, D. Zalewski, C. Bradford, P. T. DiGiovanna, J. J. Kraemer, K. H. Brewer, C. C. TI DNA repair is critical in maintaining neurologic integrity and hearing function: A 40 yr longitudinal auditory analysis of patients with xeroderma pigmentosum and trichothiodystrophy SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Totonchy, M. B.; Tamura, D.; DiGiovanna, J. J.; Kraemer, K. H.] NCI, Derm Branch, Bethesda, MD 20892 USA. [Totonchy, M. B.] NIH, Bethesda, MD 20892 USA. [Zalewski, C.; Brewer, C. C.] NIDCD, Otolaryngol Br, Bethesda, MD USA. [Bradford, P. T.] NCI, Genet Epi Br, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 251 BP S43 EP S43 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900252 ER PT J AU Trempus, CS Flake, GP Kissling, GE Stober, V Zhuo, L Kimata, K Garantziotis, S AF Trempus, C. S. Flake, G. P. Kissling, G. E. Stober, V. Zhuo, L. Kimata, K. Garantziotis, S. TI Dysregulated wound healing in inter-alpha-trypsin inhibitor deficient mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Trempus, C. S.; Stober, V.; Garantziotis, S.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Flake, G. P.] NIEHS, Comparat & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Kissling, G. E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Zhuo, L.; Kimata, K.] Aichi Med Univ, Nagakute, Aichi, Japan. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 800 BP S137 EP S137 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900801 ER PT J AU Wheless, L Kistner-Griffin, E Jorgensen, TJ Berthier-Schaad, Y Kessing, B Hoffman-Bolton, J Shugart, YY Kao, W Strickland, PT Francis, L Alani, RM Smith, MW Alberg, AJ AF Wheless, L. Kistner-Griffin, E. Jorgensen, T. J. Berthier-Schaad, Y. Kessing, B. Hoffman-Bolton, J. Shugart, Y. Y. Kao, W. Strickland, P. T. Francis, L. Alani, R. M. Smith, M. W. Alberg, A. J. TI Gene-gene interactions between nucleotide excision repair RPA3 with XPC and ERCC1 are associated with risk of nonmelanoma skin cancer SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Wheless, L.; Kistner-Griffin, E.; Francis, L.; Alberg, A. J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Berthier-Schaad, Y.] NCI, Frederick, MD 21701 USA. [Shugart, Y. Y.] NIMH, Bethesda, MD 20892 USA. [Alani, R. M.] Boston Univ, Boston, MA 02215 USA. [Kessing, B.; Smith, M. W.] SAIC Frederick Inc, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 155 BP S26 EP S26 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900156 ER PT J AU Xiao, Y Woo, W Terunuma, A Oro, AE Vogel, JC Brownell, I AF Xiao, Y. Woo, W. Terunuma, A. Oro, A. E. Vogel, J. C. Brownell, I. TI A perivascular stem cell niche in the hair follicle SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 75th Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 09-12, 2012 CL Raleigh, NC SP Soc Investigat Dermatol C1 [Xiao, Y.; Terunuma, A.; Vogel, J. C.; Brownell, I.] NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Woo, W.; Oro, A. E.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2012 VL 132 SU 1 MA 467 BP S79 EP S79 PG 1 WC Dermatology SC Dermatology GA 926XV UT WOS:000302866900466 ER PT J AU Rao, JS Kellom, M Kim, HW Rapoport, SI Reese, EA AF Rao, Jagadeesh S. Kellom, Matthew Kim, Hyung-Wook Rapoport, Stanley I. Reese, Edmund A. TI Neuroinflammation and Synaptic Loss SO NEUROCHEMICAL RESEARCH LA English DT Article DE Arachidonic acid; Cytokines; Drebrin; Synaptophysin; Excitotoxicity ID TUMOR-NECROSIS-FACTOR; NITRIC-OXIDE SYNTHASE; CYTOSOLIC PHOSPHOLIPASE A(2); MILD COGNITIVE IMPAIRMENT; NF-KAPPA-B; ARACHIDONIC-ACID METABOLISM; DENDRITIC SPINE PATHOLOGY; MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; HIV-1 TRANSGENIC RATS AB Neuroinflammation plays a critical role in the progression of many neurodegenerative, neuropsychiatric and viral diseases. In neuroinflammation, activated microglia and astrocytes release cytokines and chemokines as well as nitric oxide, which in turn activate many signal transduction pathways. The cytokines, interleukin-1 beta and tumor necrosis factor alpha, regulate transcription of a number of genes within the brain, which can lead to the formation of pro-inflammatory products of the arachidonic acid cascade. Formation of pro-inflammatory agents and associated cytotoxic products during neuroinflammation can be detrimental to neurons by altering synaptic proteins. Neuroinflammation as well as excitotoxic insults reduce synaptic markers such as synaptophysin and drebrin. Neurodegenerative, neuropsychiatric illnesses and viral infections are accompanied by loss of both pre- and post-synaptic proteins. These synaptic changes may contribute to the progressive cognitive decline and behavioral changes associated with these illnesses. C1 [Rao, Jagadeesh S.; Kellom, Matthew; Kim, Hyung-Wook; Rapoport, Stanley I.; Reese, Edmund A.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Rm 1S126 MSC 0947, Bethesda, MD 20892 USA. EM jrao@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health, Bethesda, MD FX This research was entirely supported by the Intramural Research Programs of the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892. We thank the National Cancer Institute (NCI), Center for Cancer Research (CCR) Fellows Editorial Board for proofreading the manuscript. NR 98 TC 62 Z9 64 U1 0 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD MAY PY 2012 VL 37 IS 5 BP 903 EP 910 DI 10.1007/s11064-012-0708-2 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 920LC UT WOS:000302404900001 PM 22311128 ER PT J AU Lubet, RA Clapper, ML McCormick, DL Pereira, MA Chang, WCL Steele, VE Fischer, SM Juliana, MM Grubbs, CJ AF Lubet, Ronald A. Clapper, Margie L. McCormick, David L. Pereira, Michael A. Chang, W-C L. Steele, Vernon E. Fischer, Susan M. Juliana, M. Margaret Grubbs, Clinton J. TI Chemopreventive efficacy of Targretin in rodent models of urinary bladder, colon/intestine, head and neck and mammary cancers SO ONCOLOGY REPORTS LA English DT Article DE cancer; Targretin; animal models; chemoprevention ID LUNG CARCINOGENESIS; CELL-PROLIFERATION; PREVENTION; EXPRESSION; LGD1069; CYCLOOXYGENASE-2; TRANSCRIPTION; BEXAROTENE; INHIBITORS; APOPTOSIS AB The chemopreventive efficacy of Targretin was evaluated in various rodent cancer models. In the rat model of 4-hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced urinary bladder cancer, it was found that Targretin administered in the diet (beginning one week after the last OH-BBN treatment) for 5.5 months increased the number and size of urinary bladder cancers. In the azoxymethane (AOM)-induced model of colon carcinogenesis (in which rats develop minimally invasive colonic cancers), Targretin was ineffective as a chemopreventive agent, decreasing neither tumor incidence nor multiplicity. Treatment of Min mice with Targretin for 45 days similarly failed to decrease the multiplicity of small intestinal tumors. Similarly, no preventive efficacy was noted for Targretin when the incidence of tumors in the head and neck model (squamous cell tongue tumors) induced by 4-nitroquinoline 1-oxide (4-NQO) were examined. In contrast, use of even a suboptimal dose of Targretin (40 ppm) in a sensitive breast cancer model [methylnitrosourea (MNU)-induced ER+ mammary cancers] reduced cancer multiplicity by 60%. Finally, based on the hypothesis that Targretin may decrease the expression of COX-2, the effects of Targretin and COX inhibitors were compared in these models. There was minimal overlap of efficacy. That is, models which were relatively susceptible to NSAIDs or COX-2 inhibitors tended not to be sensitive to Targretin and vice versa. C1 [Lubet, Ronald A.; Steele, Vernon E.] NCI, Canc Prevent Div, Bethesda, MD 20852 USA. [Clapper, Margie L.; Chang, W-C L.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Pereira, Michael A.] Ohio State Univ, Columbus, OH 43210 USA. [McCormick, David L.] IIT Inst, Chicago, IL USA. [Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Surg, Birmingham, AL USA. [Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Genet, Birmingham, AL USA. RP Lubet, RA (reprint author), NCI, Canc Prevent Div, Execut Plaza N,Suite 2110,6130 Execut Blvd, Bethesda, MD 20852 USA. EM lubetr@mail.nih.gov FU NCI [HHSN261200433001C] FX The authors wish to thank Jeanne Hale, Mary Jo Cagle, and Julie Gray for their secretarial and editorial services. Research materials for the studies were in part obtained by the NCI contract number HHSN261200433001C. NR 28 TC 4 Z9 4 U1 4 U2 8 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD MAY PY 2012 VL 27 IS 5 BP 1400 EP 1406 DI 10.3892/or.2012.1673 PG 7 WC Oncology SC Oncology GA 917TX UT WOS:000302202600016 PM 22307264 ER PT J AU Wang, XY Chrysovergis, K Bienstock, RJ Shim, M Eling, TE AF Wang, Xingya Chrysovergis, Kali Bienstock, Rachelle J. Shim, Minsub Eling, Thomas E. TI The H6D variant of NAG-1/GDF15 inhibits prostate xenograft growth in vivo SO PROSTATE LA English DT Article DE NAG-1; GDF15; H6D; prostate cancer ID BETA SUPERFAMILY MEMBER; CANCER CELLS; CRYSTAL-STRUCTURE; BINDING-SPECIFICITY; TRANSGENIC MICE; CYCLIN D1; IGF-I; CYTOKINE-1; INSULIN; PROTEIN AB BACKGROUND Non-steroidal anti-inflammatory drug-activated gene (NAG-1), a divergent member of the transforming growth factor-beta superfamily, has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis. Recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D) of the NAG-1 protein is associated with lower human prostate cancer incidence. The objective of the current study is to investigate the activity of NAG-1 H6D variant in prostate cancer tumorigenesis in vivo. METHODS. Human prostate cancer DU145 cells expressing the H6D NAG-1 or wild-type (WT) NAG-1 were injected subcutaneously into nude mice and tumor growth was monitored. Serum and tumor samples were collected for subsequent analysis. RESULTS. The H6D variant was more potent than the WT NAG-1 and inhibited tumor growth significantly compared to control mice. Mice with tumors expressing the WT NAG-1 have greater reduced both body weight and abdominal fat than mice with H6D variant tumors suggesting different activities of the WT NAG-1 and the H6D NAG-1. A significant reduction in adiponectin, leptin, and IGF-1 serum levels was observed in the tumor-bearing mice with a more profound reduction observed with expression of H6D variant. Cyclin D1 expression was suppressed in the tumors with a dramatic reduction observed in the tumor expressing the H6D variant. CONCLUSION. Our data suggest that the H6D variant of NAG-1 inhibits prostate tumorigenesis by suppressing IGF-1 and cyclin D1 expression but likely additional mechanisms are operative. Prostate 72:677-689, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Wang, Xingya; Chrysovergis, Kali; Shim, Minsub; Eling, Thomas E.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Bienstock, Rachelle J.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI Bienstock, Rachelle/0000-0001-5228-3610 FU NIH; National Institute of Environmental Health Sciences FX Grant sponsor: Intramural Research Program of the NIH; Grant sponsor: National Institute of Environmental Health Sciences. NR 50 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY PY 2012 VL 72 IS 6 BP 677 EP 689 DI 10.1002/pros.21471 PG 13 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 911JG UT WOS:000301712500011 PM 21809352 ER PT J AU Lee, YC Chen, DY Dodd, SJ Bouraoud, N Koretsky, AP Krishnan, KM AF Lee, Yi-Cheng Chen, Der-Yow Dodd, Stephen J. Bouraoud, Nadia Koretsky, Alan P. Krishnan, Kannan M. TI The Use of Silica Coated MnO Nanoparticles to Control MRI Relaxivity in Response to Specific Physiological Changes SO BIOMATERIALS LA English DT Article DE Manganese enhanced MRI; MnO nanoparticle; Contrast agent; pH-responsive ID MAGNETIC-RELAXATION SWITCH; RESONANCE-IMAGING MEMRI; CELLULAR MRI; AGENT; ACTIVATION; SPIN AB MnO nanoparticles have been tested to engineer a delayed increase in MRI T-1 relaxivity caused by cellular uptake via endocytosis into acidic compartments. Various coatings on core-shell structured MnO nanoparticles were tested for those that had the lowest T-1 relaxivity at pH 7.4, a pH where MnO does not dissolve into Mn2+ ions. The rate of dissolution and release of Mn2+ of the different coated MnO particles as well as changes in T-1 relaxivity were measured at pH 5, a pH routinely obtained in the endosomal-lysosomal pathway. Of a number of coatings, silica coated MnO (MnO@SiO2) had the lowest relaxivity at pH 7.4 (0.29 mM(-1) sec(-1)). About one third of the MnO dissolved within 20 min and the T-1 relaxivity increased to that of free Mn2+ (6.10 mM(-1) sec(-1)) after three days at pH 5. MRI of MnO@SiO2 particles injected into the rat brain showed time-dependent signal changes consistent with the in vitro rates. Thalamocortical tract-tracing could be observed due to the released Mn2+. Intravenous infusion of MnO@SiO2 particles showed little enhancement in any tissue except gallbladder. The gallbladder enhancement was interpreted to be due to endocytosis by liver cells and excretion of Mn2+ ions into the gallbladder. The MnO@SiO2 core-shell nanoparticles show the best potential for delaying the release of miti contrast until endocytosis into low pH compartments activate MRI contrast. The delayed enhancement may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be recycled by endocytosis. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Lee, Yi-Cheng; Krishnan, Kannan M.] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. [Chen, Der-Yow; Dodd, Stephen J.; Bouraoud, Nadia; Koretsky, Alan P.] NINDS, NIH, Bethesda, MD 20892 USA. RP Krishnan, KM (reprint author), Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. EM KoretskyA@ninds.nih.gov; kannanmk@uw.edu RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NINDS; NIH FX The authors would like to acknowledge expertise of Ms. Kathryn Sharer. This research was supported by the Intramural Research Program of the NINDS, NIH. NR 27 TC 30 Z9 30 U1 9 U2 67 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD MAY PY 2012 VL 33 IS 13 BP 3560 EP 3567 DI 10.1016/j.biomaterials.2012.01.062 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 913XD UT WOS:000301909800006 PM 22341582 ER PT J AU Groppa, S Oliviero, A Eisen, A Quartarone, A Cohen, LG Mall, V Kaelin-Lang, A Mima, T Rossi, S Thickbroom, GW Rossini, PM Ziemann, U Valls-Sole, J Siebner, HR AF Groppa, S. Oliviero, A. Eisen, A. Quartarone, A. Cohen, L. G. Mall, V. Kaelin-Lang, A. Mima, T. Rossi, S. Thickbroom, G. W. Rossini, P. M. Ziemann, U. Valls-Sole, J. Siebner, H. R. TI A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Transcranial magnetic stimulation; Clinical neurophysiology; Corticomotor conduction; Motor-evoked potentials ID MOTOR EVOKED-POTENTIALS; INFLAMMATORY DEMYELINATING POLYNEUROPATHY; CENTRAL-NERVOUS-SYSTEM; SILENT PERIOD; BRAIN-STIMULATION; MULTIPLE-SCLEROSIS; CONSCIOUS HUMANS; CEREBRAL-CORTEX; NORMAL VALUES; INTERHEMISPHERIC DIFFERENCES AB Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS. (C) 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Siebner, H. R.] Copenhagen Univ Hosp Hvidovre, DRCMR, DK-2650 Hvidovre, Denmark. [Groppa, S.] Univ Kiel, Dept Neurol, D-2300 Kiel, Germany. [Oliviero, A.] Hosp Nacl Paraplej, Toledo, Spain. [Eisen, A.] Univ British Columbia, Dept Neurol, Vancouver, BC V5Z 1M9, Canada. [Quartarone, A.] Univ Messina, Dept Neurosci Psychiat & Anesthesiol, Messina, Italy. [Cohen, L. G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD USA. [Mall, V.] Univ Freiburg, Dept Neuropediat & Muscle Disorders, D-79106 Freiburg, Germany. [Kaelin-Lang, A.] Univ Bern, Inselspital, Dept Neurol, CH-3010 Bern, Switzerland. [Mima, T.] Univ Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. [Rossi, S.] Univ Siena, Dipartimento Neurosci, Sez Neurol & Neurofisiol Clin, Policlin Le Scotte, I-53100 Siena, Italy. [Thickbroom, G. W.] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia. [Rossini, P. M.] Catholic Univ, Inst Neurol, Pol Gemelli, Italy. [Rossini, P. M.] IRCCS S Raffaele Pisana & Casa Cura S Raffaele Ca, Rome, Italy. [Ziemann, U.] Goethe Univ Frankfurt, Dept Neurol, Frankfurt, Germany. [Valls-Sole, J.] Univ Barcelona, Hosp Clin, Serv Neurol, Unitat EMG, E-08007 Barcelona, Spain. RP Siebner, HR (reprint author), Copenhagen Univ Hosp Hvidovre, DRCMR, Kettegards Alle 30, DK-2650 Hvidovre, Denmark. EM hartwig.siebner@drcmr.dk RI Rossini, Paolo /D-4994-2013; Groppa, Sergiu/G-4606-2014; Siebner, Hartwig/G-4052-2016; OI Rossini, Paolo /0000-0003-2665-534X; QUARTARONE, Angelo/0000-0003-1485-6590; Mima, Tatsuya/0000-0001-7787-4855; rossi, simone/0000-0001-6697-9459 FU Intramural NIH HHS [ZIA NS002978-12] NR 131 TC 192 Z9 195 U1 7 U2 54 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAY PY 2012 VL 123 IS 5 BP 858 EP 882 DI 10.1016/j.clinph.2012.01.010 PG 25 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 916RS UT WOS:000302121500007 PM 22349304 ER PT J AU Sato, K Corbett, J Mason, RP Kadiiska, MB AF Sato, Keizo Corbett, Jean Mason, Ronald P. Kadiiska, Maria B. TI In vivo evidence of free radical generation in the mouse lung after exposure to Pseudomonas aeruginosa bacterium: An ESR spin-trapping investigation SO FREE RADICAL RESEARCH LA English DT Article DE free radicals; mice; Pseudomonas aeruginosa pneumonia; NADPH-oxidase; xanthine-oxidase ID ENDOTHELIAL-CELL INJURY; XANTHINE-OXIDASE; LIPID-PEROXIDATION; OXIDATIVE STRESS; GENE-EXPRESSION; NADPH OXIDASE; HOST-DEFENSE; NITRIC-OXIDE; DESFERRIOXAMINE; RESONANCE AB In the Pseudomonas aeruginosa-induced rodent pneumonia model, it is thought that free radicals are significantly associated with the disease pathogenesis. However, until now there has been no direct evidence of free radical generation in vivo. Here we used electron spin resonance (ESR) and in vivo spin trapping with alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone to investigate free radical production in a murine model. We detected and identified generation of lipid-derived free radicals in vivo (a(N) = 14.86 +/- 0.03 G and a(H)beta = 2.48 +/- 0.09 G). To further investigate the mechanism of lipid radical production, we used modulating agents and knockout mice. We found that with GdCl3 (phagocytic toxicant), NADPH-oxidase knockout mice (Nox2(-/-)), allopurinol (xanthine-oxidase inhibitor) and Desferal (metal chelator), generation of lipid radicals was decreased; histopathological and biological markers of acute lung injury were noticeably improved. Our study demonstrates that lipid-derived free radical formation is mediated by NADPH-oxidase and xanthine-oxidase activation and that metal-catalysed hydroxyl radical-like species play important roles in lung injury caused by Pseudomonas aeruginosa. C1 [Corbett, Jean; Mason, Ronald P.; Kadiiska, Maria B.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Sato, Keizo] Kyushu Univ Hlth & Welf, Sch Pharmaceut Sci, Dept Biochem 1, Nobeoka, Japan. RP Kadiiska, MB (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kadiiska@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES0501 39-13] FX The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This research was supported by the Intramural Research Program of the National Institutes of Health and by the National Institute of Environmental Health Sciences Grant Z01 ES0501 39-13. NR 55 TC 2 Z9 2 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD MAY PY 2012 VL 46 IS 5 BP 645 EP 655 DI 10.3109/10715762.2012.667089 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 915KR UT WOS:000302024100007 PM 22339444 ER PT J AU Abnet, CC Wang, ZM Song, X Hu, N Zhou, FY Freedman, ND Li, XM Yu, K Shu, XO Yuan, JM Zheng, W Dawsey, SM Liao, LM Lee, MP Ding, T Qiao, YL Gao, YT Koh, WP Xiang, YB Tang, ZZ Fan, JH Chung, CC Wang, CY Wheeler, W Yeager, M Yuenger, J Hutchinson, A Jacobs, KB Giffen, CA Burdett, L Fraumeni, JF Tucker, MA Chow, WH Zhao, XK Li, JM Li, AL Sun, LD Wei, W Li, JL Zhang, P Li, HL Cui, WY Wang, WP Liu, ZC Yang, X Fu, WJ Cui, JL Lin, HL Zhu, WL Liu, M Chen, X Chen, J Guo, L Han, JJ Zhou, SL Huang, J Wu, Y Yuan, C Huang, J Ji, AF Kul, JW Fan, ZM Wang, JP Zhang, DY Zhang, LQ Zhang, W Chen, YF Ren, JL Li, XM Dong, JC Xing, GL Guo, ZG Yang, JX Mao, YM Yuan, Y Guo, ET Zhang, W Hou, ZC Liu, J Li, Y Tang, S Chang, J Peng, XQ Han, M Yin, WL Liu, YL Hu, YL Liu, Y Yang, LQ Zhu, FG Yang, XF Feng, XS Wang, Z Li, Y Gao, SG Liu, HL Yuan, L Jin, Y Zhang, YR Sheyhidin, I Li, F Chen, BP Ren, SW Liu, B Li, D Zhang, GF Yue, WB Feng, CW Qige, QRW Zhao, JT Yang, WJ Lei, GY Chen, LQ Li, EM Xu, LY Wu, ZY Bao, ZQ Chen, JL Li, XC Zhuang, X Zhou, YF Zuo, XB Dong, ZM Wang, LW Fan, XP Wang, J Zhou, Q Ma, GS Zhang, QX Liu, H Jian, XY Lian, SY Wang, JS Chang, FB Lu, CD Miao, JJ Chen, ZG Wang, R Guo, M Fan, ZL Tao, P Liu, TJ Wei, JC Kong, QP Fan, L Wang, XZ Gao, FS Wang, TY Xie, D Wang, L Chen, SQ Yang, WC Hong, JY Wang, L Qiu, SL Goldstein, AM Yuan, ZQ Chanock, SJ Zhang, XJ Taylor, PR Wang, LD AF Abnet, Christian C. Wang, Zhaoming Song, Xin Hu, Nan Zhou, Fu-You Freedman, Neal D. Li, Xue-Min Yu, Kai Shu, Xiao-Ou Yuan, Jian-Min Zheng, Wei Dawsey, Sanford M. Liao, Linda M. Lee, Maxwell P. Ding, Ti Qiao, You-Lin Gao, Yu-Tang Koh, Woon-Puay Xiang, Yong-Bing Tang, Ze-Zhong Fan, Jin-Hu Chung, Charles C. Wang, Chaoyu Wheeler, William Yeager, Meredith Yuenger, Jeff Hutchinson, Amy Jacobs, Kevin B. Giffen, Carol A. Burdett, Laurie Fraumeni, Joseph F., Jr. Tucker, Margaret A. Chow, Wong-Ho Zhao, Xue-Ke Li, Jiang-Man Li, Ai-Li Sun, Liang-Dan Wei, Wu Li, Ji-Lin Zhang, Peng Li, Hong-Lei Cui, Wen-Yan Wang, Wei-Peng Liu, Zhi-Cai Yang, Xia Fu, Wen-Jing Cui, Ji-Li Lin, Hong-Li Zhu, Wen-Liang Liu, Min Chen, Xi Chen, Jie Guo, Li Han, Jing-Jing Zhou, Sheng-Li Huang, Jia Wu, Yue Yuan, Chao Huang, Jing Ji, Ai-Fang Kul, Jian-Wei Fan, Zhong-Min Wang, Jian-Po Zhang, Dong-Yun Zhang, Lian-Qun Zhang, Wei Chen, Yuan-Fang Ren, Jing-Li Li, Xiu-Min Dong, Jin-Cheng Xing, Guo-Lan Guo, Zhi-Gang Yang, Jian-Xue Mao, Yi-Ming Yuan, Yuan Guo, Er-Tao Zhang, Wei Hou, Zhi-Chao Liu, Jing Li, Yan Tang, Sa Chang, Jia Peng, Xiu-Qin Han, Min Yin, Wan-Li Liu, Ya-Li Hu, Yan-Long Liu, Yu Yang, Liu-Qin Zhu, Fu-Guo Yang, Xiu-Feng Feng, Xiao-Shan Wang, Zhou Li, Yin Gao, She-Gan Liu, Hai-Lin Yuan, Ling Jin, Yan Zhang, Yan-Rui Sheyhidin, Ilyar Li, Feng Chen, Bao-Ping Ren, Shu-Wei Liu, Bin Li, Dan Zhang, Gao-Fu Yue, Wen-Bin Feng, Chang-Wei Qige, Qirenwang Zhao, Jian-Ting Yang, Wen-Jun Lei, Guang-Yan Chen, Long-Qi Li, En-Min Xu, Li-Yan Wu, Zhi-Yong Bao, Zhi-Qin Chen, Ji-Li Li, Xian-Chang Zhuang, Xiang Zhou, Ying-Fa Zuo, Xian-Bo Dong, Zi-Ming Wang, Lu-Wen Fan, Xue-Pin Wang, Jin Zhou, Qi Ma, Guo-Shun Zhang, Qin-Xian Liu, Hai Jian, Xin-Ying Lian, Sin-Yong Wang, Jin-Sheng Chang, Fu-Bao Lu, Chang-Dong Miao, Jian-Jun Chen, Zhi-Guo Wang, Ran Guo, Ming Fan, Zeng-Lin Tao, Ping Liu, Tai-Jing Wei, Jin-Chang Kong, Qing-Peng Fan, Lei Wang, Xian-Zeng Gao, Fu-Sheng Wang, Tian-Yun Xie, Dong Wang, Li Chen, Shu-Qing Yang, Wan-Cai Hong, Jun-Yan Wang, Liang Qiu, Song-Liang Goldstein, Alisa M. Yuan, Zhi-Qing Chanock, Stephen J. Zhang, Xue-Jun Taylor, Philip R. Wang, Li-Dong TI Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies SO HUMAN MOLECULAR GENETICS LA English DT Article ID SUSCEPTIBILITY LOCI; CASP8 PROMOTER; CANCER-RISK; PLCE1; GENE; ADENOCARCINOMA; POLYMORPHISMS; CASPASE-8; COMMON AB Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P 5 10(8), and the strongest signal was rs13016963, with a combined odds ratio (95 confidence interval) of 1.29 (1.191.40) and P 7.63 10(10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants. C1 [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, DCEG, NIH, Bethesda, MD 20892 USA. [Lee, Maxwell P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Chung, Charles C.; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin B.; Burdett, Laurie] SAIC Frederick, Core Genotyping Facil, NCI Frederick, Frederick, MD USA. [Song, Xin; Zhao, Xue-Ke; Li, Jiang-Man; Li, Ai-Li; Zhang, Peng; Cui, Wen-Yan; Cui, Ji-Li; Lin, Hong-Li; Li, Xiu-Min; Guo, Zhi-Gang; Liu, Ya-Li; Hu, Yan-Long; Liu, Hai-Lin; Jin, Yan; Chen, Zhi-Guo; Wang, Tian-Yun; Yang, Wan-Cai; Yuan, Zhi-Qing; Wang, Li-Dong] Xinxiang Med Univ, Canc Res Ctr, Xinxiang 453003, Henan, Peoples R China. [Song, Xin; Zhao, Xue-Ke; Li, Jiang-Man; Li, Hong-Lei; Wang, Wei-Peng; Liu, Zhi-Cai; Yang, Xia; Fu, Wen-Jing; Zhu, Wen-Liang; Liu, Min; Chen, Xi; Chen, Jie; Guo, Li; Han, Jing-Jing; Zhou, Sheng-Li; Huang, Jia; Wu, Yue; Yuan, Chao; Huang, Jing; Ji, Ai-Fang; Kul, Jian-Wei; Fan, Zhong-Min; Wang, Jian-Po; Zhang, Dong-Yun; Zhang, Lian-Qun; Dong, Jin-Cheng; Xing, Guo-Lan; Yang, Jian-Xue; Mao, Yi-Ming; Yuan, Yuan; Guo, Er-Tao; Zhang, Wei; Hou, Zhi-Chao; Liu, Jing; Li, Yan; Tang, Sa; Chang, Jia; Peng, Xiu-Qin; Yin, Wan-Li; Liu, Yu; Li, Dan; Yue, Wen-Bin; Zhuang, Xiang; Zhou, Ying-Fa; Wang, Lu-Wen; Fan, Xue-Pin; Wang, Jin; Wang, Ran; Guo, Ming; Wang, Li; Qiu, Song-Liang; Wang, Li-Dong] Zhengzhou Univ, Affiliated Hosp 1, Henan Key Lab Esophageal Canc Res, Zhengzhou 450052, Henan, Peoples R China. [Ren, Jing-Li; Feng, Chang-Wei] Zhengzhou Univ, Affiliated Hosp 2, Dept Basic Oncol & Pathol, Zhengzhou 450052, Henan, Peoples R China. [Zhou, Fu-You; Wang, Jian-Po; Zhang, Lian-Qun; Lu, Chang-Dong] Anyang Tumor Hosp, Dept Thorac Surg & Tumor Prevent Treatment, Anyang 455000, Henan, Peoples R China. [Li, Xue-Min; Bao, Zhi-Qin; Chen, Ji-Li; Miao, Jian-Jun; Fan, Zeng-Lin; Fan, Lei] Cixian Hosp, Dept Pathol & Thorac Surg, Ctr Hlth Screening & Endoscopy, Cixian 056500, Hebei, Peoples R China. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Yuan, Jian-Min] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Ding, Ti; Tang, Ze-Zhong] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Qiao, You-Lin; Fan, Jin-Hu] Chinese Acad Med Sci, Dept Epidemiol, Canc Inst Hosp, Beijing 100730, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Wheeler, William; Giffen, Carol A.; Li, Xian-Chang] Informat Management Serv Inc, Silver Spring, MD USA. [Li, Ai-Li; Lian, Sin-Yong] Tumor Hosp Linzhou, Dept Thorac Surg, Linzhou 456550, Henan, Peoples R China. [Sun, Liang-Dan; Zuo, Xian-Bo; Zhang, Xue-Jun] Anhui Med Univ, Key Lab Dermatol, Minist Educ, Hefei 230032, Anhui, Peoples R China. [Wei, Wu; Ji, Ai-Fang; Wang, Jin-Sheng] Changzhi Med Univ, Inst Hematol Dis, Changzhi 046000, Shanxi, Peoples R China. [Wei, Wu; Ji, Ai-Fang; Wang, Jin-Sheng] Changzhi Med Univ, Dept Pathol, Changzhi 046000, Shanxi, Peoples R China. [Li, Ji-Lin; Jian, Xin-Ying; Wei, Jin-Chang] Linzhou Esophageal Canc Hosp, Dept Pathol & Thorac Surg, Linzhou 456592, Henan, Peoples R China. [Kul, Jian-Wei] Nanyang Med Coll, Affiliated Hosp 1, Dept Oncol, Nanyang 473058, Henan, Peoples R China. [Zhang, Wei; Zhao, Jian-Ting] First Peoples Hosp Hebi, Dept Oncol, Hebi 458000, Henan, Peoples R China. [Chen, Yuan-Fang] Hebi City Publ Hlth Bur, Dept Biostat, Hebi 458000, Henan, Peoples R China. [Dong, Jin-Cheng] Qixian Commerce Bur, Hebi 456750, Henan, Peoples R China. [Yang, Jian-Xue; Mao, Yi-Ming; Peng, Xiu-Qin; Feng, Xiao-Shan; Gao, She-Gan] Henan Univ Sci & Technol, Affiliated Hosp 1, Dept Oncol, Luoyang 471003, Henan, Peoples R China. [Han, Min; Zhu, Fu-Guo] First Peoples Hosp Shangqiu, Dept Gastroenterol & Thorac Surg, Shangqiu 476100, Henan, Peoples R China. [Yang, Liu-Qin] Xinxiang Cent Hosp, Dept Radiotherapy, Xinxiang 453000, Henan, Peoples R China. [Yang, Xiu-Feng] Hebi Dahejian Hosp, Dept Surg, Hebi 458000, Henan, Peoples R China. [Wang, Zhou] Shandong Univ, Prov Hosp, Dept Thorac Surg, Jinan 250021, Shandong, Peoples R China. [Li, Yin; Yuan, Ling] Zhengzhou Univ, Canc Hosp, Dept Thorac Surg & Radiotherapy, Zhengzhou 450008, Henan, Peoples R China. [Zhang, Yan-Rui] Zhengzhou Univ, Dept Gastroenterol, Peoples Hosp, Zhengzhou 450003, Henan, Peoples R China. [Sheyhidin, Ilyar] Xinjiang Med Univ, Dept Thorac Surg, Affiliated Hosp 1, Urumqi 830054, Xinjiang, Peoples R China. [Sheyhidin, Ilyar] Xinjiang Med Univ, Med Res Ctr, Affiliated Hosp 1, Urumqi 830054, Xinjiang, Peoples R China. [Li, Feng] Shihezi Univ, Sch Med, Dept Pathol, Shihezi 832002, Xinjiang, Peoples R China. [Chen, Bao-Ping] Henan Univ, Huaihe Hosp, Dept Nephrol, Kaifeng 475000, Henan, Peoples R China. [Ren, Shu-Wei] Xinyang Cent Hosp, Dept Oncol, Xinyang 464000, Henan, Peoples R China. [Liu, Bin; Gao, Fu-Sheng] Capital Med Univ, Beijing Tongren Hosp, Dept Gastroenterol, Beijing 100176, Peoples R China. [Li, Dan; Zhang, Gao-Fu; Liu, Tai-Jing] Red Cross Hosp Huojia, Dept Surg, Xinxiang 453800, Henan, Peoples R China. [Yue, Wen-Bin] Puyang City Oil Field Hosp, Dept Oncol, Puyang 457000, Henan, Peoples R China. [Qige, Qirenwang] Inner Mongolia Med Coll, Affiliated Hosp, Dept Internal Mongolia Med, Hohhot 010050, Inner Mongolia, Peoples R China. [Yang, Wen-Jun] Ningxia Med Univ, Dept Biotechnol, Yinchuan 750004, Ningxia, Peoples R China. [Lei, Guang-Yan] Tumor Hosp Shaanxi Prov, Dept Thorac Surg, Xian 710061, Shaanxi, Peoples R China. [Chen, Long-Qi] Sichuan Univ, Dept Thorac & Cardiovasc Surg, W China Hosp, Chengdu 610041, Sichuan, Peoples R China. [Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong] Shantou Univ, Dept Oncol Pathol, Coll Med, Shantou 515041, Guangdong, Peoples R China. [Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong] Shantou Univ, Coll Med, Dept Biochem & Mol Biol, Shantou 515041, Guangdong, Peoples R China. [Dong, Zi-Ming; Zhou, Qi; Zhang, Qin-Xian] Zhengzhou Univ, Basic Med Coll, Dept Pathol & Oncol, Zhengzhou 450052, Henan, Peoples R China. [Ma, Guo-Shun] Neihuang Publ Hlth Bur, Dept Biostat, Anyang 4563000, Henan, Peoples R China. [Liu, Hai] Third Peoples Hosp Yunnan Prov, Dept Gastroenterol, Kunming 650011, Yunnan, Peoples R China. [Chang, Fu-Bao] Chinese Med Hosp Linzhou, Dept Thorac Surg, Linzhou 456550, Henan, Peoples R China. [Tao, Ping] Langzhongshi Peoples Hosp, Dept Oncol Pathol, Langzhong 637400, Sichuan, Peoples R China. [Kong, Qing-Peng] Chinese Acad Sci, State Key Lab Genet Resource & Evolut, Kunming Inst Zool, Kunming 650223, Yunnan, Peoples R China. [Wang, Xian-Zeng] Linzhou Peoples Hosp, Dept Thorac Surg, Linzhou 456550, Henan, Peoples R China. [Xie, Dong] Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Chen, Shu-Qing; Hong, Jun-Yan] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China. [Wang, Liang] Med Coll Wisconsin, MCW Canc Ctr, Dept Pathol, Milwaukee, WI 53226 USA. RP Abnet, CC (reprint author), NCI, Nutr Epidemiol Branch, DCEG, NIH, EPS 320, Bethesda, MD 20892 USA. EM abnetc@mail.nih.gov; ldwang@xxmu.edu.cn RI Chen, Gang/G-2722-2010; Qiao, You-Lin/B-4139-2012; Tucker, Margaret/B-4297-2015; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; ren, jingli/0000-0001-9891-0579; Liao, Linda/0000-0002-1923-5294; Chen, Shuqing/0000-0002-0792-3735; Yuan, Jian-Min/0000-0002-4620-3108 FU Xinxiang Medical University [2009-5]; National Natural Science Foundations of China [30670956, 30971133]; 863 HighTech Key Projects [2006AA02A403, 2007AA02Z161]; China Key Program on Basic Research [2007CB516812]; Science and Technology Department [2009-8]; Health Department [2009-10]; Education Department of Henan Province [2008-7]; Anhui Provincial Special Scientific Program [2007-7]; National Cancer Institute [R01 CA82729, R37 CA70837, NO2-CP-11010, R01 CA55069, R35 CA53890, R01 CA80205, R01 CA144034, NO2-SC-66211, NO1-SC-91030, HHSN261200477001C]; Vanderbilt University; Shanxi Cancer Hospital; Institute, Taiyuan, Shanxi, China; Cancer Institute of the Chinese Academy of Medical Sciences, Beijing, China; NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Xinxiang Medical University Key Scientific Program (2009-5), the National Natural Science Foundations of China (30670956, 30971133), 863 HighTech Key Projects (2006AA02A403, 2007AA02Z161), China Key Program on Basic Research (2007CB516812), Special Scientific Programs from Science and Technology Department (2009-8), Health Department (2009-10) and Education Department (2008-7) of Henan Province and the Anhui Provincial Special Scientific Program (2007-7). The Shanghai Men's Health Study (SMHS) was supported by the National Cancer Institute extramural research grant (R01 CA82729). The Shanghai Women's Health Study (SWHS) was supported by the National Cancer Institute extramural research grant (R37 CA70837) and, partially for biological sample collection, National Cancer Institute Intramural Research Program contract NO2-CP-11010 with Vanderbilt University. The Singapore Chinese Health Study (SCHS) was supported by the National Cancer Institute extramural research grants (R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA144034). The Shanxi Upper Gastrointestinal Cancer Genetics Project was supported by the National Cancer Institute Intramural Research Program contract NO2-SC-66211 with the Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China. The Nutrition Intervention Trials (NIT) were supported by National Cancer Institute Intramural Research Program contracts NO1-SC-91030 and HHSN261200477001C with the Cancer Institute of the Chinese Academy of Medical Sciences, Beijing, China. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 34 TC 25 Z9 27 U1 2 U2 45 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 MAY 1 PY 2012 VL 21 IS 9 BP 2132 EP 2141 DI 10.1093/hmg/dds029 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 919DU UT WOS:000302302800018 PM 22323360 ER PT J AU Zwingenberger, AL Vernau, W Shi, CY Yan, WS Chen, XB Gordon, IK Kent, MS AF Zwingenberger, Allison L. Vernau, William Shi, Changying Yan, Wensheng Chen, Xinbin Gordon, Ira K. Kent, Michael S. TI Development and characterization of 5 canine B-cell lymphoma cell lines SO LEUKEMIA RESEARCH LA English DT Article DE Canine; B-cell lymphoma; Cell line; Non-Hodgkin's ID DNA-DAMAGE; MDM2; P53; MODELS; CANCER; DEGRADATION; CLEAVAGE; MASKING AB Canine and human lymphoma share similar characteristics in disease development and response to therapy. Translational research can be furthered using tools such as canine cell lines to model therapeutic compounds and strategies. We developed 5 B-cell lymphoma cell lines from dogs with confirmed large B-cell lymphoma. These cell lines were CD3, CD18, CD20, and CD90 positive with variable CD79a, CD1c and CD34 expression. All cell lines were tumorigenic in Nu/nu mice and were wild type for p53. Canine lymphoma cell lines serve as an important resource for translational lymphoma research. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Zwingenberger, Allison L.; Shi, Changying; Yan, Wensheng; Chen, Xinbin; Kent, Michael S.] Univ Calif Davis, Dept Surg & Radiol Sci, Sch Vet Med, Davis, CA 95616 USA. [Vernau, William] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Gordon, Ira K.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Zwingenberger, AL (reprint author), Univ Calif Davis, Dept Surg & Radiol Sci, Sch Vet Med, 1 Shields Ave, Davis, CA 95616 USA. EM azwingen@ucdavis.edu RI perumal, murugiah/D-1565-2012; OI /0000-0002-8982-2558 FU Toni Wiebe Memorial Research Fund; UCD Cancer Center [NIH CA093373] FX Toni Wiebe Memorial Research Fund and the UCD Cancer Center Core Support Grant NIH CA093373. The above sponsors had no involvement in study design, data collection, analysis, interpretation of data, writing of the manuscript, or the decision to submit the manuscript for publication. NR 23 TC 3 Z9 3 U1 0 U2 5 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 MAY PY 2012 VL 36 IS 5 BP 601 EP 606 DI 10.1016/j.leukres.2011.11.004 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 916QB UT WOS:000302117200024 PM 22136758 ER PT J AU Vosters, JL Roescher, N Illei, GG Chiorini, JA Tak, PP AF Vosters, J. L. Roescher, N. Illei, G. G. Chiorini, J. A. Tak, P. P. TI TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice SO ORAL DISEASES LA English DT Article DE TACI-Fc; gene therapy; salivary gland; non-obese diabetic mice; Sjogren's syndrome ID PRIMARY SJOGRENS-SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NECROSIS-FACTOR FAMILY; MEMORY B-CELLS; RHEUMATOID-ARTHRITIS; TNF RECEPTOR; AUTOANTIBODY PRODUCTION; CONTROLLED-TRIAL; IMAGE-ANALYSIS; MEMBERS APRIL AB OBJECTIVE: Patients with Sjogren's syndrome (SS) show aberrant expression of the B cell-related mediators, B cell-activating factor (BAFF), and a proliferationinducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. MATERIAL AND METHODS: A recombinant serotype 2 adeno-associated virus (rAAV2) encoding TACI-Fc was constructed, and its efficacy was tested in the SGs of nonobese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. RESULTS: AAV2-TACI-Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD(+) cells and CD138(+) cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2-TACIFc- treated mice. Salivary flow was unaffected. CONCLUSION: Although local expression of soluble TACI-Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI-Fc can provide a satisfying treatment for the clinical symptoms of patients. Oral Diseases (2012) 18, 365-374 C1 [Vosters, J. L.; Roescher, N.; Tak, P. P.] Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. [Vosters, J. L.; Roescher, N.; Illei, G. G.; Chiorini, J. A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Vosters, JL (reprint author), Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, F4-105,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM j.l.vosters@amc.uva.nl FU Dutch Arthritis Association [NR 07-1-406]; National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR) FX The authors thank the NIH Fellows Editorial Board for critical review of this manuscript and Scott A. Loiler (Arthrogen B. V., the Netherlands) for designing the primers for TACI-ED construction. This work is supported by a Dutch Arthritis Association grant [NR 07-1-406] to JLV and National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR) intramural research grant to JAC and NR. The authors declare no conflict of interest. NR 56 TC 11 Z9 12 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD MAY PY 2012 VL 18 IS 4 BP 365 EP 374 DI 10.1111/j.1601-0825.2011.01885.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 915DK UT WOS:000302003800006 PM 22212434 ER PT J AU Doroshow, JH Juhasz, A Ge, Y Holbeck, S Lu, JM Antony, S Wu, YZ Jiang, GJ Roy, K AF Doroshow, James H. Juhasz, Agnes Ge, Yun Holbeck, Susan Lu, Jiamo Antony, Smitha Wu, Yongzhong Jiang, Guojian Roy, Krishnendu TI Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Diphenylene iodonium; Dithienyliodonium; Reactive oxygen; Stat signaling; NADPH oxidase; NCI-60 tumor panel ID INTESTINAL EPITHELIAL-CELLS; ACTIVATED PROTEIN-KINASE; JAK-STAT PATHWAY; NADPH OXIDASE; CYCLE PROGRESSION; HYDROGEN-PEROXIDE; REDOX REGULATION; GENE-EXPRESSION; CANCER-CELLS; MUSCLE CELLS AB Flavoprotein-dependent reactive oxygen species (ROS) play a critical role in cytokine-mediated signal transduction in normal tissues and tumor cells. The flavoenzyme inhibitors diphenylene iodonium (DPI) and di-2-thienyliodonium (DTI) have been used to inhibit membrane-bound, flavoprotein-containing NADPH oxidases, including epithelial and leukocyte NADPH oxidases (Nox1-5 and Duox 1 and 2). Recent evidence suggests that DPI can decrease tumor cell proliferation; however, the molecular mechanisms involved remain poorly defined. To explore the mechanisms underlying DPI- and DTI-related tumor cell growth delay, we examined growth inhibition patterns produced by both agents in the NCI-60 tumor panel, and determined expression levels of Nox gene family members across these cell lines. Possible molecular targets were predicted using the COMPARE program. DPI was more potent than DTI (GI(50): 10 nM versus 10 mu M); DPI and DTI exposure produced unique patterns of growth inhibition when evaluated against the small molecule anticancer database of the National Cancer Institute. Growth inhibition profiling of DPI revealed a modest positive correlation with Nox1 levels; novel mechanisms of DPI and DTI action, including alterations in Stat, Erk1/2, and Akt pathways, were inferred by correlation with NCI-60 Affymetrix (R) array data. Exposure of HT-29 colon cancer cells, which express Nox1, to DPI and DTI confirmed their inhibitory effects on steady state ROS levels, and demonstrated decreased Stat, Erk1/2, and Akt signaling mediated by IL-4, IL-6, IL-13, and IL-22, possibly due to a concomitant increase in tumor cell phosphatase activity. These findings suggest that DPI and DTI may act therapeutically by altering ROS-related signal transduction. Published by Elsevier Inc. C1 [Doroshow, James H.; Holbeck, Susan; Roy, Krishnendu] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.; Juhasz, Agnes; Ge, Yun; Lu, Jiamo; Antony, Smitha; Wu, Yongzhong; Jiang, Guojian] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bldg 31,Room 3A-44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov; juhasza@mail.nih.gov; Yun.Ge@fda.hhs.gov; holbecks@mail.nih.gov; lujiamo@mail.nih.gov; antonys@mail.nih.gov; wuy@mail.nih.gov; gjiang@mail.nih.gov; royk@navmed.nci.nih.gov FU Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health FX This work was supported in whole or in part with federal funds from the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 51 TC 12 Z9 13 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2012 VL 83 IS 9 SI SI BP 1195 EP 1207 DI 10.1016/j.bcp.2012.01.022 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 913WA UT WOS:000301906900007 PM 22305747 ER PT J AU Lai, CY Tian, LL Schisterman, EF AF Lai, Chin-Ying Tian, Lili Schisterman, Enrique F. TI Exact confidence interval estimation for the Youden index and its corresponding optimal cut-point SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Confidence interval; ROC curve; Sensitivity and specificity; Youden index; Optimal cut-point; Generalized pivotal quantity ID GENERALIZED VARIABLE METHOD; NORMAL-POPULATIONS; ROC CURVES; CORRELATION-COEFFICIENT; PAIRED AREAS; INFERENCES AB In diagnostic studies, the receiver operating characteristic (ROC) curve and the area under the ROC curve are important tools in assessing the utility of biomarkers in discriminating between non-diseased and diseased populations. For classifying a patient into the non-diseased or diseased group, an optimal cut-point of a continuous biomarker is desirable. Youden's index (J), defined as the maximum vertical distance between the ROC curve and the diagonal line, serves as another global measure of overall diagnostic accuracy and can be used in choosing an optimal cut-point. The proposed approach is to make use of a generalized approach to estimate the confidence intervals of the Youden index and its corresponding optimal cut-point. Simulation results are provided for comparing the coverage probabilities of the confidence intervals based on the proposed method with those based on the large sample method and the parametric bootstrap method. Finally, the proposed method is illustrated via an application to a data set from a study on Duchenne muscular dystrophy (DMD). (C) 2010 Elsevier B.V. All rights reserved. C1 [Lai, Chin-Ying; Tian, Lili] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Schisterman, Enrique F.] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. RP Lai, CY (reprint author), SUNY Buffalo, Dept Biostat, 249 Farber Hall,3435 Main St,Bldg 26, Buffalo, NY 14214 USA. EM clai2@buffalo.edu OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [Z01 HD008761-05] NR 20 TC 17 Z9 17 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD MAY 1 PY 2012 VL 56 IS 5 SI SI BP 1103 EP 1114 DI 10.1016/j.csda.2010.11.023 PG 12 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 910ZW UT WOS:000301688100011 PM 27099407 ER PT J AU McCoy, MK Cookson, MR AF McCoy, Melissa K. Cookson, Mark R. TI Mitochondrial Quality Control and Dynamics in Parkinson's Disease SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID DROSOPHILA DJ-1 MUTANTS; DOMINANT OPTIC ATROPHY; INDUCED CELL-DEATH; DOPAMINERGIC-NEURONS; OXIDATIVE STRESS; ALPHA-SYNUCLEIN; PINK1/PARKIN-MEDIATED MITOPHAGY; SPORADIC PARKINSONS; MEDIATED AUTOPHAGY; RESPIRATORY-CHAIN AB Significance: Studies of sporadic cases, toxin models, and genetic causes of Parkinson's disease suggest that mitochondrial dysfunction may be an early feature of pathogenesis. Recent Advances: Compelling evidence of a causal relationship between mitochondrial function and disease was found with the identification of several genes for recessive parkinsonism, PINK1, DJ-1, and parkin. There is evidence that each of these regulates responses to cellular stresses, including oxidative stress and depolarization of the mitochondrial membrane. Specifically, PINK1 and parkin modulate mitochondrial dynamics by promoting autophagic removal of depolarized mitochondria. Mutations in all genes linked to Parkinson's disease lead to enhanced sensitivity to mitochondrial toxins and oxidative stress. Critical Issues: Both increased mitochondrial damage due to complex 1 inhibition, mishandling of calcium, oxidant stress, or impaired clearance of dysfunctional mitochondria would lead to the accumulation of nonfunctional organelles and could contribute to neuronal dysfunction. However, several unanswered questions remain about the underlying mechanism(s) involved. Future Directions: PINK1 and parkin have been demonstrated to regulate mitochondrial dynamics, but the pathways linking PINK1 activity to parkin function are still unclear and warrant further investigation. Antioxid. Redox Signal. 16, 869-882. C1 [McCoy, Melissa K.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 115 TC 36 Z9 36 U1 2 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD MAY PY 2012 VL 16 IS 9 BP 869 EP 882 DI 10.1089/ars.2011.4019 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 904VC UT WOS:000301225200002 PM 21568830 ER PT J AU Stewart, DR Pemov, A Van Loo, P Beert, E Brems, H Sciot, R Claes, K Pak, E Dutra, A Lee, CCR Legius, E AF Stewart, Douglas R. Pemov, Alexander Van Loo, Peter Beert, Eline Brems, Hilde Sciot, Raf Claes, Kathleen Pak, Evgenia Dutra, Amalia Lee, Chyi-Chia Richard Legius, Eric TI Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-associated glomus tumors SO GENES CHROMOSOMES & CANCER LA English DT Article ID NERVE SHEATH TUMORS; ISOCHROMOSOME 17Q; GENE; INSTABILITY; MECHANISMS; MUTATIONS; IDENTIFICATION; PATHOGENESIS; ANEUPLOIDY; LEUKEMIA AB Neurofibromatosis type 1 (NF1) is a common, autosomal dominant, tumor-predisposition syndrome that arises secondary to mutations in NF1. Glomus tumors are painful benign tumors that originate from the glomus body in the fingers and toes due to biallelic inactivation of NF1. We karyotyped cultures from four previously reported and one new glomus tumor and hybridized tumor (and matching germline) DNA on Illumina HumanOmni1-Quad SNP arrays (similar to 1 x 10(6) SNPs). Two tumors displayed evidence of copy-neutral loss of heterozygosity of chromosome arm 17q not observed in the germline sample, consistent with a mitotic recombination event. One of these two tumors, NF1-G12, featured extreme polyploidy (near-tetraploidy, near-hexaploidy, or near-septaploidy) across all chromosomes. In the remaining four tumors, there were few cytogenetic abnormalities observed, and copy-number analysis was consistent with diploidy in all chromosomes. This is the first study of glomus tumors cytogenetics, to our knowledge, and the first to report biallelic inactivation of NF1 secondary to mitotic recombination of chromosome arm 17q in multiple NF1-associated glomus tumors. We have observed mitotic recombination in 22% of molecularly characterized NF1-associated glomus tumors, suggesting that it is a not uncommon mechanism in the reduction to homozygosity of the NF1 germline mutation in these tumors. In tumor NF1-G12, we hypothesize that mitotic recombination also unmasked (reduced to homozygosity) a hypomorphic germline allele in a gene on chromosome arm 17q associated with chromosomal instability, resulting in the extreme polyploidy. (C) 2012 Wiley Periodicals, Inc. C1 [Stewart, Douglas R.; Pemov, Alexander] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Van Loo, Peter] Wellcome Trust Sanger Inst, Cambridge, England. [Van Loo, Peter] VIB, Dept Mol & Dev Genet, Louvain, Belgium. [Beert, Eline; Brems, Hilde; Legius, Eric] Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. [Sciot, Raf] Catholic Univ Louvain, Dept Pathol, B-3000 Louvain, Belgium. [Pak, Evgenia] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Pak, Evgenia; Dutra, Amalia] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Stewart, DR (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7022B, Rockville, MD 20852 USA. EM drstewart@mail.nih.gov RI Van Loo, Peter/A-3287-2012; Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Van Loo, Peter/0000-0003-0292-1949 FU Division of Intramural Research of the National Human Genome Research Institute (NHGRI); Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen [G.0578.06]; Cancer Foundation Stichting tegen Kanker [C.0011-204-208]; KULeuven [GOA/11/010]; Vlaamse Liga tegen Kanker FX Supported by: The Division of Intramural Research of the National Human Genome Research Institute (NHGRI), The Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute's Intramural Research Program, The National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E; Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen; Grant number: G.0578.06; The Cancer Foundation Stichting tegen Kanker; Grant number: C.0011-204-208; KULeuven; Grant number: GOA/11/010; "Vlaamse Liga tegen Kanker". NR 33 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 2012 VL 51 IS 5 BP 429 EP 437 DI 10.1002/gcc.21928 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 903LN UT WOS:000301118100002 PM 22250039 ER PT J AU Hirsch, D Camps, J Varma, S Kemmerling, R Stapleton, M Ried, T Gaiser, T AF Hirsch, Daniela Camps, Jordi Varma, Sudhir Kemmerling, Ralf Stapleton, Mark Ried, Thomas Gaiser, Timo TI A new whole genome amplification method for studying clonal evolution patterns in malignant colorectal polyps SO GENES CHROMOSOMES & CANCER LA English DT Article ID CHROMOSOMAL GAINS; CYTOGENETIC ANALYSIS; ARRAY CGH; HYBRIDIZATION; PROGRESSION; CANCER; TUMORS; DNA; CARCINOMA; ADENOMA AB To identify the genetic drivers of colorectal tumorigenesis, we applied array comparative genomic hybridization (aCGH) to 13 formalin-fixed paraffin-embedded (FFPE) samples of early, localized human colon adenocarcinomas arising in high-grade adenomas (so-called malignant polyps). These lesions are small and hence the amount of DNA is limited. Additionally, the quality of DNA is compromised due to the fragmentation as a consequence of formalin fixation. To overcome these problems, we optimized a newly developed isothermal whole genome amplification system (NuGEN Ovation (R) WGA FFPE System). Starting with 100 ng of FFPE DNA, the amplification system produced 4.01 +/- 0.29 mu g (mean +/- standard deviation) of DNA. The excellent quality of amplified DNA was further indicated by a high signal-to-noise ratio and a low derivative log2 ratio spread. Both, the amount of amplified DNA and aCGH performance were independent of the age of the FFPE blocks and the associated degradation of the extracted DNA. We observed losses of chromosome arms 5q and 18q in the adenoma components of the malignant polyp samples, while the embedded early carcinomas revealed losses of 8p, 17p, and 18, and gains of 7, 13, and 20. Aberrations detected in the adenoma components were invariably maintained in the embedded carcinomas. This approach demonstrates that using isothermally whole genome amplified FFPE DNA is technically suitable for aCGH. In addition to demonstrating the clonal origin of the adenoma and carcinoma part within a malignant polyp, the gain of chromosome arm 20q was an indicator for progression from adenoma to carcinoma. Published 2012 Wiley Periodicals, Inc. C1 [Hirsch, Daniela; Camps, Jordi; Ried, Thomas; Gaiser, Timo] NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] HiThru Analyt, Bethesda, MD USA. [Kemmerling, Ralf] Paracelsus Med Univ, Inst Pathol, Salzburg, Austria. [Stapleton, Mark] NuGEN Technol Inc, San Carlos, CA USA. RP Ried, T (reprint author), NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, Bldg 50,Room 1408,50 South Dr, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov; timo_gaiser@web.de RI perumal, murugiah/D-1565-2012; Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU National Institutes of Health, National Cancer Institute; German Academic Exchange Service; NuGEN FX Supported by: The Intramural Research Program of the National Institutes of Health, National Cancer Institute; RISE Program of the German Academic Exchange Service.; DH received travel sponsoring from NuGEN to the AACR Annual Meeting 2011. MS is employed by NuGEN, the manufacturer of the Ovation (R) VR WGA FFPE System. NR 30 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 2012 VL 51 IS 5 BP 490 EP 500 DI 10.1002/gcc.21937 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 903LN UT WOS:000301118100009 PM 22334367 ER PT J AU Taverna, S Flugy, A Saieva, L Kohn, EC Santoro, A Meraviglia, S De Leo, G Alessandro, R AF Taverna, Simona Flugy, Anna Saieva, Laura Kohn, Elise C. Santoro, Alessandra Meraviglia, Serena De Leo, Giacomo Alessandro, Riccardo TI Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE exosomes; chronic myelogenous leukemia cells; endothelial cells; tumor microenvironment ID CHRONIC MYELOID-LEUKEMIA; VASCULAR ENDOTHELIAL-CELLS; TUMOR-GROWTH; K562 CELLS; CANCER; MICROVESICLES; MECHANISMS; JUNCTIONS; INHIBITION; EXPRESSION AB Our study is designed to assess if exosomes released from chronic myelogenous leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion molecules was paralleled by a dose-dependent increase of adhesion of CML cells to a HUVEC monolayer. We further showed that the treatment with exosomes from CML cells caused an increase in endothelial cell motility accompanied by a loss of VE-cadherin and beta-catenin from the endothelial cell surface. Functional characterization of exosomes isolated from CML patients confirmed the data obtained with exosomes derived from CML cell line. CML exosomes caused reorganization into tubes of HUVEC cells cultured on Matrigel. When added to Matrigel plugs in vivo, exosomes induced ingrowth of murine endothelial cells and vascularization of the Matrigel plugs. Our results suggest for the first time that exosomes released from CML cells directly affect endothelial cells modulating the process of neovascularization. C1 [Taverna, Simona; Flugy, Anna; Saieva, Laura; Meraviglia, Serena; De Leo, Giacomo; Alessandro, Riccardo] Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, Sez Biol & Genet, I-90133 Palermo, Italy. [Kohn, Elise C.] NCI, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Santoro, Alessandra] Osped Riuniti Villa Sofia Cervello, Lab Diagnost Integrata Oncoematol, Palermo, Italy. RP Alessandro, R (reprint author), Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, Sez Biol & Genet, Via Divisi 83, I-90133 Palermo, Italy. EM ricale@unipa.it FU Italian Association for Cancer Research (AIRC); University of Palermo; MURST; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Grant sponsors: Italian Association for Cancer Research (AIRC), University of Palermo (International Cooperation), ex 60% MURST, Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health NR 47 TC 46 Z9 50 U1 3 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2012 VL 130 IS 9 BP 2033 EP 2043 DI 10.1002/ijc.26217 PG 11 WC Oncology SC Oncology GA 897XB UT WOS:000300693100007 PM 21630268 ER PT J AU Liang, XS Pfeiffer, RM Wheeler, W Maeder, D Burdette, L Yeager, M Chanock, S Tucker, MA Goldstein, AM Yang, XHR AF Liang, Xueying Sharon Pfeiffer, Ruth M. Wheeler, William Maeder, Dennis Burdette, Laurie Yeager, Meredith Chanock, Stephen Tucker, Margaret A. Goldstein, Alisa M. Yang, Xiaohong R. TI Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; cancer; genetics; DNA repair; association; pathway; CMM; family ID ASSOCIATION; CANCER; DAMAGE AB Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 similar to 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations. C1 [Liang, Xueying Sharon; Pfeiffer, Ruth M.; Tucker, Margaret A.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Maeder, Dennis; Burdette, Laurie; Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Yang, XHR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM royang@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU NIH, NCI, DCEG FX We are indebted to the participating families, whose generosity and cooperation have made our study possible. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, and Mary Fraser. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG. NR 16 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2012 VL 130 IS 9 BP 2062 EP 2066 DI 10.1002/ijc.26231 PG 5 WC Oncology SC Oncology GA 897XB UT WOS:000300693100010 PM 21671477 ER PT J AU Gage, JC Ajenifuja, KO Wentzensen, NA Adepiti, AC Eklund, C Reilly, M Hutchinson, M Wacholder, S Harford, J Soliman, AS Burk, RD Schiffman, M AF Gage, Julia C. Ajenifuja, Kayode O. Wentzensen, Nicolas A. Adepiti, Akinfolarin C. Eklund, Claire Reilly, Mary Hutchinson, Martha Wacholder, Sholom Harford, Joe Soliman, Amr S. Burk, Robert D. Schiffman, Mark TI The age-specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: Implications for screen-and-treat strategies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV prevalence; age; screening ID CERVICAL INTRAEPITHELIAL NEOPLASIA; INTERNATIONAL INCIDENCE RATES; GENOTYPE DISTRIBUTION; INFECTION; CANCER; WOMEN; CRYOTHERAPY; WORLDWIDE; LESIONS; COHORT AB Cervical screening for carcinogenic human papillomavirus (HPV) infection is being considered for low-income countries. Effectiveness requires targeted screening in older women in whom prevalent infections are more likely to be persistent and predictive of precancer. Some studies in West Africa have found unusually high HPV prevalences across all adult ages, which may reduce the positive predictive value (PPV) of HPV-based screening, if positivity in older women does not sufficiently predict elevated risk. We conducted a population-based study in rural Nigeria to identify HPV prevalence and associated cervical abnormalities. Using stratified random sampling, we enrolled women age 15+. Nonvirgins had a cervical exam including liquid-based cytology and PCR HPV DNA testing from residual cytology specimens. Two-thirds of invited women participated, and 14.7% had detectable carcinogenic HPV, a proportion that did not decline with age (p-trend = 0.36) and showed slight peaks in the 1529 and 6069 age groups. Among women of the age typically considered for screen-and-treat programs (3049 years), 12.8% were HPV positive, and the PPV for high-grade or worse cytology was 16.4%. Comparatively, women age < 30 were more likely to be HPV positive (18.9%, p = 0.03) with a lower PPV (4.2% p = 0.05). Among women age 50+ (typically excluded from screening in resource-poor settings because inexpensive treatment is not available), HPV positivity was 14.2% with a PPV of 13.9%. In Irun and similar settings where HPV does not decline with age, HPV-based screen-and-treat programs might be feasible for mid-adult women because prevalence is sufficiently low and positivity predicts elevated risk of more easily treated precancer. C1 [Gage, Julia C.] NCI, Clin Genet Branch, DCEG, NIH,DHHS, Rockville, MD 20852 USA. [Ajenifuja, Kayode O.; Adepiti, Akinfolarin C.] Obafemi Awolowo Univ, Dept Obstet Gynaecol & Perinatol, Ife, Nigeria. [Eklund, Claire; Reilly, Mary; Hutchinson, Martha] Brown Univ, Women & Infants Hosp, Dept Pathol & Lab Med, Providence, RI USA. [Harford, Joe] NCI, Off Int Affairs, NIH, DHHS, Rockville, MD 20852 USA. [Soliman, Amr S.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Pediat, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Gage, JC (reprint author), NCI, Clin Genet Branch, DCEG, NIH,DHHS, 6120 Execut Blvd,MSC 7231, Rockville, MD 20852 USA. EM gagej@mail.nih.gov RI perumal, murugiah/D-1565-2012 FU National Cancer Institute [CA78527]; Einstein-Montefiore Center for AIDS from the National Institutes of Health [AI-51519]; Einstein Cancer Research Center from the National Cancer Institute [P30CA013330]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services; NIH [HHSN261200900303P] FX Grant sponsor: National Cancer Institute; Grant number: CA78527; Grant sponsor: Einstein-Montefiore Center for AIDS from the National Institutes of Health; Grant number: AI-51519; Grant sponsor: Einstein Cancer Research Center from the National Cancer Institute; Grant number: P30CA013330; This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services and NIH contract #HHSN261200900303P. The careHPV equipment and supplies used in our study were donated by Qiagen Corporation (Gaithersburg, MD); careHPV is not the subject of our report. NR 29 TC 20 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2012 VL 130 IS 9 BP 2111 EP 2117 DI 10.1002/ijc.26211 PG 7 WC Oncology SC Oncology GA 897XB UT WOS:000300693100016 PM 21630264 ER PT J AU Kolb, EA Gorlick, R Maris, JM Keir, ST Morton, CL Wu, JR Wozniak, AW Smith, MA Houghton, PJ AF Kolb, E. Anders Gorlick, Richard Maris, John M. Keir, Stephen T. Morton, Christopher L. Wu, Jianrong Wozniak, Amy W. Smith, Malcolm A. Houghton, Peter J. TI Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; IMC-A12; preclinical testing; rapamycin ID GROWTH-FACTOR-II; RENAL-CELL CARCINOMA; HUMAN NEUROBLASTOMA; AUTOCRINE GROWTH; TUMOR XENOGRAFTS; CANCER MODELS; IN-VIVO; RHABDOMYOSARCOMA; CHEMOTHERAPY; TEMSIROLIMUS AB Background IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. Procedures. IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement'' measure, and (2) a linear regression model for time-to-event to formally evaluate for sub-and supra-additivity for the combination compared to the agents used alone. Results. Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. Conclusions. The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective. Pediatr Blood Cancer 2012;58:729-735. (C) 2011 Wiley Periodicals, Inc. C1 [Kolb, E. Anders] Alfred I DuPont Hosp Children, Nemours Ctr Childhood Canc Res, Wilmington, DE 19803 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Morton, Christopher L.; Wu, Jianrong; Wozniak, Amy W.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Kolb, EA (reprint author), Alfred I DuPont Hosp Children, Nemours Ctr Childhood Canc Res, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM eakolb@nemours.org RI Houghton, Peter/E-3265-2011 FU National Cancer Institute [NO1-CM-42216, NO1-CM91001-03, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, NO1-CM91001-03, CA21765, CA108786. NR 31 TC 25 Z9 26 U1 0 U2 5 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 MAY PY 2012 VL 58 IS 5 BP 729 EP 735 DI 10.1002/pbc.23157 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 901RM UT WOS:000300984500012 PM 21630428 ER PT J AU Kolb, EA Gorlick, R Keir, ST Maris, JM Lock, R Carol, H Kurmasheva, RT Reynolds, CP Kang, MH Wu, JR Houghton, PJ Smith, MA AF Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Maris, John M. Lock, Richard Carol, Hernan Kurmasheva, Raushan T. Reynolds, C. Patrick Kang, Min H. Wu, Jianrong Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a ?-secretase inhibitor targeting notch signaling SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; Notch; preclinical testing ID DIFFERENTIATION; LEUKEMIA; MODELS AB RO4929097 is a potent and selective inhibitor of ?-secretase and as a result is able to inhibit Notch pathway signaling. The activity of RO4929097 was evaluated against the in vivo panels of the Pediatric Preclinical Testing Program (PPTP). RO4929097 induced significant differences in event-free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The most consistent tumor growth delay effects were noted in the osteosarcoma panel. RO4929097 at the dose and schedule evaluated demonstrated little antitumor activity against childhood cancer xenografts. Pediatr Blood Cancer 2012; 58: 815818. (C) 2011 Wiley Periodicals, Inc. C1 [Kolb, E. Anders] Alfred I DuPont Hosp Children, Dept Oncol, Wilmington, DE 19803 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [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. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Wu, Jianrong] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kolb, EA (reprint author), Alfred I DuPont Hosp Children, Dept Oncol, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM eakolb@nemours.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013 OI Carol, Hernan/0000-0002-9443-8032; FU National Cancer Institute [NO1-CM-42216, CA21765, CA16058, CA108786] FX This work was supported by NO1-CM-42216, CA21765, CA16058, and CA108786 from the National Cancer Institute and used RO4929097 supplied by Roche Pharmaceuticals, Inc. In addition to the authors this article represents work contributed by the following: Sherry Ansher, Catherine A. Billups, Joshua Courtright, Edward Favours, Henry S. Friedman, Danuta Gasinski, Melissa Sammons, Chandra Tucker, Jianrong Wu, Joe Zeidner, Ellen Zhang, and Jian Zhang. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. NR 18 TC 12 Z9 13 U1 0 U2 3 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAY PY 2012 VL 58 IS 5 BP 815 EP 818 DI 10.1002/pbc.23290 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 901RM UT WOS:000300984500027 PM 22052798 ER PT J AU Lim, C Sen, PK Peddada, SD AF Lim, Changwon Sen, Pranab K. Peddada, Shyamal D. TI Accounting for uncertainty in heteroscedasticity in nonlinear regression SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Asymptotic normality; Dose-response study; Heteroscedasticity; Hill model; M-estimation procedure; Preliminary test estimation; Toxicology ID PARTIALLY LINEAR-MODELS; VARIANCE FUNCTION; LIKELIHOOD; ESTIMATORS; SHRINKAGE; INFERENCE; ERRORS AB Toxicologists and pharmacologists often describe toxicity of a chemical using parameters of a nonlinear regression model. Thus estimation of parameters of a nonlinear regression model is an important problem. The estimates of the parameters and their uncertainty estimates depend upon the underlying error variance structure in the model. Typically, a priori the researcher would not know if the error variances are homoscedastic (i.e., constant across dose) or if they are heteroscedastic (i.e., the variance is a function of dose). Motivated by this concern, in this paper we introduce an estimation procedure based on preliminary test which selects an appropriate estimation procedure accounting for the underlying error variance structure. Since outliers and influential observations are common in toxicological data, the proposed methodology uses M-estimators. The asymptotic properties of the preliminary test estimator are investigated: in particular its asymptotic covariance matrix is derived. The performance of the proposed estimator is compared with several standard estimators using simulation studies. The proposed methodology is also illustrated using a data set obtained from the National Toxicology Program. Published by Elsevier B.V. C1 [Lim, Changwon; Peddada, Shyamal D.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Sen, Pranab K.] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Sen, Pranab K.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Peddada, SD (reprint author), NIEHS, Biostat Branch, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX This research was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04]. We thank Drs. Gregg Dinse and Paramita Saha as well as the editors and the referees for many important comments which helped to improve the presentation of the manuscript. NR 27 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD MAY PY 2012 VL 142 IS 5 BP 1047 EP 1062 DI 10.1016/j.jspi.2011.11.003 PG 16 WC Statistics & Probability SC Mathematics GA 896DW UT WOS:000300546600003 PM 22345900 ER PT J AU Klauzinska, M Baljinnyam, B Raafat, A Rodriguez-Canales, J Strizzi, L Greer, YE Rubin, JS Callahan, R AF Klauzinska, Malgorzata Baljinnyam, Bolormaa Raafat, Ahmed Rodriguez-Canales, Jaime Strizzi, Luigi Greer, Yoshimi Endo Rubin, Jeffrey S. Callahan, Robert TI Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID BETA-CATENIN; TRANSGENIC MICE; WNT PATHWAY; GENE-EXPRESSION; FAMILY-MEMBERS; TUMOR VIRUS; ACTIVATION; GLAND; LRP6; CARCINOGENESIS AB Rspo2 was identified as a novel common integration site (CIS) for the mouse mammary tumor virus (MMTV) in viral induced mouse mammary tumors. Here we show that Rspo2 modulates Wnt signaling in mouse mammary epithelial cells. Co-expression of both genes resulted in an intermediate growth phenotype on plastic and had minor effects on the growth-promoting properties of Wnt1 in soft agar. However, individual Rspo2 and Wnt1 HC11 transfectants as well as the double transfectant were tumorigenic in athymic nude mice, with tumors from each line having distinctive histological characteristics. Rspo2 and Rspo2/Wnt1 tumors contained many spindle cells, consistent with an epithelialmesenchymal transformation (EMT) phenotype. When Rspo2 and Rspo2/Wnt1 tumor cells were transferred into naive mice, they exhibited greater metastatic activity than cells derived from Wnt1 tumors. For comparison, C57MG/Wnt1/Rspo2 co-transfectants exhibited invasive properties in three-dimensional (3D) Matrigel cultures that were not seen with cells transfected only with Wnt1 or Rspo2. Use of Dickkopf-1, a specific antagonist of the Wnt/beta-catenin pathway, or short hairpin RNA targeting beta-catenin expression demonstrated that the invasive activity was not mediated by beta-catenin. Our results indicate that Rspo2 and Wnt1 have mutually distinct effects on mammary epithelial cell growth and these effects are context-dependent. While Rspo2 and Wnt1 act synergistically in the beta-catenin pathway, other mechanisms are responsible for the invasive properties of stable double transfectants observed in 3D Matrigel cultures. J. Cell. Physiol. 227: 1960-1971, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Callahan, Robert] NCI, Oncogenet Sect, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. [Baljinnyam, Bolormaa; Greer, Yoshimi Endo; Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Rodriguez-Canales, Jaime] NCI, Laser Microdissect Core, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Strizzi, Luigi] Northwestern Univ, Childrens Mem Res Ctr, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. RP Callahan, R (reprint author), NCI, Oncogenet Sect, Mammary Biol & Tumorigenesis Lab, NIH, 37 Convent Dr,Bldg 37,Rm 1118A, Bethesda, MD 20892 USA. EM rc54d@nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU NIH; National Cancer Institute; Center for Cancer Research FX Contract grant sponsor: NIH.; Contract grant sponsor: National Cancer Institute.; Contract grant sponsor: Center for Cancer Research. NR 38 TC 13 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD MAY PY 2012 VL 227 IS 5 BP 1960 EP 1971 DI 10.1002/jcp.22924 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 879ZS UT WOS:000299373900020 PM 21732367 ER PT J AU Robinette, SL Holmes, E Nicholson, JK Dumas, ME AF Robinette, Steven L. Holmes, Elaine Nicholson, Jeremy K. Dumas, Marc E. TI Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations SO GENOME MEDICINE LA English DT Review DE Metabonomics/metabolomics; Quantitative Trait Locus Mapping; Biochemical Genetics; NMR; MS ID QUANTITATIVE TRAIT LOCUS; MAGNETIC-RESONANCE-SPECTROSCOPY; TANDEM MASS-SPECTROMETRY; SERUM LEPTIN LEVELS; SYSTEMS BIOLOGY; INBORN-ERRORS; NMR-SPECTROSCOPY; H-1-NMR SPECTROSCOPY; SUSCEPTIBILITY LOCUS; PROFILING PROCEDURES AB Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed. C1 [Robinette, Steven L.; Holmes, Elaine; Nicholson, Jeremy K.; Dumas, Marc E.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Surg & Canc, London SW7 2AZ, England. [Robinette, Steven L.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nicholson, JK (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Surg & Canc, Sir Alexander Fleming Bldg,Exhibit Rd, London SW7 2AZ, England. EM j.nicholson@imperial.ac.uk; m.dumas@imperial.ac.uk RI Dumas, Marc/C-1736-2008; Nicholson, Jeremy/B-3395-2012 OI Dumas, Marc/0000-0001-9523-7024; Nicholson, Jeremy/0000-0002-8123-8349 FU NSF; Marshall Aid Commemoration Commission; Nestle [RDLS015375]; Agence Nationale de la Recherche [ANR-08-GENO-030-02]; EU-FP7 EURATRANS [HEALTH-F4-2010-241504] FX SLR acknowledges support from the NSF Graduate Research Fellowship Program and from the Marshall Aid Commemoration Commission. M-ED is funded by Nestle (RDLS015375), Agence Nationale de la Recherche (ANR-08-GENO-030-02), and EU-FP7 EURATRANS (HEALTH-F4-2010-241504). NR 104 TC 16 Z9 16 U1 2 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD APR 30 PY 2012 VL 4 AR 30 DI 10.1186/gm329 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 084WA UT WOS:000314569200001 PM 22546284 ER PT J AU Xu, X Veenstra, TD AF Xu, Xia Veenstra, Timothy D. TI Concentration of endogenous estrogens and estrogen metabolites in the NCI-60 human tumor cell lines SO GENOME MEDICINE LA English DT Article ID HUMAN-MELANOMA CELLS; PROGESTERONE-RECEPTORS; REPLACEMENT THERAPY; CUTANEOUS MELANOMA; LUNG-CARCINOMA; BINDING-SITES; CANCER; AROMATASE; ESTRADIOL; BREAST AB Background: Endogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers. Methods: In this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been previously utilized for biological fluids such as serum and urine. Results: Endogenous estrogens and estrogen metabolites were found in all NCI-60 human tumor cell lines and some were substantially elevated and exceeded the levels found in well known estrogen-dependent and estrogen receptor-positive tumor cells such as MCF-7 and T-47D. While estrogens were expected to be present at high levels in cell lines representing the female reproductive system (that is, breast and ovarian), other cell lines, such as leukemia and colon, also contained very high levels of these steroid hormones. The leukemia cell line RMPI-8226 contained the highest levels of estrone (182.06 pg/10(6) cells) and 17 beta-estradiol (753.45 pg/10(6) cells). In comparison, the ovarian cancer cell line with the highest levels of these estrogens contained only 19.79 and 139.32 pg/10(6) cells of estrone and 17 beta-estradiol, respectively. The highest levels of estrone and 17 beta-estradiol in breast cancer cell lines were only 8.45 and 87.37 pg/10(6) cells in BT-549 and T-47D cells, respectively. Conclusions: The data provided evidence for the presence of significant amounts of endogenous estrogens and estrogen metabolites in cell lines not commonly associated with these steroid hormones. This broad discovery of endogenous estrogens and estrogen metabolites in these cell lines suggest that several human tumors may be beneficially treated using endocrine therapy aimed at estrogen biosynthesis and estrogen-related signaling pathways. C1 [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. EM veenstrat@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] 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 N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 35 TC 7 Z9 7 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD APR 30 PY 2012 VL 4 AR 31 DI 10.1186/gm330 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 084WA UT WOS:000314569200002 PM 22546321 ER PT J AU Soula, HA Coulon, A Beslon, G AF Soula, Hedi A. Coulon, Antoine Beslon, Guillaume TI Membrane microdomains emergence through non-homogeneous diffusion SO BMC BIOPHYSICS LA English DT Article DE Membrane domains; Non-homogeneous diffusion; Individual-based model ID SINGLE-PARTICLE TRACKING; PLASMA-MEMBRANE; LIPID RAFTS; MONTE-CARLO; CELL-MEMBRANES; CHOLESTEROL DEPLETION; ANOMALOUS DIFFUSION; LATERAL DIFFUSION; MODEL MEMBRANES; PROTEIN DIFFUSION AB Background: In the classical view, cell membrane proteins undergo isotropic random motion, that is a 2D Brownian diffusion that should result in an homogeneous distribution of concentration. It is, however, far from the reality: Membrane proteins can assemble into so-called microdomains (sometimes called lipid rafts) which also display a specific lipid composition. We propose a simple mechanism that is able to explain the colocalization of protein and lipid rafts. Results: Using very simple mathematical models and particle simulations, we show that a variation of membrane viscosity directly leads to variation of the local concentration of diffusive particles. Since specific lipid phases in the membrane can account for diffusion variation, we show that, in such a situation, the freely diffusing proteins (or any other component) still undergo a Brownian motion but concentrate in areas of lower diffusion. The amount of this so-called overconcentration at equilibrium issimply related to the ratio of diffusion coefficients between zones of high and low diffusion. Expanding the model to include particle interaction, we show that inhomogeneous diffusion can impact particles clusterization as well. The clusters of particles were more numerous and appear for a lower value of interaction strength in the zones of low diffusion compared to zones of high diffusion. Conclusion: Provided we assume stable viscosity heterogeneity in the membrane, our model propose a simple mechanism to explain particle concentration heterogeneity. It has also a non-trivial impact on density of particles when interaction is added. This could potentially have an impact on membrane chemical reactions and oligomerization. C1 [Soula, Hedi A.] Univ Lyon, INSERM, UMR1060, F-69621 Villeurbanne, France. [Beslon, Guillaume] Univ Lyon, CNRS INSA Lyon, LIRIS UMR5205, F-69621 Villeurbanne, France. [Soula, Hedi A.; Beslon, Guillaume] INRIA, EPI BEAGLE, F-69603 Paris, France. [Coulon, Antoine] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Soula, HA (reprint author), Univ Lyon, INSERM, UMR1060, F-69621 Villeurbanne, France. EM hedi.soula@insa-lyon.fr RI Beslon, Guillaume/D-7369-2014; Coulon, Antoine/A-9006-2012 FU Institut of Complex System of Rhones-Alphes (IXXI) FX This work has been partly supported by the Institut of Complex System of Rhones-Alphes (IXXI). NR 60 TC 6 Z9 6 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2046-1682 J9 BMC BIOPHYS JI BMC Biophys. PD APR 30 PY 2012 VL 5 AR 6 DI 10.1186/2046-1682-5-6 PG 12 WC Biophysics SC Biophysics GA 059NR UT WOS:000312712700001 PM 22546236 ER PT J AU Grewal, J Wernicke, M Zhang, J AF Grewal, Jagteshwar Wernicke, Meghan Zhang, Jun TI Early childhood development when second-trimester ultrasound dating disagrees with last menstrual period: a prospective cohort study SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Gestational age discrepancy; Childhood development; Cognitive functioning; LMP ID FOR-GESTATIONAL-AGE; INTRAUTERINE GROWTH-RETARDATION; BIPARIETAL DIAMETER; INCREASED RISK; PRETERM BIRTH; INFANTS; CHILDREN; PREGNANCY; TERM; DISCREPANCY AB Background: When an ultrasound-based estimate of gestational age (GA) is less (greater) than an estimate based on a definite last menstrual period, the fetus may grow slower (faster) than average. While the association between these discrepancies in GA estimates and adverse perinatal outcomes has been examined extensively, there is scant evidence about long-term effects, such as child neurodevelopment. Methods: Using data from a prospective cohort study titled, NICHD Study of Successive Small-for-Gestational Age Births, we examined if GA discrepancies in early second trimester of pregnancy (17 weeks' gestation) are associated with: (1) impaired motor and mental function at 13 months (measured using Bayley Scales of Infant Development (Bayley)), and (2) impaired cognitive development at five years (assessed by Wechsler Preschool and Primary Scale of Intelligence - Revised Intelligence Quotient (WPPSI-R)) in the infant. The study population consisted of 572 (30% of the overall sample of 1,945) women who presented for prenatal care in Norway and Sweden between 1986 and 1988. Results: Our results showed that GA discrepancies in early second trimester are significantly associated with birthweight. We found no significant relationship, however, with the Bayley development scores at 13 months and with the WPPSI-R IQ measures at five years. Conclusions: GA discrepancies at 17 weeks' gestation are not associated child neurodevelopment. These discrepancies do, however, relate to birthweights, providing a basis for detecting fetal growth patterns early in the second trimester of pregnancy. Our study, however, was unable to evaluate the impact of first-trimester discrepancies on impaired neurodevelopment in the infant. C1 [Grewal, Jagteshwar; Wernicke, Meghan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, MOE & Shanghai Key Lab Childrens Environm Hlth, Shanghai 200092, Peoples R China. RP Grewal, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Executive Blvd,Room 7B03G, Rockville, MD 20852 USA. EM grewalja@mail.nih.gov OI Grewal, Jagteshwar/0000-0002-0141-4876 FU Intramural Research Program of the 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 30 TC 0 Z9 0 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD APR 30 PY 2012 VL 12 AR 32 DI 10.1186/1471-2393-12-32 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 038ZG UT WOS:000311212000001 PM 22545943 ER PT J AU Sraj, I Szatmary, AC Desai, SA Marr, DWM Eggleton, CD AF Sraj, Ihab Szatmary, Alex C. Desai, Sanjay A. Marr, David W. M. Eggleton, Charles D. TI Erythrocyte deformation in high-throughput optical stretchers SO PHYSICAL REVIEW E LA English DT Article ID PLASMODIUM-FALCIPARUM; BLOOD-CELLS; RHEOLOGIC PROPERTIES; LASER TRAP; SHEAR-FLOW; DEFORMABILITY; AGGREGATION; SIMULATION; MEMBRANES; TWEEZERS AB Optical stretchers can be used to quantify elastic and homeostatic properties of cells. Because they can apply forces to cells without requiring direct contact, they may noninvasively measure mechanical properties related to cell and membrane health. Present-day optical stretchers are, however, limited to measurements on individual stationary cells, limiting throughput. To overcome this limitation and allow study of variations in cell populations, we recently developed and tested a microfluidic chamber that measures optical stretching parameters for erythrocytes under dynamic flowing conditions. The method uses a single linear diode laser bar and permitted measurements at low flow rates and higher throughput. Here, we numerically investigate the feasibility of further increasing the measurement rates of the optical stretcher in parameter domains where hydrodynamic and optical forces are of comparable magnitude. To do this we couple a recently implemented dynamic optical ray-tracing technique with a fluid-structure interaction solver to simulate the deformation of osmotically swollen erythrocytes in fluid flow of variable rate. Our results demonstrate that a detectable steady-state stretch is induced at nominal optical powers and flow rates. In addition, we find that flow rates can be increased significantly with no major effect on net cell stretch showing the feasibility of application of this technique at greatly increased throughputs. C1 [Sraj, Ihab; Szatmary, Alex C.; Eggleton, Charles D.] Univ Maryland Baltimore Cty, Dept Mech Engn, Baltimore, MD 21250 USA. [Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Marr, David W. M.] Colorado Sch Mines, Dept Chem & Biol Engn, Golden, CO 80401 USA. RP Eggleton, CD (reprint author), Univ Maryland Baltimore Cty, Dept Mech Engn, Baltimore, MD 21250 USA. EM eggleton@umbc.edu RI Szatmary, Alex/K-1971-2012; OI Szatmary, Alex/0000-0002-2986-5281; Sraj, Ihab/0000-0002-6158-472X FU National Institutes of Health [R01 AI079347-01] FX This research was funded by the National Institutes of Health Grant No. R01 AI079347-01. We thank the Pittsburgh Supercomputing Center for computational resources under DAC allocation MCB090098. NR 45 TC 10 Z9 10 U1 3 U2 23 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD APR 30 PY 2012 VL 85 IS 4 AR 041923 DI 10.1103/PhysRevE.85.041923 PN 1 PG 9 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 967IF UT WOS:000305899700003 PM 22680514 ER PT J AU Kim, SH Xiao, S Shive, H Collins, PL Samal, SK AF Kim, Shin-Hee Xiao, Sa Shive, Heather Collins, Peter L. Samal, Siba K. TI Replication, Neurotropism, and Pathogenicity of Avian Paramyxovirus Serotypes 1-9 in Chickens and Ducks SO PLOS ONE LA English DT Article ID NEWCASTLE-DISEASE VIRUS; COMPLETE GENOME SEQUENCE; HEMAGGLUTININ-NEURAMINIDASE PROTEINS; FUSION PROTEIN; PROTECTIVE IMMUNITY; CLEAVAGE SITE; YUCAIPA; TURKEYS; INFECTION; VIRULENCE AB Avian paramyxovirus (APMV) serotypes 1-9 have been isolated from many different avian species. APMV-1 (Newcastle disease virus) is the only well-characterized serotype, because of the high morbidity, mortality, and economic loss caused by highly virulent strains. Very little is known about the pathogenesis, replication, virulence, and tropism of the other APMV serotypes. Here, this was evaluated for prototypes strains of APMV serotypes 2-9 in cell culture and in chickens and ducks. In cell culture, only APMV-1, -3 and -5 induced syncytium formation. In chicken DF1 cells, APMV-3 replicated with an efficiency approaching that of APMV-1, while APMV-2 and -5 replicated to lower, intermediate titers and the others were much lower. Mean death time (MDT) assay in chicken eggs and intracerebral pathogenicity index (ICPI) test in 1-day-old SPF chicks demonstrated that APMV types 2-9 were avirulent. Evaluation of replication in primary neuronal cells in vitro as well as in the brains of 1-day-old chicks showed that, among types 2-9, only APMV-3 was neurotropic, although this virus was not neurovirulent. Following intranasal infection of 1-day-old and 2-week-old chickens, replication of APMV types 2-9 was mostly restricted to the respiratory tract, although APMV-3 was neuroinvasive and neurotropic (but not neurovirulent) and also was found in the spleen. Experimental intranasal infection of 3-week-old mallard ducks with the APMVs did not produce any clinical signs (even for APMV-1) and exhibited restricted viral replication of the APMVs (including APMV-1) to the upper respiratory tract regardless of their isolation source, indicating avirulence of APMV types 1-9 in mallard ducks. The link between the presence of a furin cleavage site in the F protein, syncytium formation, systemic spread, and virulence that has been well-established with APMV-1 pathotypes was not evident with the other APMV serotypes. C1 [Kim, Shin-Hee; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Shive, Heather] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Kim, SH (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU National Institute of Allergy and Infection Diseases (NIAID) [N01A060009]; NIAID, National Institutes of Health Intramural Research Program FX This research was supported by National Institute of Allergy and Infection Diseases (NIAID) contract no N01A060009 (85% support) and NIAID, National Institutes of Health Intramural Research Program (15% support). The views expressed herein 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 United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 17 Z9 17 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 APR 30 PY 2012 VL 7 IS 4 AR e34927 DI 10.1371/journal.pone.0034927 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UL UT WOS:000305340200007 PM 22558104 ER PT J AU Lea, WA Simeonov, A AF Lea, Wendy A. Simeonov, Anton TI Differential Scanning Fluorometry Signatures as Indicators of Enzyme Inhibitor Mode of Action: Case Study of Glutathione S-Transferase SO PLOS ONE LA English DT Article ID PROMOTE PROTEIN STABILITY; ELECTROPHILE BINDING-SITE; THERMAL SHIFT ASSAYS; PI CLASS GLUTATHIONE; SCHISTOSOMA-JAPONICUM; ETHACRYNIC-ACID; CONFORMATIONAL STABILITY; 3-DIMENSIONAL STRUCTURE; SCREENING METHODS; DRUG DISCOVERY AB Differential scanning fluorometry (DSF), also referred to as fluorescence thermal shift, is emerging as a convenient method to evaluate the stabilizing effect of small molecules on proteins of interest. However, its use in the mechanism of action studies has received far less attention. Herein, the ability of DSF to report on inhibitor mode of action was evaluated using glutathione S-transferase (GST) as a model enzyme that utilizes two distinct substrates and is known to be subject to a range of inhibition modes. Detailed investigation of the propensity of small molecule inhibitors to protect GST from thermal denaturation revealed that compounds with different inhibition modes displayed distinct thermal shift signatures when tested in the presence or absence of the enzyme's native co-substrate glutathione (GSH). Glutathione-competitive inhibitors produced dose-dependent thermal shift trendlines that converged at high compound concentrations. Inhibitors acting via the formation of glutathione conjugates induced a very pronounced stabilizing effect toward the protein only when GSH was present. Lastly, compounds known to act as noncompetitive inhibitors exhibited parallel concentration-dependent trends. Similar effects were observed with human GST isozymes A1-1 and M1-1. The results illustrate the potential of DSF as a tool to differentiate diverse classes of inhibitors based on simple analysis of co-substrate dependency of protein stabilization. C1 [Lea, Wendy A.; Simeonov, Anton] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Lea, WA (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov FU Molecular Libraries of Initiative of the NIH Roadmap for Medical Research; Intramural Research Program of the NHGRI, NIH FX Funding by the Molecular Libraries of Initiative of the NIH Roadmap for Medical Research, and the Intramural Research Program of the NHGRI, NIH, is hereby gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 11 Z9 11 U1 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 APR 30 PY 2012 VL 7 IS 4 AR e36219 DI 10.1371/journal.pone.0036219 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UL UT WOS:000305340200051 PM 22558390 ER PT J AU Piskulic, D Addington, J Cadenhead, KS Cannon, TD Cornblatt, BA Heinssen, R Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW McGlashan, TH AF Piskulic, Danijela Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Heinssen, Robert Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. McGlashan, Thomas H. TI Negative symptoms in individuals at clinical high risk of psychosis SO PSYCHIATRY RESEARCH LA English DT Article DE Psychosis prodrome; Negative symptoms; Conversion to psychosis; Longitudinal study; NAPLS1 project ID EPISODE PSYCHOSIS; MENTAL STATES; SCHIZOPHRENIA; SCALE; PREDICTION; TRANSITION; PRODROME AB Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n = 138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate, and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent overtime in those who converted to psychosis, significantly predicting the likelihood of conversion. Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Piskulic, Danijela] Univ Calgary, Mental Hlth Ctr Res & Educ, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychol & Psychiat & Biobehav Sci, Los Angeles, CA USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Heinssen, Robert] NIMH, Schizophrenia Spectrum Disorders Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Tsuang, Ming T.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Woods, Scott W.; McGlashan, Thomas H.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. RP Piskulic, D (reprint author), Univ Calgary, Mental Hlth Ctr Res & Educ, Hotchkiss Brain Inst, Dept Psychiat, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM dpiskuli@ucalgary.ca FU National Institute of Mental Health [U01 MH066160, U01 MH066134, R01 MH60720, K24 MH76191, R01 MH065079, R01 MH061523, R01 MH066069, K23 MH01905, R18 MH 43518, R01 MH065562, P50 MH080272, R21MH075027, RO1MH062066, K05MH01654]; Donaghue Foundation; Eli Lilly Co. FX This work was supported by the National Institute of Mental Health (grant numbers U01 MH066160 to SWW, U01 MH066134 to JA, R01 MH60720 and K24 MH76191 to KSC, R01 MH065079 to TDC, R01 MH061523 to BAC, R01 MH066069 and K23 MH01905to DOP, R18 MH 43518 (MTT and LJS), R01 MH065562 and P50 MH080272 to LJS, R21MH075027 to MTT, RO1MH062066 to EFW, K05MH01654 to THM); Donaghue Foundation (to SWW); and Eli Lilly & Co. (to THM, JA, and DOP). NR 26 TC 54 Z9 56 U1 3 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD APR 30 PY 2012 VL 196 IS 2-3 BP 220 EP 224 DI 10.1016/j.psychres.2012.02.018 PG 5 WC Psychiatry SC Psychiatry GA 962MG UT WOS:000305548600009 PM 22445704 ER PT J AU Bedford, T Rambaut, A Pascual, M AF Bedford, Trevor Rambaut, Andrew Pascual, Mercedes TI Canalization of the evolutionary trajectory of the human influenza virus SO BMC BIOLOGY LA English DT Article ID A VIRUS; SEASONAL INFLUENZA; POSITIVE SELECTION; DYNAMICS; TRANSMISSION; MODEL; H3N2; ESCAPE; IMPACT; DRIFT AB Background: Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. However, despite strong pressure to evolve away from human immunity and to diversify in antigenic phenotype, H3N2 influenza shows paradoxically limited genetic and antigenic diversity present at any one time. Here, we propose a simple model of antigenic evolution in the influenza virus that accounts for this apparent discrepancy. Results: In this model, antigenic phenotype is represented by a N-dimensional vector, and virus mutations perturb phenotype within this continuous Euclidean space. We implement this model in a large-scale individual-based simulation, and in doing so, we find a remarkable correspondence between model behavior and observed influenza dynamics. This model displays rapid evolution but low standing diversity and simultaneously accounts for the epidemiological, genetic, antigenic, and geographical patterns displayed by the virus. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis. Conclusions: Selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable. In the model, the influenza population shows a 1- to 2-year timescale of repeatability, suggesting a window in which evolutionary dynamics could be, in theory, predictable. C1 [Bedford, Trevor; Pascual, Mercedes] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Bedford, Trevor; Pascual, Mercedes] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Bedford, Trevor; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bedford, T (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM t.bedford@ed.ac.uk OI Bedford, Trevor/0000-0002-4039-5794; Rambaut, Andrew/0000-0003-4337-3707 FU European Molecular Biology Organization FX TB holds a Long-Term Fellowship from the European Molecular Biology Organization. AR works as a part of the Interdisciplinary Centre for Human and Avian Influenza Research (ICHAIR) and the University of Edinburgh's Centre for Immunity, Infection and Evolution (CIIE). MP is an investigator of the Howard Hughes Medical Institute. NR 42 TC 31 Z9 31 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD APR 30 PY 2012 VL 10 AR 38 DI 10.1186/1741-7007-10-38 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 957QO UT WOS:000305178000001 PM 22546494 ER PT J AU Di, XD Andrews, DMK Tucker, CJ Yu, LD Moore, AB Zheng, XL Castro, L Hermon, T Xiao, H Dixon, D AF Di, Xudong Andrews, Danica M. K. Tucker, Charles J. Yu, Linda Moore, Alicia B. Zheng, Xiaolin Castro, Lysandra Hermon, Tonia Xiao, Hang Dixon, Darlene TI A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE activin A; genistein; leiomyoma; myometrium; oligonucleotide array sequence analysis; Smad3 protein; transforming growth factor beta ID GROWTH-FACTOR-BETA; BREAST-CANCER CELLS; HORMONE ANALOG THERAPY; IN-VITRO; EXPRESSION; PROLIFERATION; MICROARRAY; METASTASIS; INHIBITION; FIBROIDS AB Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis (TM), we identified genes (up- or down-regulated, >= 1.5 fold, P <= 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 mu g/ml) in UtLM cells. Downregulation of TGF-beta signaling pathway genes, activin A, activin B, Smad3, TGF-beta 2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that downregulation of activin A and Smad3, both members of the TGF-beta pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. C1 [Di, Xudong; Yu, Linda; Moore, Alicia B.; Zheng, Xiaolin; Castro, Lysandra; Hermon, Tonia; Dixon, Darlene] Natl Inst Environm Hlth Sci, Mol Pathogenesis Grp, Natl Toxicol Program NTP, Labs Branch,NTP,NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Andrews, Danica M. K.; Tucker, Charles J.] Natl Inst Environm Hlth Sci, Microarray Grp, Mol Toxicol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Di, Xudong] Bur Hlth, Changzhou 213159, Peoples R China. [Xiao, Hang] Nanjing Med Univ, Sch Publ Hlth, Dept Toxicol, Nanjing 210029, Jiangsu, Peoples R China. RP Dixon, D (reprint author), Natl Inst Environm Hlth Sci, Mol Pathogenesis Grp, Natl Toxicol Program NTP, Labs Branch,NTP,NIH,DHHS, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU National Toxicology Program (NTP); NIH; National Institute of Environmental Health Sciences (NIEHS) FX The authors would like to thank Ms. Maria Sifre for her expert assistance with the flow cytometry studies and acknowledge the editorial assistance of the National Institutes of Health (NIH) Fellows Editorial Board. This research was supported by the National Toxicology Program (NTP) and the Intramural Research Program of the 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, NTP, NIH, however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NTP, NIH or the United States government. NR 34 TC 15 Z9 16 U1 1 U2 8 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD APR 30 PY 2012 VL 44 IS 4 BP 281 EP 292 DI 10.3858/emm.2012.44.4.024 PG 12 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 936UZ UT WOS:000303616800004 PM 22228119 ER PT J AU Petrie, RJ Gavara, N Chadwick, RS Yamada, KM AF Petrie, Ryan J. Gavara, Nuria Chadwick, Richard S. Yamada, Kenneth M. TI Nonpolarized signaling reveals two distinct modes of 3D cell migration SO JOURNAL OF CELL BIOLOGY LA English DT Article ID LIVING CELLS; AMEBOID MOVEMENT; DIFFERENTIAL REGULATION; EXTRACELLULAR-MATRIX; NONLINEAR ELASTICITY; RAC ACTIVATION; STRESS FIBERS; LEADING-EDGE; ACTIN; FIBROBLASTS AB We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix. C1 [Petrie, Ryan J.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Gavara, Nuria; Chadwick, Richard S.] Natl Inst Deafness & Other Commun Disorders, Auditory Mech Sect, NIH, Bethesda, MD 20892 USA. RP Petrie, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM petrier@mail.nih.gov; kyamada@mail.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU National Institute of Dental and Craniofacial Research; National Institute on Deafness and Other Communication Disorders at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Dental and Craniofacial Research and the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. NR 79 TC 137 Z9 137 U1 4 U2 47 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 APR 30 PY 2012 VL 197 IS 3 BP 439 EP 455 DI 10.1083/jcb.201201124 PG 17 WC Cell Biology SC Cell Biology GA 934SU UT WOS:000303467800012 PM 22547408 ER PT J AU Yuan, A Xu, JF Yue, QQ Zheng, G AF Yuan, Ao Xu, Jinfeng Yue, Qingqi Zheng, Gang TI Detecting case-control expression quantitative trait loci using locally most powerful or maximin robust rank tests SO STATISTICS IN MEDICINE LA English DT Article DE case-control study; eQTL; gene expression; genome wide; locally most powerful rank test; maximin efficiency robust test; quantitative trait loci ID GENE-EXPRESSION; NONPARAMETRIC TEST; ASSOCIATION TESTS; EFFICIENCY; STATISTICS; LINKAGE AB In testing genome-wide gene expression quantitative trait loci, efficiency robust statistical methods and their computational convenience are most relevant. For this purpose, we propose to use a modified locally most powerful rank test for the analysis of case-control expression data. This modified rank test statistic is computationally simple, robust for non-normally distributed expression data, and asymptotically locally most powerful. It depends on the specification of a location distribution form for data but is not sensitive to misspecifications. When such a location distribution form cannot be specified, we apply Gastwirth's maximin efficiency robust rank test to gene expression data to maximize the worst Pitman asymptotic relative efficiency among a family of location distributions. We conduct simulation studies to assess their performance and use an application to real data for illustration. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Yuan, Ao; Yue, Qingqi] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. [Xu, Jinfeng] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [Zheng, Gang] DCVS Natl Heart Lung & Blood Inst, Off Biostat Res, Bethesda, MD 20892 USA. RP Yuan, A (reprint author), Howard Univ, Natl Human Genome Ctr, 2216 6th St NW, Washington, DC 20059 USA. EM yuanao@hotmail.com OI Xu, Jinfeng/0000-0002-3165-2015 FU National University of Singapore [R-155-000-112-112]; National Center for Research Resources (NIH) [2G12RR003048] FX Xu's work is supported by a grant from the National University of Singapore (R-155-000-112-112). Yuan's work is supported in part by the National Center for Research Resources (NIH grant no. 2G12RR003048). We thank two referees and the associate editor for their very helpful comments and insight, which greatly improved our presentation. NR 40 TC 2 Z9 2 U1 1 U2 5 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 APR 30 PY 2012 VL 31 IS 9 BP 887 EP 900 DI 10.1002/sim.4461 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 923JO UT WOS:000302615800007 PM 22173706 ER PT J AU Obolensky, OI Wu, WW Shen, RF Yu, YK AF Obolensky, O. I. Wu, Wells W. Shen, Rong-Fong Yu, Yi-Kuo TI Using dissociation energies to predict observability of b- and y-peaks in mass spectra of short peptides SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID COLLISION-INDUCED DISSOCIATION; DENSITY-FUNCTIONAL THEORY; SURFACE-INDUCED DISSOCIATION; MAIN FRAGMENTATION PATHWAYS; AMIDE BOND-CLEAVAGE; FT-ICR MS; PROTONATED TRIPEPTIDES; GLY-XXX; KINETIC METHOD; GAS-PHASE AB RATIONALE: Peptide identification reliability can be improved by excluding from analysis those m/z peaks of candidate peptides which cannot be observed in practice due to various physical, chemical or thermodynamic considerations. We propose using dissociation energies (as opposed to proton affinities) as a predictor of observability of different m/z peaks in spectra of short peptides. METHODS: Mass spectra of the tetrapeptides AAAA, AAFA, AAVA, AFAA, AVAA, AFFA, and AVVA were measured in the collision-induced dissociation (CID) activation mode on a grid of activation times 0.05 to 100 ms and normalized collision energy 10 to 35%. The lowest energy geometries and vibrational spectra were calculated for the precursor ions and their charged and neutral fragments using density functional theory (DFT) at the TPSS/6-31G(d, p) level. Dissociation energies were calculated for all fragmentation channels leading to b- or y-fragments. RESULTS: It is demonstrated that m/z peaks observed in the mass spectra correspond to the fragmentation channels with the lowest dissociation energies. Using 50 kcal/mol as the cut-off value of dissociation energy, it was predicted that 28 out of 42 possible peaks in the b- and y-series of the seven tetrapeptides can be observed in mass spectra. In the experiments, 26 b- or y-peaks were observed, all of which are among the 28 predicted ones. CONCLUSIONS: The use of dissociation energies generalizes the use of proton affinities for semi-quantitative predictions of relative intensities of different m/z peaks of short peptides. Further advances in this direction will pave the way for reliable quantitative predictions and, hence, for a significant improvement in robustness and accuracy of peptide and protein identification tools. Published in 2012 by John Wiley & Sons, Ltd. C1 [Obolensky, O. I.; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Wu, Wells W.] NIA, NIH, Baltimore, MD 21224 USA. [Shen, Rong-Fong] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Obolensky, OI (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM obolensk@ncbi.nlm.nih.gov; yyu@ncbi.nlm.nih.gov RI Obolensky, Oleg/A-5839-2008 OI Obolensky, Oleg/0000-0003-3315-1828 FU NIH, NLM FX We thank Dr. Julia Laskin and Dr. Aleksey Ogurtsov for useful discussions. This research was supported by the Intramural Research Program of the NIH, NLM. The computations were carried out on the Biowulf computer cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov). NR 58 TC 3 Z9 3 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-4198 EI 1097-0231 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD APR 30 PY 2012 VL 26 IS 8 BP 915 EP 920 DI 10.1002/rcm.6180 PG 6 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 904FP UT WOS:000301179800005 PM 22396027 ER PT J AU Kawel, N Nacif, M Zavodni, A Jones, J Liu, ST Sibley, CT Bluemke, DA AF Kawel, Nadine Nacif, Marcelo Zavodni, Anna Jones, Jacquin Liu, Songtao Sibley, Christopher T. Bluemke, David A. TI T1 mapping of the myocardium: intra-individual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 mapping; Modified Look-Locker Inversion Recovery; Extracellular volume fraction; ECV; Gadobenate dimeglumine; Gadopentetate dimeglumine ID CARDIOVASCULAR MAGNETIC-RESONANCE; DOSE GADOBENATE DIMEGLUMINE; GADOPENTETATE DIMEGLUMINE; PARTITION-COEFFICIENT; HEART; T-1; FIBROSIS; HUMANS; BLOOD; LIVER AB Purpose: Myocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in patients with diffuse myocardial fibrosis. The purpose of this study was to perform an intra-individual assessment of normal T1 time and ECV for two different contrast agents. Methods: A modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired at 3 T in 24 healthy subjects (8 men; 28 +/- 6 years) at mid-ventricular short axis pre-contrast and every 5 min between 5-45 min after injection of a bolus of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist (R)) (exam 1) and 0.1 mmol/kg gadobenate dimeglumine (Gd-BOPTA; Multihance (R)) (exam 2) during two separate scanning sessions. T1 times were measured in myocardium and blood on generated T1 maps. ECVs were calculated as (Delta R1(myocardium)/Delta R1(blood)) * (1-hematocrit). Results: Mean pre-contrast T1 relaxation times for myocardium and blood were similar for both the first and second CMR exam (p > 0.5). Overall mean post-contrast myocardial T1 time was 15 +/- 2 ms (2.5 +/- 0.7%) shorter for Gd-DTPA at 0.15 mmol/kg compared to Gd-BOPTA at 0.1 mmol/kg (p < 0.01) while there was no significant difference for T1 time of blood pool (p > 0.05). Between 5 and 45 minutes after contrast injection, mean ECV values increased linearly with time for both contrast agents from 0.27 +/- 0.03 to 0.30 +/- 0.03 (p < 0.0001). Mean ECV values were slightly higher (by 0.01, p < 0.05) for Gd-DTPA compared to Gd-BOPTA. Inter-individual variation of ECV was higher (CV 8.7% [exam 1, Gd-DTPA] and 9.4% [exam 2, Gd-BOPTA], respectively) compared to variation of pre-contrast myocardial T1 relaxation time (CV 4.5% [exam 1] and 3.0% [exam 2], respectively). ECV with Gd-DTPA was highly correlated to ECV by Gd-BOPTA (r = 0.803; p < 0.0001). Conclusion: In comparison to pre-contrast myocardial T1 relaxation time, variation in ECV values of normal subjects is larger. However, absolute differences in ECV between Gd-DTPA and Gd-BOPTA were small and rank correlation was high. There is a small and linear increase in ECV over time, therefore ideally images should be acquired at the same delay after contrast injection. C1 [Kawel, Nadine; Nacif, Marcelo; Zavodni, Anna; Liu, Songtao; Sibley, Christopher T.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, NIH, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Sibley, Christopher/C-9900-2013; OI Bluemke, David/0000-0002-8323-8086 FU NIH FX This study was supported by the NIH intramural research program. NR 35 TC 49 Z9 50 U1 0 U2 7 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 APR 28 PY 2012 VL 14 AR 26 DI 10.1186/1532-429X-14-26 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 979FJ UT WOS:000306801100001 PM 22540153 ER PT J AU Gyombolai, P Pap, D Turu, G Catt, KJ Bagdy, G Hunyady, L AF Gyombolai, Pal Pap, Dorottya Turu, Gabor Catt, Kevin J. Bagdy, Gyoergy Hunyady, Laszlo TI Regulation of endocannabinoid release by G proteins: A paracrine mechanism of G protein-coupled receptor action SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Endocannabinoid; CB1; GPCR; Angiotensin II ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; CANNABINOID CB1 RECEPTOR; SYMPATHO-ADRENOMEDULLARY OUTFLOW; MIDDLE CEREBRAL-ARTERY; ENDOGENOUS CANNABINOIDS; ANGIOTENSIN-II; METABOTROPIC GLUTAMATE; NEOCORTICAL INTERNEURONS; DIACYLGLYCEROL LIPASE; SYNAPTIC-TRANSMISSION AB In the past years, the relationship between the endocannabinoid system (ECS) and other hormonal and neuromodulatory systems has been intensively studied. G protein-coupled receptors (GPCRs) can stimulate endocannabinoid (eCB) production via activation of G(q/11) proteins and, in some cases, G(s) proteins. In this review, we summarize the pathways through which GPCR activation can trigger eCB release, as well as the best known examples of this process throughout the body tissues. Angiotensin II-induced activation of AT(1) receptors, similar to other G(q/11)-coupled receptors, can lead to the formation of 2-arachidonoylglycerol (2-AG), an important eCB. The importance of eCB formation in angiotensin II action is supported by the finding that the hypertensive effect of angiotensin II, injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats, can be abolished by AM251, an inverse agonist of CB1 cannabinoid receptors (CB(1)Rs). We conclude that activation of the ECS should be considered as a general consequence of the stimulation of GG(q/11)-coupled receptors, and may mediate some of the physiological effects of GPCRs. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Gyombolai, Pal; Turu, Gabor; Hunyady, Laszlo] Semmelweis Univ, Dept Physiol, Fac Med, H-1444 Budapest, Hungary. [Pap, Dorottya; Bagdy, Gyoergy] Semmelweis Univ, Fac Pharm, H-1444 Budapest, Hungary. [Catt, Kevin J.] NICHHD, Sect Hormonal Regulat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Bagdy, Gyoergy] Semmelweis Univ, Grp Neuropsychopharmacol & Neurochem, H-1444 Budapest, Hungary. [Hunyady, Laszlo] Semmelweis Univ, Lab Neurobiochem & Mol Physiol, H-1444 Budapest, Hungary. [Bagdy, Gyoergy; Hunyady, Laszlo] Hungarian Acad Sci, Budapest, Hungary. RP Hunyady, L (reprint author), Semmelweis Univ, Dept Physiol, Fac Med, POB 259, H-1444 Budapest, Hungary. EM hunyady@eok.sote.hu OI Turu, Gabor/0000-0002-4421-3812; Bagdy, Gyorgy/0000-0001-8141-3410 FU Hungarian Science Foundation [OTKA NK-072661]; Hungarian Ministry of Public Health [ETT 337/2009, ETT 318/2009]; EU [LSHM-CT-2004-503474]; [TAMOP-4.2.1.B-09/1/KMR-2010-0001] FX The help provided by Jolan Jozan in the drawing of the figures is greatly appreciated. This work was supported in part by Grants from the Hungarian Science Foundation (OTKA NK-072661), the Hungarian Ministry of Public Health (ETT 337/2009, ETT 318/2009), TAMOP-4.2.1.B-09/1/KMR-2010-0001 and EU, LSHM-CT-2004-503474. NR 89 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD APR 28 PY 2012 VL 353 IS 1-2 SI SI BP 29 EP 36 DI 10.1016/j.mce.2011.10.011 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 921YF UT WOS:000302513300005 PM 22075205 ER PT J AU Majone, F Jeang, KT AF Majone, Franca Jeang, Kuan-Teh TI Unstabilized DNA breaks in HTLV-1 Tax expressing cells correlate with functional targeting of Ku80, not PKcs, XRCC4, or H2AX SO CELL AND BIOSCIENCE LA English DT Article DE HTLV-1; Tax; Ku80; PKcs; XRCC4; H2AX; DNA damage ID DOUBLE-STRAND BREAKS; CELLULAR-TRANSFORMATION; GENE-EXPRESSION; DAMAGE RESPONSE; REPAIR FACTORS; HISTONE H2AX; LIGASE-IV; ONCOPROTEIN; INSTABILITY; INDUCTION AB Background: Expression of the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein rapidily induces a significant increase of micronuclei (MN) and unstabilized DNA breaks in cells. Unstabilized DNA breaks can have free 3'-OH ends accessible to in situ addition of digoxygenin (DIG)-labeled dUTP using terminal deoxynucleotidyl transferase. In the present work, we used a GFP-Tax (green fluorescent protein) plasmid, which produces a functionally active GFP-tagged Tax protein, to detect the cellular target(s) for Tax which might mechanistically explain the clastogenic phenomenon. We examined the induction of MN and unstabilized DNA breaks in wild type cells and cells individually knocked out for Ku80, PKcs, XRCC4, and H2AX proteins. We also assessed in the same cells, the signal strengths produced by DIG-dUTP incorporation at the unstable DNA breaks in the presence and absence of Tax. Results: Cells mutated for PKcs, XRCC4 and H2AX showed increased frequency of MN and unstabilized DNA breaks in response to the expression of Tax, while cells genetically mutated for Ku80 were refractory to Tax's induction of these cytogenetic effects. Moreover, by measuring the size of DIG-dUTP incorporation signal, which indicates the extent of unstable DNA ends, we found that Tax induces larger signals than those in control cells. However, in xrs-6 cells deficient for Ku80, this Tax effect was not seen. Conclusions: The data here demonstrate that clastogenic DNA damage in Tax expressing cells is explained by Tax targeting of Ku80, but not PKcs, XRCC4 or H2AX, which are all proteins directly or indirectly related to the non-homologous end-joining (NHEJ) repair system. Of note, the Ku80 protein plays an important role at the initial stage of the NHEJ repair system, protecting and stabilizing DNA-breaks. Accordingly, HTLV-1 Tax is shown to interfere with a normal cellular protective mechanism for stabilizing DNA breaks. These DNA breaks, unprotected by Ku80, are unstable and are subject to erosion or end-to-end fusion, ultimately leading to additional chromosomal aberrations. C1 [Majone, Franca] Dept Biol, I-35131 Padua, Italy. [Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Majone, F (reprint author), Dept Biol, Via Bassi 58-B, I-35131 Padua, Italy. EM franca.majone@unipd.it FU Ministry of Education, University and Research [60A06-5770, 60A06-1802]; NIAID; Intramural AIDS Targeted Antiviral Program (IATAP) from the office of the Director, NIH FX We thank Renzo Mazzaro and Matteo Simonetti for preparation of figures. This study was in part supported by Ministry of Education, University and Research grants No. 60A06-5770 and 60A06-1802 to FM. Work in KTJ's laboratory is supported in part by intramural funding from the NIAID and from the Intramural AIDS Targeted Antiviral Program (IATAP) from the office of the Director, NIH. NR 31 TC 7 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD APR 27 PY 2012 VL 2 AR 15 DI 10.1186/2045-3701-2-15 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 011ZT UT WOS:000309205800001 PM 22541714 ER PT J AU Grimsby, JL Porneala, BC Vassy, JL Yang, QH Florez, JC Dupuis, J Liu, TB Yesupriya, A Chang, MH Ned, RM Dowling, NF Khoury, MJ Meigs, JB AF Grimsby, Jonna L. Porneala, Bianca C. Vassy, Jason L. Yang, Quanhe Florez, Jose C. Dupuis, Josee Liu, Tiebin Yesupriya, Ajay Chang, Man-Huei Ned, Renee M. Dowling, Nicole F. Khoury, Muin J. Meigs, James B. CA MAGIC Investigators TI Race-ethnic differences in the association of genetic loci with HbA(1c) levels and mortality in US adults: the third National Health and Nutrition Examination Survey (NHANES III) SO BMC MEDICAL GENETICS LA English DT Article ID IRON-DEFICIENCY ANEMIA; HISPANIC WHITE ADULTS; HEMOGLOBIN A(1C); CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; HUMAN GENOME; GLYCATED HEMOGLOBIN; RACIAL-DIFFERENCES; PLASMA-GLUCOSE; A1C LEVELS AB Background: Hemoglobin A(1c) (HbA(1c)) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA(1c)-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA(1c) and 3) association of SNPs with mortality. Methods: We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05. Results: RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA(1c) in NHW (beta = 0.012 HbA(1c) increase per risk allele, p = 0.04) and MA (beta = 0.021, p = 0.005) but not NHB (beta = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71). Conclusion: At many HbA(1c) loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA(1c)-associated variants on HbA(1c) levels varied by race-ethnicity, but did not influence mortality. C1 [Grimsby, Jonna L.; Porneala, Bianca C.; Vassy, Jason L.; Florez, Jose C.; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Grimsby, Jonna L.; Vassy, Jason L.; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Yang, Quanhe; Yesupriya, Ajay; Chang, Man-Huei; Ned, Renee M.; Dowling, Nicole F.; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM jmeigs@partners.org OI Dupuis, Josee/0000-0003-2871-3603 FU American Diabetes Association Mentored Post-Doctoral Fellowship Award; National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616]; NIDDK [K24 DK080140]; NIDDK Research Career Award [K23 DK65978]; Massachusetts General Hospital Physician Scientist Development Award; Doris Duke Charitable Foundation Clinical Scientist Development Award FX The data are from the NHANES III Public Use and Genetic Data Sets (http://www.cdc.gov/nchs/nhanes/genetics/genetic.htm). Supported by an American Diabetes Association Mentored Post-Doctoral Fellowship Award (Dr. Grimsby), National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 (Dr Meigs), NIDDK K24 DK080140 (Dr Meigs), NIDDK Research Career Award K23 DK65978 (Dr Florez), a Massachusetts General Hospital Physician Scientist Development Award, and a Doris Duke Charitable Foundation Clinical Scientist Development Award (Dr Florez). The MAGIC Investigators are listed in the on-line supplement. We thank Sekar Kathiresan MD, for assistance in obtaining the NHANES III DNA that we used for genotyping, and Peter Shrader MS for analytic assistance. NR 56 TC 17 Z9 18 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD APR 27 PY 2012 VL 13 AR 30 DI 10.1186/1471-2350-13-30 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 000GA UT WOS:000308373300001 PM 22540250 ER PT J AU Keller, JM Noben-Trauth, K AF Keller, James M. Noben-Trauth, Konrad TI Genome-wide linkage analyses identify Hfhl1 and Hfhl3 with frequency-specific effects on the hearing spectrum of NIH Swiss mice SO BMC GENETICS LA English DT Article DE NIH Swiss; Sensorineural hearing loss; Quantitative trait loci analyses; Tonotopy; DPOAE ID QUANTITATIVE TRAIT LOCI; OUTER HAIR-CELLS; MOUSE MODEL; LOSS DFNA36; BEETHOVEN; COCHLEA; MAP AB Background: The mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map. Although much is known about the cell-level molecular defects responsible for severe hearing loss, the genetics responsible for less severe and frequency-specific hearing loss remains unclear. We recently identified quantitative trait loci (QTLs) Hfhl1 and Hfhl2 that affect high-frequency hearing loss in NIH Swiss mice. Here we used 2f1-f2 distortion product otoacoustic emissions (DPOAE) measurements to refine the hearing loss phenotype. We crossed the high frequency hearing loss (HFHL) line of NIH Swiss mice to three different inbred strains and performed linkage analysis on the DPOAE data obtained from the second-generation populations. Results: We identified a QTL of moderate effect on chromosome 7 that affected 2f1-f2 emissions intensities (Hfhl1), confirming the results of our previous study that used auditory brainstem response (ABR) thresholds to identify QTLs affecting HFHL. We also identified a novel significant QTL on chromosome 9 (Hfhl3) with moderate effects on 2f1-f2 emissions intensities. By partitioning the DPOAE data into frequency subsets, we determined that Hfhl1 and Hfhl3 affect hearing primarily at frequencies above 24 kHz and 35 kHz, respectively. Furthermore, we uncovered additional QTLs with small effects on isolated portions of the DPOAE spectrum. Conclusions: This study identifies QTLs with effects that are isolated to limited portions of the frequency map. Our results support the hypothesis that frequency-specific hearing loss results from variation in gene activity along the cochlear partition and suggest a strategy for creating a map of cochlear genes that influence differences in hearing sensitivity and/or vulnerability in restricted portions of the cochlea. C1 [Keller, James M.; Noben-Trauth, Konrad] Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Keller, JM (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. EM kellerjm@nidcd.nih.gov FU NIDCD FX We would like to thank Dr. Larry Leamy for his assistance calculating Principal Components and for helpful discussions regarding their use in our analyses. We would also like to thank Steven Raft and Richard Chadwick for their comments regarding this manuscript. This work was supported by the Intramural Program of NIDCD. NR 30 TC 4 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD APR 27 PY 2012 VL 13 AR 32 DI 10.1186/1471-2156-13-32 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 986RA UT WOS:000307360700001 PM 22540152 ER PT J AU Bonar, SL Brydges, SD Mueller, JL McGeough, MD Pena, C Chen, D Grimston, SK Hickman-Brecks, CL Ravindran, S McAlinden, A Novack, DV Kastner, DL Civitelli, R Hoffman, HM Mbalaviele, G AF Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel TI Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice SO PLOS ONE LA English DT Article ID OSTEOCLAST DIFFERENTIATION; CIAS1 MUTATIONS; GROWTH-PLATE; TNF-ALPHA; BONE; DISEASE; CELLS; CRYSTALS; INCREASE; COLLAGEN AB The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1 beta. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1 beta and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue "spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling. C1 [Bonar, Sheri L.; Grimston, Susan K.; Hickman-Brecks, Cynthia L.; Novack, Deborah V.; Civitelli, Roberto; Mbalaviele, Gabriel] Washington Univ, Sch Med, Div Bone & Mineral Dis, St Louis, MO 63130 USA. [Brydges, Susannah D.; Mueller, James L.; McGeough, Matthew D.; Pena, Carla; Chen, Debbie; Hoffman, Hal M.] Univ Calif San Diego, Div Allergy Immunol & Rheumatol, La Jolla, CA 92093 USA. [Brydges, Susannah D.; Mueller, James L.; McGeough, Matthew D.; Pena, Carla; Chen, Debbie; Hoffman, Hal M.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Brydges, Susannah D.; Mueller, James L.; McGeough, Matthew D.; Pena, Carla; Chen, Debbie; Hoffman, Hal M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Ravindran, Soumya; McAlinden, Audrey] Washington Univ, Sch Med, Dept Orthopaed Surg, St Louis, MO USA. [Kastner, Daniel L.] NHGRI, Med Genet Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Bonar, SL (reprint author), Washington Univ, Sch Med, Div Bone & Mineral Dis, St Louis, MO 63130 USA. EM gmbalavi@DOM.wustl.edu OI McAlinden, Audrey/0000-0001-8433-4224; Novack, Deborah/0000-0001-7101-5582; Civitelli, Roberto/0000-0003-4076-4315 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH [RO1-AI52430]; National Institutes of Health/Core Center for Musculoskeletal Biology and Medicine [5 P30 AR057235]; Arthritis National Research Foundation FX This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, extramural grants NIH RO1-AI52430, the 5 P30 AR057235 National Institutes of Health/Core Center for Musculoskeletal Biology and Medicine and the Arthritis National Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 25 Z9 25 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 APR 27 PY 2012 VL 7 IS 4 AR e35979 DI 10.1371/journal.pone.0035979 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TJ UT WOS:000305336000095 PM 22558291 ER PT J AU Krejci, P Aklian, A Kaucka, M Sevcikova, E Prochazkova, J Masek, JK Mikolka, P Pospisilova, T Spoustova, T Weis, M Paznekas, WA Wolf, JH Gutkind, JS Wilcox, WR Kozubik, A Jabs, EW Bryja, V Salazar, L Vesela, I Balek, L AF Krejci, Pavel Aklian, Anie Kaucka, Marketa Sevcikova, Eva Prochazkova, Jirina Masek, Jan Kukla Mikolka, Pavol Pospisilova, Tereza Spoustova, Tereza Weis, MaryAnn Paznekas, William A. Wolf, Joshua H. Gutkind, J. Silvio Wilcox, William R. Kozubik, Alois Jabs, Ethylin Wang Bryja, Vitezslav Salazar, Lisa Vesela, Iva Balek, Lukas TI Receptor Tyrosine Kinases Activate Canonical WNT/beta-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct beta-Catenin Phosphorylation SO PLOS ONE LA English DT Article ID WNT; INSULIN; FGFR3; LRP6; MUTATIONS; DYSPLASIA; MECHANISM; CANCER AB Receptor tyrosine kinase signaling cooperates with WNT/beta-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/beta-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate beta-catenin at Tyr142, which is known to increase cytoplasmic beta-catenin concentration via release of beta-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct beta-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling. C1 [Krejci, Pavel; Aklian, Anie; Wilcox, William R.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Krejci, Pavel; Kaucka, Marketa; Sevcikova, Eva; Prochazkova, Jirina; Masek, Jan Kukla; Mikolka, Pavol; Pospisilova, Tereza; Spoustova, Tereza; Kozubik, Alois; Bryja, Vitezslav; Vesela, Iva; Balek, Lukas] Masaryk Univ, Dept Anim Physiol & Immunol, Inst Expt Biol, Brno, Czech Republic. [Krejci, Pavel; Kozubik, Alois; Bryja, Vitezslav] Inst Biophys AS CR, Dept Cytokinet, Brno, Czech Republic. [Weis, MaryAnn] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Paznekas, William A.; Jabs, Ethylin Wang] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Wolf, Joshua H.; Gutkind, J. Silvio] NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Wilcox, William R.] Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90024 USA. [Salazar, Lisa] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. RP Krejci, P (reprint author), Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. EM krejcip@sci.muni.cz RI Prochazkova, Jirina/D-7528-2012; Kozubik, Alois/H-1954-2014; Krejci, Pavel/I-4285-2014; Bryja, Vit?zslav/H-1925-2014; Masek, Jan/I-9029-2014; OI Bryja, Vit?zslav/0000-0002-9136-5085; Kaucka, Marketa/0000-0002-8781-9769; Krejci, Pavel/0000-0003-0618-9134 FU National Institutes of Health (NIH) [5P01HD022657-21A]; NIH GCRC [M01-RR00425]; Ministry of Education, Youth and Sports of the Czech Republic [MSM0021622430]; Grant Agency of the Czech Republic [301/09/0587, 204/09/H058, 204/09/J030, 305/11/0752]; Winnick Family Research Scholars award; EMBO FX This work was supported by: National Institutes of Health (NIH) 5P01HD022657-21A, NIH GCRC Grant M01-RR00425 (www.nih.gov/); Ministry of Education, Youth and Sports of the Czech Republic (MSM0021622430) (www.msmt.cz/); Grant Agency of the Czech Republic (301/09/0587, 204/09/H058, 204/09/J030, 305/11/0752) (www.gacr.cz); Winnick Family Research Scholars award (WRW) (www.winnickfamilyfoundation.com); and EMBO Installation grant (VB) (www.embo.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 54 Z9 56 U1 0 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 APR 27 PY 2012 VL 7 IS 4 AR e35826 DI 10.1371/journal.pone.0035826 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TJ UT WOS:000305336000063 PM 22558232 ER PT J AU Marzi, A Yoshida, R Miyamoto, H Ishijima, M Suzuki, Y Higuchi, M Matsuyama, Y Igarashi, M Nakayama, E Kuroda, M Saijo, M Feldmann, F Brining, D Feldmann, H Takada, A AF Marzi, Andrea Yoshida, Reiko Miyamoto, Hiroko Ishijima, Mari Suzuki, Yasuhiko Higuchi, Megumi Matsuyama, Yukie Igarashi, Manabu Nakayama, Eri Kuroda, Makoto Saijo, Masayuki Feldmann, Friederike Brining, Douglas Feldmann, Heinz Takada, Ayato TI Protective Efficacy of Neutralizing Monoclonal Antibodies in a Nonhuman Primate Model of Ebola Hemorrhagic Fever SO PLOS ONE LA English DT Article ID VIRUS INFECTION; DEPENDENT ENHANCEMENT; MARBURG VIRUSES; GLYCOPROTEIN; EPITOPES; IDENTIFICATION; MECHANISMS; RNA; GP AB Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF. C1 [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Yoshida, Reiko; Miyamoto, Hiroko; Ishijima, Mari; Suzuki, Yasuhiko; Higuchi, Megumi; Matsuyama, Yukie; Nakayama, Eri; Kuroda, Makoto; Takada, Ayato] Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan. [Igarashi, Manabu] Hokkaido Univ, Res Ctr Zoonosis Control, Div Bioinformat, Sapporo, Hokkaido, Japan. [Saijo, Masayuki] Natl Inst Infect Dis, Dept Virol 1, Tokyo, Japan. [Feldmann, Friederike] NIAID, Off Operat Management, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Brining, Douglas] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. RP Marzi, A (reprint author), NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. EM atakada@czc.hokudai.ac.jp RI Igarashi, Manabu/F-6871-2012; YOSHIDA, Reiko/F-6883-2012; Suzuki, Yasuhiko/F-6890-2012; Takada, Ayato/A-6679-2012 FU Japan Initiative for Global Research Network on Infectious Diseases (J-GRID); Ministry of Education, Culture, Sports, Science and Technology (MEXT); Japan Science and Technology Agency Basic Research Programs; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) and the Global COE Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and a Grant-in-Aid for JSPS Fellows Japan. The work was further supported by Japan Science and Technology Agency Basic Research Programs. Funding was also provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 61 Z9 65 U1 4 U2 33 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 APR 27 PY 2012 VL 7 IS 4 AR e36192 DI 10.1371/journal.pone.0036192 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TJ UT WOS:000305336000150 PM 22558378 ER PT J AU Mendez-Rios, JD Martens, CA Bruno, DP Porcella, SF Zheng, ZM Moss, B AF Mendez-Rios, Jorge D. Martens, Craig A. Bruno, Daniel P. Porcella, Stephen F. Zheng, Zhi-Ming Moss, Bernard TI Genome Sequence of Erythromelalgia-Related Poxvirus Identifies it as an Ectromelia Virus Strain SO PLOS ONE LA English DT Article ID EPIDEMIC ERYTHROMELALGIA; INFECTIOUS ECTROMELIA; CAUSATIVE AGENT; MOUSE SERUM; VACCINIA; ANTIBODY AB Erythromelagia is a condition characterized by attacks of burning pain and inflammation in the extremeties. An epidemic form of this syndrome occurs in secondary students in rural China and a virus referred to as erythromelalgia-associated poxvirus (ERPV) was reported to have been recovered from throat swabs in 1987. Studies performed at the time suggested that ERPV belongs to the orthopoxvirus genus and has similarities with ectromelia virus, the causative agent of mousepox. We have determined the complete genome sequence of ERPV and demonstrated that it has 99.8% identity to the Naval strain of ectromelia virus and a slighly lower identity to the Moscow strain. Small DNA deletions in the Naval genome that are absent from ERPV may suggest that the sequenced strain of Naval was not the immediate progenitor of ERPV. C1 [Mendez-Rios, Jorge D.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Mendez-Rios, Jorge D.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Martens, Craig A.; Bruno, Daniel P.; Porcella, Stephen F.] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Hamilton, MT USA. [Zheng, Zhi-Ming] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Mendez-Rios, JD (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research; NIAID; NIH FX The word was supported by the Division of Intramural Research, NIAID, NIH. 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 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 APR 27 PY 2012 VL 7 IS 4 AR e34604 DI 10.1371/journal.pone.0034604 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TJ UT WOS:000305336000013 PM 22558090 ER PT J AU Wong, KA Wilson, J Russo, A Wang, L Okur, MN Wang, XR Martin, NP Scappini, E Carnegie, GK O'Bryan, JP AF Wong, Katy A. Wilson, Jessica Russo, Angela Wang, Li Okur, Mustafa Nazir Wang, Xuerong Martin, Negin P. Scappini, Erica Carnegie, Graeme K. O'Bryan, John P. TI Intersectin (ITSN) Family of Scaffolds Function as Molecular Hubs in Protein Interaction Networks SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; CLATHRIN-MEDIATED ENDOCYTOSIS; BIMOLECULAR FLUORESCENCE COMPLEMENTATION; ADAPTER PROTEIN; SIGNALING PATHWAYS; EPS15 HOMOLOGY; BINDING; MEMBRANE; DOMAINS; DYNAMIN AB Members of the intersectin (ITSN) family of scaffold proteins consist of multiple modular domains, each with distinct ligand preferences. Although ITSNs were initially implicated in the regulation of endocytosis, subsequent studies have revealed a more complex role for these scaffold proteins in regulation of additional biochemical pathways. In this study, we performed a high throughput yeast two-hybrid screen to identify additional pathways regulated by these scaffolds. Although several known ITSN binding partners were identified, we isolated more than 100 new targets for the two mammalian ITSN proteins, ITSN1 and ITSN2. We present the characterization of several of these new targets which implicate ITSNs in the regulation of the Rab and Arf GTPase pathways as well as regulation of the disrupted in schizophrenia 1 (DISC1) interactome. In addition, we demonstrate that ITSN proteins form homomeric and heteromeric complexes with each other revealing an added level of complexity in the function of these evolutionarily conserved scaffolds. C1 [Wong, Katy A.; Wilson, Jessica; Russo, Angela; Wang, Li; Okur, Mustafa Nazir; Wang, Xuerong; Carnegie, Graeme K.; O'Bryan, John P.] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60680 USA. [Wong, Katy A.; Wilson, Jessica; Russo, Angela; Okur, Mustafa Nazir; Wang, Xuerong; O'Bryan, John P.] Univ Illinois, Coll Med, Cardiovasc Res Ctr, Chicago, IL USA. [Wong, Katy A.; Wilson, Jessica; Russo, Angela; Okur, Mustafa Nazir; Wang, Xuerong; O'Bryan, John P.] Univ Illinois, Coll Med, UIC Canc Ctr, Chicago, IL USA. [Okur, Mustafa Nazir] Univ Illinois, Coll Med, Dept Biochem & Mol Genet, Chicago, IL USA. [Martin, Negin P.; Scappini, Erica] NIEHS, Neurobiol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Wong, KA (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60680 USA. EM obryanj@uic.edu OI Martin, Negin/0000-0003-3166-8989 FU Foundation Jerome Lejeune; American Heart Association [11SDG5230003]; National Institutes of Health; National Institutes of Health [HL090651]; Department of Defense [PR080428]; St. Baldrick's Foundation FX KAW was supported by a grant from the Foundation Jerome Lejeune, and LW and GKC were supported by an American Heart Association grant (11SDG5230003). These studies were supported by funds from the intramural research program of the National Institutes of Health (JPO) and by grants to JPO from the National Institutes of Health (HL090651), Department of Defense (PR080428), the Foundation Jerome Lejeune, and the St. Baldrick's Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 16 Z9 18 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 APR 27 PY 2012 VL 7 IS 4 AR e36023 DI 10.1371/journal.pone.0036023 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TJ UT WOS:000305336000102 ER EF