FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hanover, JA Wang, P Keembiyehetty, C Ghosh, S Bond, M Krause, M Love, D AF Hanover, John A. Wang, Peng Keembiyehetty, Chithra Ghosh, Salil Bond, Michelle Krause, Michael Love, Dona TI Targeted Knockouts of Enzymes of O-GlcNAc Cycling and Epigenetic Regulation SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Hanover, John A.; Wang, Peng; Keembiyehetty, Chithra; Ghosh, Salil; Bond, Michelle; Krause, Michael; Love, Dona] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 117 BP 1488 EP 1489 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300116 ER PT J AU Zhang, LP Ten Hagen, K AF Zhang, Liping Ten Hagen, Kelly TI Mucin-Type O-glycosylation is Required for Digestive System Formation and Function in Drosophila SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Zhang, Liping; Ten Hagen, Kelly] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 126 BP 1491 EP 1492 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300125 ER PT J AU Tian, E Hoffman, M Ten Hagen, K AF Tian, E. Hoffman, Matthew Ten Hagen, Kelly TI Disruption of Protein O-glycosylation Alters FGF Signaling by Modulating Basement Membrane Composition SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Tian, E.; Hoffman, Matthew; Ten Hagen, Kelly] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 131 BP 1493 EP 1493 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300130 ER PT J AU Mercer, N Ramakrishnan, B Pasek, M Boeggeman, E Verdi, L Qasba, PK AF Mercer, Natalia Ramakrishnan, Boopathy Pasek, Marta Boeggeman, Elizabeth Verdi, Luke Qasba, Pradman K. TI Detection of LacNAc and GlcNAc Moieties on the Cell's Surface with Glycosyltransferases SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Mercer, Natalia; Ramakrishnan, Boopathy; Pasek, Marta; Boeggeman, Elizabeth; Verdi, Luke; Qasba, Pradman K.] NCI Frederick, SGS, CCR NP, Frederick, MD USA. [Ramakrishnan, Boopathy; Boeggeman, Elizabeth] SAIC Frederick Inc, BSP, SGS, CCR NP, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 168 BP 1505 EP 1506 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300167 ER PT J AU Tran, D Lim, JM Liu, M Wells, L Ten Hagen, K Live, D AF Duy Tran Lim, Jae-Min Liu, Mian Wells, Lance Ten Hagen, Kelly Live, David TI O-GalNAc Glycosylation of alpha Dystroglycan SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Duy Tran; Ten Hagen, Kelly] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD USA. [Lim, Jae-Min; Liu, Mian; Wells, Lance; Live, David] Univ Georgia, CCRC, Athens, GA 30602 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 169 BP 1506 EP 1506 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300168 ER PT J AU Azadi, P Ishihara, M Heiss, C Talabnin, K Wang, ZR Dimitrievska, S Huizing, M Niklason, L Sonon, R AF Azadi, Parastoo Ishihara, Mayumi Heiss, Christian Talabnin, Krajang Wang, Zhirui Dimitrievska, Sashka Huizing, Marjan Niklason, Laura Sonon, Roberto TI Strategies for Glycomics and Glycoproteomics and Glycosaminoglycan Analysis by Mass Spectrometry and HPLC SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Azadi, Parastoo; Ishihara, Mayumi; Heiss, Christian; Talabnin, Krajang; Wang, Zhirui; Sonon, Roberto] UGA, Complex Carbohydrate Res Ctr, Athens, GA USA. [Dimitrievska, Sashka; Niklason, Laura] Yale Univ, New Haven, CT USA. [Huizing, Marjan] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 231 BP 1526 EP 1526 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300230 ER PT J AU Perdivara, I Petrovich, R Tokar, EJ Waalkes, M Fraser, P Tomer, K AF Perdivara, Irina Petrovich, Robert Tokar, Erik J. Waalkes, Mike Fraser, Paul Tomer, Ken TI Characterization of O-glycosylation of the beta-amyloid Precursor Protein from Wild Type and CRND8 Transgenic Mice Models of Alzheimer's Disease SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Tokar, Erik J.; Waalkes, Mike] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. [Fraser, Paul] Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 232 BP 1526 EP 1527 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300231 ER PT J AU Krieger, A Iordachita, II Guion, P Singh, AK Kaushal, A Menard, C Pinto, PA Camphausen, K Fichtinger, G Whitcomb, LL AF Krieger, Axel Iordachita, Iulian I. Guion, Peter Singh, Anurag K. Kaushal, Aradhana Menard, Cynthia Pinto, Peter A. Camphausen, Kevin Fichtinger, Gabor Whitcomb, Louis L. TI An MRI-Compatible Robotic System With Hybrid Tracking for MRI-Guided Prostate Intervention SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Image-guided intervention; MRI; prostate cancer; robot manipulators ID MAGNETIC-RESONANCE; TRANSGLUTEAL BIOPSIES; CLINICAL-SIGNIFICANCE; NEEDLE PLACEMENT; FIELD SYSTEM; 1.5 T; CANCER; INTEGRATION; SCANNER; FEASIBILITY AB This paper reports the development, evaluation, and first clinical trials of the access to the prostate tissue (APT) II system-a scanner independent system for magnetic resonance imaging (MRI)-guided transrectal prostate interventions. The system utilizes novel manipulator mechanics employing a steerable needle channel and a novel six degree-of-freedom hybrid tracking method, comprising passive fiducial tracking for initial registration and subsequent incremental motion measurements. Targeting accuracy of the system in prostate phantom experiments and two clinical human-subject procedures is shown to compare favorably with existing systems using passive and active tracking methods. The portable design of the APT II system, using only standard MRI image sequences and minimal custom scanner interfacing, allows the system to be easily used on different MRI scanners. C1 [Krieger, Axel; Iordachita, Iulian I.; Whitcomb, Louis L.] Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. [Krieger, Axel; Iordachita, Iulian I.; Whitcomb, Louis L.] Johns Hopkins Univ, Lab Computat Sensing & Robot, Baltimore, MD 21218 USA. [Guion, Peter; Singh, Anurag K.; Kaushal, Aradhana; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Menard, Cynthia] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada. [Menard, Cynthia] Univ Toronto, Dept Radiat Oncol, Toronto, ON M5S 3E2, Canada. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Fichtinger, Gabor] Queens Univ, Sch Comp, Kingston, ON K7L 3N6, Canada. RP Whitcomb, LL (reprint author), Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. EM krieger.axel@gmail.com; iordachita@jhu.edu; guionp@mail.nih.gov; Anurag.Singh@RoswellPark.org; kaushala@mail.nih.gov; Cynthia.Menard@rmp.uhn.on.ca; pintop@mail.nih.gov; camphauk@mail.nih.gov; gabor@cs.queensu.ca; llw@jhu.edu RI Iordachita, Iulian/A-3507-2010 OI Iordachita, Iulian/0000-0002-2510-9008 FU National Institutes of Health [RO1-EB02963]; Cancer Care Ontario Research Chair in Medical Imaging FX This work was supported by the National Institutes of Health under Grant RO1-EB02963 to the Johns Hopkins University. The work of G. Fichtinger was supported by a Cancer Care Ontario Research Chair in Medical Imaging. The Johns Hopkins University has licensed intellectual property for the device and system described herein to Sentinelle Medical Inc., Toronto, Canada. NR 65 TC 31 Z9 31 U1 1 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD NOV PY 2011 VL 58 IS 11 BP 3049 EP 3060 DI 10.1109/TBME.2011.2134096 PG 12 WC Engineering, Biomedical SC Engineering GA 835FA UT WOS:000296019500002 PM 22009867 ER PT J AU Tadayyon, H Lasso, A Kaushal, A Guion, P Fichtinger, G AF Tadayyon, Hadi Lasso, Andras Kaushal, Aradhana Guion, Peter Fichtinger, Gabor TI Target Motion Tracking in MRI-guided Transrectal Robotic Prostate Biopsy SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Biopsy; motion tracking and compensation; MRI; prostate cancer; registration ID REGISTRATION; CANCER; INTERVENTIONS AB Purpose: MRI-guided prostate needle biopsy requires compensation for organ motion between target planning and needle placement. Two questions are studied and answered in this paper: 1) is rigid registration sufficient in tracking the targets with an error smaller than the clinically significant size of prostate cancer and 2) what is the effect of the number of intraoperative slices on registration accuracy and speed? Methods: we propose multislice-to-volume registration algorithms for tracking the biopsy targets within the prostate. Three orthogonal plus additional transverse intraoperative slices are acquired in the approximate center of the prostate and registered with a high-resolution target planning volume. Both rigid and deformable scenarios were implemented. Both simulated and clinical MRI-guided robotic prostate biopsy data were used to assess tracking accuracy. Results: average registration errors in clinical patient data were 2.6mm for the rigid algorithm and 2.1mm for the deformable algorithm. Conclusion: rigid tracking appears to be promising. Three tracking slices yield significantly high registration speed with an affordable error. C1 [Lasso, Andras; Fichtinger, Gabor] Queens Univ, Sch Comp, Kingston, ON K7L 3N6, Canada. [Tadayyon, Hadi] Queens Univ, Dept Elect & Comp Engn, Kingston, ON K7L 3N6, Canada. [Kaushal, Aradhana; Guion, Peter] NIH, Bethesda, MD 20892 USA. RP Fichtinger, G (reprint author), Queens Univ, Sch Comp, Kingston, ON K7L 3N6, Canada. EM hadi.tadayyon@utoronto.ca; lasso@cs.queensu.ca; kaushala@mail.nih.gov; guionp@mail.nih.gov; gabor@cs.queensu.ca FU National Institutes of Health [R01 EB002963]; Cancer Care Ontario Research Chair FX The work of H. Tadayyon and A. Lasso were supported in part by the National Institutes of Health under Grant R01 EB002963. The work of G. Fichtinger was supported by Cancer Care Ontario Research Chair. NR 23 TC 10 Z9 10 U1 0 U2 2 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 NOV PY 2011 VL 58 IS 11 BP 3135 EP 3142 DI 10.1109/TBME.2011.2163633 PG 8 WC Engineering, Biomedical SC Engineering GA 835FA UT WOS:000296019500012 PM 21824841 ER PT J AU Hirahara, K Vahedi, G Ghoreschi, K Yang, XP Nakayamada, S Kanno, Y O'Shea, JJ Laurence, A AF Hirahara, Kiyoshi Vahedi, Golnaz Ghoreschi, Kamran Yang, Xiang-Ping Nakayamada, Shingo Kanno, Yuka O'Shea, John J. Laurence, Arian TI Helper T-cell differentiation and plasticity: insights from epigenetics SO IMMUNOLOGY LA English DT Review DE epigenetics; histone modification; signal transducer and activator of transcription; T-cell differentiation; T-cell plasticity ID ROR-GAMMA-T; RANGE INTRACHROMOSOMAL INTERACTIONS; EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTOR; TGF-BETA; TH17 CELLS; HISTONE MODIFICATIONS; GENE-EXPRESSION; IN-VIVO; SIGNALING PATHWAYS AB CD4(+) T cells have critical roles in orchestrating immune responses to diverse microbial pathogens. This is accomplished through the differentiation of CD4(+) T helper cells to specialized subsets in response to microbial pathogens, which evoke a distinct cytokine milieu. Signal transducer and activator of transcription family transcription factors sense these cytokines and they in turn regulate expression of lineage-defining master regulators that programme selective gene expression, resulting in distinctive phenotypes. However, phenotype and restricted gene expression are determined not only by the action of transcription factors; chromatin accessibility is required for these factors to exert their effect. Technical advances have greatly expanded our understanding of transcription factor action and dynamic changes in the epigenome that accompany cellular differentiation. In this review, we will discuss recent progress in the understanding of how cytokines influence gene expression and epigenetic modifications, and the impact of these findings on our views of helper cell lineage commitment and plasticity. C1 [Hirahara, Kiyoshi; Vahedi, Golnaz; Ghoreschi, Kamran; Yang, Xiang-Ping; Nakayamada, Shingo; Kanno, Yuka; O'Shea, John J.; Laurence, Arian] NIAMSD, Dept Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Hirahara, K (reprint author), NIAMSD, Dept Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, 10 Ctr Dr,Bldg10,Room 13C103, Bethesda, MD 20892 USA. EM hiraharak@mail.nih.gov; laurencea@mail.nih.gov RI Laurence, Arian/A-8770-2009; Kanno, Yuka/B-5802-2013; Hirahara, Kiyoshi/E-2460-2017; OI Laurence, Arian/0000-0003-0942-8292; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319 FU NIH/NIAMS FX We would like to acknowledge the assistance of Gustavo Gutierrez-Cruz and the NIAMS Solexa Sequencing Core, and Dr. Hongwei Sun and the NIAMS Biodata Mining Section. This work was supported by NIH/NIAMS Intramural Research Program (IRP). NR 148 TC 44 Z9 47 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD NOV PY 2011 VL 134 IS 3 BP 235 EP 245 DI 10.1111/j.1365-2567.2011.03483.x PG 11 WC Immunology SC Immunology GA 836BD UT WOS:000296080800001 PM 21977994 ER PT J AU Gujer, C Sundling, C Seder, RA Hedestam, GBK Lore, K AF Gujer, Cornelia Sundling, Christopher Seder, Robert A. Hedestam, Gunilla B. Karlsson Lore, Karin TI Human and rhesus plasmacytoid dendritic cell and B-cell responses to Toll-like receptor stimulation SO IMMUNOLOGY LA English DT Article DE adjuvants; B cells; CpGDNA; dendritic cells; plasmacytoid; Type I interferon/toll-like receptors ID BLOOD MONONUCLEAR-CELLS; NATURAL-KILLER-CELLS; HIV-1 ENV TRIMERS; I INTERFERON; IMMUNODEFICIENCY VIRUS; NONHUMAN-PRIMATES; CPG OLIGODEOXYNUCLEOTIDES; HUMORAL RESPONSES; ADAPTIVE IMMUNITY; VACCINE ADJUVANTS AB Interferon-alpha (IFN-alpha) produced at high levels by human plasmacytoid dendritic cells (pDCs) can specifically regulate B-cell activation to Toll-like receptor (TLR) 7/8 stimulation. To explore the influence of IFN-alpha and pDCs on B-cell functions in vivo, studies in non-human primates that closely resemble humans in terms of TLR expression on different subsets of immune cells are valuable. Here, we performed a side-by side comparison of the response pattern between human and rhesus macaque B cells and pDCs in vitro to well-defined TLR ligands and tested whether IFN-alpha enhanced B-cell function comparably. We found that both human and rhesus B cells proliferated while pDCs from both species produced high levels of IFN-alpha in response to ligands targeting TLR7/8 and TLR9. Both human and rhesus B-cell proliferation to TLR7/8 ligand and CpG class C was significantly increased in the presence of IFN-alpha. Although both human and rhesus B cells produced IgM upon stimulation, only human B cells acquired high expression of CD27 associated with plasmablast formation. Instead, rhesus B-cell differentiation and IgM levels correlated to down-regulation of CD20. These data suggest that the response pattern of human and rhesus B cells and pDCs to TLR7/8 and TLR9 is similar, although some differences in the cell surface phenotype of the differentiating cells exist. A more thorough understanding of potential similarities and differences between human and rhesus cells and their response to potential vaccine components will provide important information for translating non-human primate studies into human trials. C1 [Gujer, Cornelia; Lore, Karin] Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. [Sundling, Christopher; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Seder, Robert A.; Lore, Karin] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Lore, K (reprint author), Karolinska Inst, Dept Med, Ctr Infect Med, F59, Stockholm, Sweden. EM Karin.Lore@ki.se OI Sundling, Christopher/0000-0002-6138-690X FU Vetenskapsradet, the Swedish International Development Agency (Sida); International AIDS Vaccine Initiative (IAVI); Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Society of Medicine FX This work was supported by grants from Vetenskapsradet, the Swedish International Development Agency (Sida), the International AIDS Vaccine Initiative (IAVI), the Swedish Governmental Agency for Innovation Systems (Vinnova) and the Swedish Society of Medicine. We are grateful for the assistance of the veterinarians Drs Mats Spangberg and Helene Fredlund, and to the personnel at the Astrid Fagraeus Laboratory at the Swedish Institute for Infectious Disease Control. NR 64 TC 23 Z9 23 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD NOV PY 2011 VL 134 IS 3 BP 257 EP 269 DI 10.1111/j.1365-2567.2011.03484.x PG 13 WC Immunology SC Immunology GA 836BD UT WOS:000296080800003 PM 21977996 ER PT J AU Vargas-Inchaustegui, DA Demberg, T Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Demberg, Thorsten Robert-Guroff, Marjorie TI A CD8 alpha(-) subpopulation of macaque circulatory natural killer cells can mediate both antibody-dependent and antibody-independent cytotoxic activities SO IMMUNOLOGY LA English DT Article DE antibody-dependent cellular cytotoxicity; CD16; CD56; simian immunodeficiency virus ID SIMIAN IMMUNODEFICIENCY VIRUS; RHESUS MACAQUES; NK-CELLS; HIV-INFECTION; ADAPTIVE IMMUNITY; CELLULAR CYTOTOXICITY; PROTECTIVE EFFICACY; EFFECTOR-CELLS; LEUKEMIA-CELLS; LYMPHOID-CELLS AB Natural killer (NK) cells are important components of the innate immune system that mediate effector and regulatory functions. As effector cells, NK cells help control virus-infected cells through cell-mediated antibody-dependent mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). Although macaques are an important and reliable animal model for the study of retrovirus-induced human diseases, and despite the crucial role played by NK cells in innate and adaptive immune responses against simian immunodeficiency virus (SIV), only a few studies have attempted to characterize different macaque NK cell subpopulations. In the present study, we identified a subpopulation of circulatory CD8 alpha(-) macaque NK cells that express NK lineage markers and exhibit cytotoxic potential. CD8 alpha(-) NK cells were phenotypically characterized as CD3(-) CD14(-) CD20(-) CD8 alpha(-) cells that express NK cell markers including CD16, CD56, granzyme B, perforin, NKG2D and KIR2D. Based on their CD56/CD16 expression patterns, cells within the CD8 alpha(-) gate can be divided into four subpopulations: CD56(dim) CD16(bright), CD56(dim) CD16(-), CD56(bright) CD16(-), and CD56(-) CD16(-) cells. In contrast, CD8 alpha+ NK cells are 95% CD56(dim) CD16(bright), which correlates with their high cytotoxic potential. Upon interleukin-15 activation, CD8 alpha(-) cells up-regulated CD69 expression and produced low levels of interferon-gamma and tumour necrosis factor-a. Sorted CD8 alpha(-) NK cells were capable of killing MHC-I-devoid target cells and mediated ADCC responses against SIV gp120-coated target cells in the presence of macaque anti-gp120 antibodies. Taking into account CD8 alpha(-) myeloid dendritic cells, we show that about 35% of macaque CD8 alpha(-) cells represent a novel, functional population of circulatory NK cells that possesses cytotoxic potential and is capable of mediating anti-viral immune responses. C1 [Vargas-Inchaustegui, Diego A.; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU NIH, National Cancer Institute FX We thank the NIH/NCRR Resource for Nonhuman Primate Immune Reagents (Emory University, Atlanta, GA) for the macaque recombinant proteins; the NIH Division of Veterinary Resources (Bethesda, MD) for providing macaque blood samples; Dr Bernard A. P. Lafont (Laboratory of Molecular Microbiology, NIAID/NIH) for providing 721.221 cells; Drs Alison E. Hogg and L. Jean Patterson (Vaccine Branch, NCI/NIH) for helpful discussions; and Katherine M. McKinnon (Vaccine Branch Flow Cytometry Core, NCI/NIH) for expert advice. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 63 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD NOV PY 2011 VL 134 IS 3 BP 326 EP 340 DI 10.1111/j.1365-2567.2011.03493.x PG 15 WC Immunology SC Immunology GA 836BD UT WOS:000296080800009 PM 21978002 ER PT J AU Easterbrook, JD Dunfee, RL Schwartzman, LM Jagger, BW Sandouk, A Kash, JC Memoli, MJ Taubenberger, JK AF Easterbrook, Judith D. Dunfee, Rebecca L. Schwartzman, Louis M. Jagger, Brett W. Sandouk, Aline Kash, John C. Memoli, Matthew J. Taubenberger, Jeffery K. TI Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE IFN-beta; influenza; leptin; obesity; testosterone ID DIET-INDUCED OBESITY; SEASONAL INFLUENZA; IMMUNE-RESPONSES; C57BL/6J MOUSE; HOSPITALIZATION; DEATH AB Background Obesity has been identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections. Objectives Our aim was to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus. Methods Diet-induced obese (DIO) and their non-obese, age-matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09), current seasonal H1N1, A/NY/312/2001 (NY312), or highly pathogenic 1918-like H1N1, A/Iowa/Swine/1931 (Sw31), virus. Results Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post-inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon-beta and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection. Conclusions Together, these data support epidemiologic reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear. C1 [Easterbrook, Judith D.; Dunfee, Rebecca L.; Schwartzman, Louis M.; Jagger, Brett W.; Sandouk, Aline; Kash, John C.; Memoli, Matthew J.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIH; NIAID FX We thank the Comparative Medicine Branch (NIH/NIAID) for their assistance with animal studies. This work was supported by the Intramural Research Program of the NIH and the NIAID. NR 30 TC 17 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD NOV PY 2011 VL 5 IS 6 BP 418 EP 425 DI 10.1111/j.1750-2659.2011.00254.x PG 8 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 836BA UT WOS:000296080300010 PM 21668672 ER PT J AU Baca-Garcia, E Perez-Rodriguez, MM Oquendo, MA Keyes, KM Hasin, DS Grant, BF Blanco, C AF Baca-Garcia, Enrique Mercedes Perez-Rodriguez, M. Oquendo, Maria A. Keyes, Katherine M. Hasin, Deborah S. Grant, Bridget F. Blanco, Carlos TI Estimating risk for suicide attempt: Are we asking the right questions? Passive suicidal ideation as a marker for suicidal behavior SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Attempted suicide; Suicidal ideation; Desire for death ID NATIONAL EPIDEMIOLOGIC SURVEY; MAJOR DEPRESSIVE DISORDER; TOWER-OF-BABEL; UNITED-STATES; ANTIDEPRESSANT TREATMENT; CLINICAL PREDICTORS; COMORBIDITY SURVEY; PREVALENCE; ACTS; NOMENCLATURE AB Background: Desire for death is not generally considered a harbinger of more severe suicidal behavior and is not routinely included in suicide research and assessment interviews. We aimed to compare desire for death and suicidal ideation as clinical markers for suicide attempts. Methods: Using data from two nationally representative surveys (n = 42,862 and n = 43,093 respectively), we examined whether desire for death predicts suicide attempts. We compared the odds ratio (OR) and "Number Needed to be Exposed for one additional person to be Harmed" [NNEH] for lifetime suicide attempts among those with desire for death but no suicidal ideation; those with suicidal ideation but no desire for death, and those with both desire for death and suicidal ideation, compared to those with neither desire for death nor suicidal ideation. Results: The risk for lifetime suicide attempt was similar among those with lifetime desire for death with no suicidal ideation and those with lifetime suicidal ideation with no desire for death. Respondents with both lifetime desire for death and suicidal ideation had the highest risk for lifetime suicide attempts. Limitations: Cross-sectional design and self-reported suicidal ideation/attempts are viewed as limitations of this study. Conclusions: Querying individuals on desire for death has the same value as assessing suicidal ideation to examine risk for suicide attempt. A combination of desire for death and suicidal ideation is the best predictor for suicide attempts. This is of high clinical relevance since we suggest that desire for death should be included as a potential clinical marker of suicidality in clinical assessments. (C) 2011 Elsevier B.V. All rights reserved. C1 [Mercedes Perez-Rodriguez, M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Baca-Garcia, Enrique; Oquendo, Maria A.; Hasin, Deborah S.; Blanco, Carlos] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Baca-Garcia, Enrique; Oquendo, Maria A.; Hasin, Deborah S.; Blanco, Carlos] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Baca-Garcia, Enrique] Fdn Jimenez Diaz Hosp, Dept Psychiat, Madrid 28040, Spain. [Baca-Garcia, Enrique] Univ Autonoma Madrid, CIBERSAM, Madrid 28040, Spain. [Mercedes Perez-Rodriguez, M.] Ramon y Cajal Univ Hosp, CIBERSAM, Dept Psychiat, Madrid 28034, Spain. [Keyes, Katherine M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Perez-Rodriguez, MM (reprint author), Mt Sinai Sch Med, Dept Psychiat, Psychiat Box 1230,1 Gustave L Levy Pl, New York, NY 10029 USA. EM merperez2@yahoo.com RI Blanco, Carlos/I-4906-2013; Perez Rodriguez, Maria/B-9410-2013; Baca-Garcia, Enrique/F-4106-2015 OI Blanco, Carlos/0000-0001-6187-3057; Perez Rodriguez, Maria/0000-0001-5137-1993; Baca-Garcia, Enrique/0000-0002-6963-6555 FU NIMH; NIAAA; American Foundation for Suicide Prevention; Moody's Foundation; Eli Lilly; GlaxoSmithKline; Pfizer; Alicia Koplowitz Foundation; Instituto de Salud Carlos III; Spanish Ministry of Health; NIH [DA019606, DA020783, DA023200, DA023973, MH076051, MH082773, CA133050, AA014223]; New York State Psychiatric Institute; National Institute on Drug Abuse (NIDA); CIBERSAM FX Dr. Oquendo has received funding from NIMH, NIAAA, American Foundation for Suicide Prevention, Moody's Foundation, an unrestricted educational grant from Eli Lilly and has served as a consultant to Pfizer.; Dr. Blanco is an investigator or co-investigator in studies supported by Eli Lilly, GlaxoSmithKline and Pfizer.; The following authors of this study were supported by Alicia Koplowitz Foundation (Dr. Baca-Garcia), Instituto de Salud Carlos III, CIBERSAM and the Spanish Ministry of Health (Drs. Baca-Garcia and Perez-Rodriguez), NIH grants DA019606, DA020783, DA023200, DA023973, MH076051, MH082773 and CA133050 (Dr. Blanco) and AA014223 (Dr. Hasin), the American Foundation for Suicide Prevention (Dr. Blanco), and the New York State Psychiatric Institute (Drs. Blanco, Hasin and Oquendo). The NESARC was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse (NIDA). NR 46 TC 40 Z9 46 U1 3 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 NOV PY 2011 VL 134 IS 1-3 BP 327 EP 332 DI 10.1016/j.jad.2011.06.026 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 831TG UT WOS:000295753400041 PM 21784532 ER PT J AU Waters, LS Sandoval, M Storz, G AF Waters, Lauren S. Sandoval, Melissa Storz, Gisela TI The Escherichia coli MntR Miniregulon Includes Genes Encoding a Small Protein and an Efflux Pump Required for Manganese Homeostasis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; BACILLUS-SUBTILIS; SMALL-RNA; DEINOCOCCUS-RADIODURANS; COMPARATIVE GENOMICS; HYDROGEN-PEROXIDE; IDENTIFICATION; RESISTANCE; FUR; REGULATOR AB Manganese is a critical micronutrient for cells, serving as an enzyme cofactor and protecting against oxidative stress. Yet, manganese is toxic in excess and little is known about its distribution in cells. Bacteria control intracellular manganese levels by the transcription regulator MntR. When this work began, the only Escherichia coli K-12 gene known to respond to manganese via MntR repression was mntH, which encodes a manganese importer. We show that mntS (formerly the small RNA gene rybA) is repressed by manganese through MntR and encodes an unannotated 42-amino-acid protein. Overproduction of MntS causes manganese sensitivity, while a lack of MntS perturbs proper manganese-dependent repression of mntH. We also provide evidence that mntP (formerly yebN), which encodes a putative efflux pump, is positively regulated by MntR. Deletion of mntP leads to profound manganese sensitivity and to elevated intracellular manganese levels. This work thus defines two new proteins involved in manganese homeostasis and suggests mechanisms for their action. C1 [Waters, Lauren S.; Sandoval, Melissa; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD USA. RP Storz, G (reprint author), NIH, 18 Lib Dr, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of General Medical Sciences; National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Pharmacology Research Associate Program at the National Institute of General Medical Sciences (L.S.W.), and the National Institutes of Health Undergraduate Scholarship Program (M.S.). NR 51 TC 44 Z9 47 U1 0 U2 16 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 NOV PY 2011 VL 193 IS 21 BP 5887 EP 5897 DI 10.1128/JB.05872-11 PG 11 WC Microbiology SC Microbiology GA 836XW UT WOS:000296153400001 PM 21908668 ER PT J AU Makarova, KS Wolf, YI Snir, S Koonin, EV AF Makarova, Kira S. Wolf, Yuri I. Snir, Sagi Koonin, Eugene V. TI Defense Islands in Bacterial and Archaeal Genomes and Prediction of Novel Defense Systems SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ABORTIVE INFECTION SYSTEM; RESTRICTION-MODIFICATION SYSTEMS; STREPTOMYCES-COELICOLOR A3(2); ESCHERICHIA-COLI; LACTOCOCCUS-LACTIS; RNA-POLYMERASE; ANTAGONISTIC COEVOLUTION; GENETIC ELEMENTS; CONTEXT ANALYSIS; IMMUNE-SYSTEM AB The arms race between cellular life forms and viruses is a major driving force of evolution. A substantial fraction of bacterial and archaeal genomes is dedicated to antivirus defense. We analyzed the distribution of defense genes and typical mobilome components (such as viral and transposon genes) in bacterial and archaeal genomes and demonstrated statistically significant clustering of antivirus defense systems and mobile genes and elements in genomic islands. The defense islands are enriched in putative operons and contain numerous overrepresented gene families. A detailed sequence analysis of the proteins encoded by genes in these families shows that many of them are diverged variants of known defense system components, whereas others show features, such as characteristic operonic organization, that are suggestive of novel defense systems. Thus, genomic islands provide abundant material for the experimental study of bacterial and archaeal antivirus defense. Except for the CRISPR-Cas systems, different classes of defense systems, in particular toxin-antitoxin and restriction-modification systems, show nonrandom clustering in defense islands. It remains unclear to what extent these associations reflect functional cooperation between different defense systems and to what extent the islands are genomic "sinks" that accumulate diverse nonessential genes, particularly those acquired via horizontal gene transfer. The characteristics of defense islands resemble those of mobilome islands. Defense and mobilome genes are nonrandomly associated in islands, suggesting nonadaptive evolution of the islands via a preferential attachment-like mechanism underpinned by the addictive properties of defense systems such as toxins-antitoxins and an important role of horizontal mobility in the evolution of these islands. C1 [Makarova, Kira S.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Snir, Sagi] Univ Haifa Mt Carmel, Dept Evolutionary & Environm Biol, IL-31905 Haifa, Israel. [Snir, Sagi] Univ Haifa Mt Carmel, Inst Evolut, IL-31905 Haifa, Israel. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Department of Health and Human Services (NIH, National Library of Medicine); Yeshaya Horowitz Association through the Center for Complexity Science FX K.S.M., Y.I.W., and E.V.K. are supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). S.S. is supported by the Yeshaya Horowitz Association through the Center for Complexity Science. NR 95 TC 62 Z9 65 U1 2 U2 21 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 NOV PY 2011 VL 193 IS 21 BP 6039 EP 6056 DI 10.1128/JB.05535-11 PG 18 WC Microbiology SC Microbiology GA 836XW UT WOS:000296153400016 PM 21908672 ER PT J AU Klein, WMP Harris, PR Ferrer, RA Zajac, LE AF Klein, William M. P. Harris, Peter R. Ferrer, Rebecca A. Zajac, Laura E. TI Feelings of vulnerability in response to threatening messages: Effects of self-affirmation SO JOURNAL OF EXPERIMENTAL SOCIAL PSYCHOLOGY LA English DT Article DE Self-affirmation; Feelings of vulnerability; Defensive responses to threat ID LOW SOCIOECONOMIC-STATUS; HEALTH-RISK INFORMATION; CANCER WORRY; REDUCE DEFENSIVENESS; BEHAVIOR; PERCEPTIONS; SMOKERS; ACCEPTANCE; PSYCHOLOGY; WARNINGS AB We examined effects of self-affirmation on feelings of vulnerability and behavioral intentions following exposure to personally threatening messages varying in message strength. In Experiment 1, female alcohol consumers read a strong message linking alcohol to breast cancer risk. Self-affirmed participants exhibited higher feelings of vulnerability concerning consumption levels and personal risk. In Experiment 2, female caffeine consumers read a weak or strong message linking caffeine to breast disease. Self-affirmed participants reported greater feelings of vulnerability to breast disease and greater intentions to reduce caffeine consumption (relative to control participants) only when reading the strong message. Effects on intentions were mediated by effects on feelings of vulnerability. These studies show that feelings of vulnerability can mediate effects of self-affirmation on intentions to change behavior under threat, although only in the presence of strong messages. Published by Elsevier Inc. C1 [Klein, William M. P.; Ferrer, Rebecca A.] NCI, Bethesda, MD 20892 USA. [Klein, William M. P.; Zajac, Laura E.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Harris, Peter R.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. RP Klein, WMP (reprint author), NCI, 6130 Execut Blvd,Room 4060, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov NR 67 TC 23 Z9 23 U1 4 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-1031 J9 J EXP SOC PSYCHOL JI J. Exp. Soc. Psychol. PD NOV PY 2011 VL 47 IS 6 BP 1237 EP 1242 DI 10.1016/j.jesp.2011.05.005 PG 6 WC Psychology, Social SC Psychology GA 833QO UT WOS:000295900200026 ER PT J AU Fraum, TJ Kreisl, TN Sul, J Fine, HA Iwamoto, FM AF Fraum, Tyler J. Kreisl, Teri N. Sul, Joohee Fine, Howard A. Iwamoto, Fabio M. TI Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioma; Glioblastoma; Antiangiogenic agents; Bevacizumab; Stroke; CNS hemorrhage ID BRAIN-TUMOR CONSORTIUM; RECURRENT MALIGNANT GLIOMAS; PHASE-II TRIAL; ANTI-VEGF THERAPY; GLIOBLASTOMA-MULTIFORME; BEVACIZUMAB; CANCER; CHEMOTHERAPY; PROGRESSION; IRINOTECAN AB Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received FDA approval for recurrent glioblastoma. Additionally, several VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have entered trials for recurrent glioma. Phase II studies of bevacizumab for recurrent GBM have reported incidents of ischemic stroke (IS) and intracranial hemorrhage (ICH); however, their clinical features and outcomes were not described in detail. We conducted a retrospective study of recurrent malignant glioma patients with radiographically-confirmed IS or ICH while on antiangiogenic therapy. The study population included patients treated between 2005 and 2010 at the National Cancer Institute on four different phase I and II trials of antiangiogenic agents for recurrent malignant glioma, as well as patients receiving bevacizumab off clinical trial during this same period. Eight patients developed IS (50% lacunar) and 14 experienced ICH (79% intratumoral) while on antiangiogenic therapy for malignant glioma recurrence. The median age was 53 years, 17 patients (77%) were men, and 59% had glioblastoma. The frequencies of IS and ICH were 1.9% and 1.9% in bevacizumab trials. None of the patients on VEGFR TKI trials developed IS, while 3.8% experienced ICH. Patients with IS were treated with antiangiogenic agents longer than those with ICH (median, 16.2 vs. 2.6 months, P = 0.001). Median survival was 7.8 months after IS and 2.6 months after ICH. The most common IS subtype was lacunar, while most ICHs were asymptomatic and intratumoral. Overall, IS seems to be a complication of prolonged antiangiogenic therapy, while intratumoral bleeds often occur in the setting of tumor progression. C1 [Fraum, Tyler J.; Kreisl, Teri N.; Sul, Joohee; Fine, Howard A.; Iwamoto, Fabio M.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Fraum, Tyler J.; Kreisl, Teri N.; Sul, Joohee; Fine, Howard A.; Iwamoto, Fabio M.] NINDS, NIH, Bethesda, MD 20892 USA. [Fraum, Tyler J.] Duke Univ, Sch Med, Durham, NC USA. RP Iwamoto, FM (reprint author), NCI, Neurooncol Branch, 9030 Old Georgetown Rd,Room 221, Bethesda, MD 20892 USA. EM tyler.fraum@duke.edu; kreislt@mail.nih.gov; joohee.sul@nih.gov; hfine@mail.nih.gov; iwamotofm@mail.nih.gov FU NIH [1ZI-DBC011098-02, 1ZIABC011347-01, 1ZIABC011348-01]; Pfizer Inc; National Cancer Institute FX NIH Intramural Research Program (1ZI-DBC011098-02). T.J.F. is a Fellow in 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 Inc). F.M.I. is supported by the National Cancer Institute's Clinical Investigator Development Program and the NIH Intramural Program (1ZIABC011347-01 and 1ZIABC011348-01). NR 26 TC 26 Z9 26 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2011 VL 105 IS 2 BP 281 EP 289 DI 10.1007/s11060-011-0579-4 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 835VK UT WOS:000296064200018 PM 21603965 ER PT J AU Steffen-Smith, EA Shih, JH Hipp, SJ Bent, R Warren, KE AF Steffen-Smith, Emilie A. Shih, Joanna H. Hipp, Sean J. Bent, Robyn Warren, Katherine E. TI Proton magnetic resonance spectroscopy predicts survival in children with diffuse intrinsic pontine glioma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Pediatric; Brain; Brainstem tumor; MRI; MR spectroscopy; Prognosis ID BRAIN-STEM GLIOMAS; MR SPECTROSCOPY; STEREOTACTIC BIOPSY; IMAGING BIOMARKERS; TUMORS; GRADE; RADIOTHERAPY; PERFUSION; PROGRESSION; CEREBELLUM AB Patients with diffuse intrinsic pontine glioma (DIPG) face a grim prognosis with limited treatment options. Many patients will enroll on investigational trials though the role of chemotherapy or immunotherapy is unclear. Radiographic changes on conventional MRI are used to evaluate tumor response and progression, but are not predictive of outcome in these patients. More sensitive measures of tumor biology are needed to improve patient management. We evaluated changes in magnetic resonance spectroscopy (MRS) biomarkers in patients with DIPG. Thirty-eight patients were enrolled prospectively on an IRB-approved protocol, which included standard MRI, single voxel spectroscopy (SVS) and multi-slice multi-voxel spectroscopy (MRSI). Scans were performed at multiple time points during each patient's clinical course, with a total of 142 scans. The prognostic values of Choline:N-acetylaspartate (Cho:NAA), Cho:Creatine (Cho:Cr) and the presence of lactate and lipids (+Lac/Lip) were evaluated. Cho:NAA and variance in Cho:NAA values among different voxels within a tumor were each predictive of shorter survival. This prospective study shows that MRS can be used to identify high-risk patients and monitor changes in tumor metabolism, which may reflect changes in tumor behavior. C1 [Steffen-Smith, Emilie A.; Hipp, Sean J.; Bent, Robyn; Warren, Katherine E.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Hipp, Sean J.] Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. [Hipp, Sean J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov OI Steffen-Smith, Emilie/0000-0002-4966-3046 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors thank Dr. Alan Barnett and Dr. Jan Willem van der Veen for their contributions towards the MRSI acquisition and data analysis. This work was presented in part at the ASNR 47th Annual Meeting, Vancouver 2009. Research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views expressed in this article are those of the authors and do not reflect the official policy of the National Institutes of Health, Department of Army, Department of Defense, or U.S. Government. NR 56 TC 20 Z9 23 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2011 VL 105 IS 2 BP 365 EP 373 DI 10.1007/s11060-011-0601-x PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 835VK UT WOS:000296064200027 PM 21567301 ER PT J AU Balamurugan, A Rees, JR Kosary, C Rim, SH Li, J Stewart, SL AF Balamurugan, Appathurai Rees, Judy R. Kosary, Carol Rim, Sun Hee Li, Jun Stewart, Sherri L. TI Subsequent primary cancers among men and women with in situ and invasive melanoma of the skin SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE melanoma; posttreatment surveillance; screening; subsequent primary cancer; survivors ID CUTANEOUS MALIGNANT-MELANOMA; MULTIPLE PRIMARY MELANOMAS; 2ND PRIMARY CANCERS; FOLLOW-UP; EARLIER DIAGNOSIS; RISK; EXPOSURE; SURVIVORS; SURVEILLANCE; SUN AB Background: An estimated 750,000 melanoma survivors in the United States are at increased risk of subsequent primary cancers. Objective: We sought to assess the risk of developing subsequent primary cancers among people with cutaneous melanoma. Methods: Using 1992 to 2006 data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program, 40,881 people with in situ melanoma and 76,041 people with invasive melanoma were followed up (mean of 5.6 years) for the development of subsequent primary cancers. The observed number of subsequent cancers was compared with those expected based on age-/race-/year-/site-specific rates in the Surveillance, Epidemiology, and End Results population. Standardized incidence ratios (SIRs) (SIR = observed number/expected number) were considered statistically significant if they differed from 1, with an alpha level of 0.05. Results: After a first primary in situ melanoma, risk was significantly elevated for subsequent invasive melanoma and chronic lymphocytic leukemia among men (SIRs = 8.43 and 1.44, respectively) and women (SIRs = 12.33 and 1.79, respectively). After a first primary invasive melanoma, risk was significantly elevated for subsequent invasive melanoma, thyroid cancer, non-Hodgkin lymphoma, and chronic lymphocytic leukemia among both men (SIRs = 12.50, 2.67, 1.56, and 1.57, respectively) and women (SIRs = 15.67, 1.77, 1.42, and 1.63, respectively). Limitations: Case ascertainment issues particularly affecting in situ melanoma cases could affect results. The role of detection bias in the diagnoses of some subsequent cancers cannot be completely eliminated. Conclusions: The findings of the study should guide the development of strategies such as posttreatment surveillance, screening, and ultraviolet exposure education among melanoma survivors to improve cancer survivorship. (J Am Acaci Dermatol 2011;65:S69-77.) C1 [Balamurugan, Appathurai] Univ Arkansas Med Sci, Dept Family & Prevent Med, Little Rock, AR 72205 USA. [Rees, Judy R.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch,New Hampshire State Canc Regist, Dept Community & Family Med,Biostat & Epidemiol S, Hanover, NH 03756 USA. [Kosary, Carol] NCI, Bethesda, MD 20892 USA. [Rim, Sun Hee; Li, Jun; Stewart, Sherri L.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Balamurugan, A (reprint author), Univ Arkansas Med Sci, Dept Family & Prevent Med, 4301 W Markham,Slot 530, Little Rock, AR 72205 USA. EM abalamurugan@uams.edu FU Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC) FX Publication of this supplement to the JAAD was supported by the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC). NR 27 TC 17 Z9 17 U1 0 U2 1 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 NOV PY 2011 VL 65 IS 5 SU S BP S69 EP S77 DI 10.1016/j.jaad.2011.04.033 PG 9 WC Dermatology SC Dermatology GA 838DX UT WOS:000296268100009 PM 22018070 ER PT J AU Buller, DB Cokkinides, V Hall, HI Hartman, AM Saraiya, M Miller, E Paddock, L Glanz, K AF Buller, David B. Cokkinides, Vilma Hall, H. Irene Hartman, Anne M. Saraiya, Mona Miller, Eric Paddock, Lisa Glanz, Karen TI Prevalence of sunburn, sun protection, and indoor tanning behaviors among Americans: Review from national surveys and case studies of 3 states SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE adults; Behavioral Risk Factor Surveillance System; children; Health Information National Trends Survey; indoor tanning; National Health Interview Survey; skin cancer risk; sun protection; sunburn; sunscreen; ultraviolet radiation; Youth Risk Behavior Survey ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; SUNSCREEN USE; SKIN-CANCER; US POPULATION; EXPOSURE; RISK; MELANOMA; ADULTS; ADOLESCENTS AB Background: Exposure to ultraviolet radiation (from solar and nonsolar sources) is a risk factor for skin cancer. Objective: We sought to summarize recent estimates on sunburns, sun-protection behaviors, and indoor tanning available from national and selected statewide behavioral surveys. Methods: Estimates of the prevalence of sunburn, sun-protection behaviors,. and indoor tanning by US adults, adolescents, and children collected in national surveys in 1992, 2004 to 2005, and 2007 to 2009 were identified and extracted from searches of computerized databases (ie, MEDLINE and PsychINFO), reference lists, and survey World Wide Web sites. Sunburn estimates from 3 state Behavioral Risk Factors Surveillance Systems were also analyzed. Results: Latest published estimates (2005) showed that 34.4% of US adults were sunburned in the past year. Incidence of sunburns was highest among men, non-Hispanic whites, young adults, and high-income groups in national surveys. About 3 in 10 adults routinely practiced sun-protection behaviors, and women and. older adults took the most precautions. Among adolescents, 69% were sunburned in the previous summer and less than 40% practiced sun protection. Approximately 60% of parents applied sunscreen and a quarter used shade to protect children. Indoor tanning was prevalent among younger adults and females. Limitations: Limitations include potential recall errors and social desirability in Self-report measures, and lack of current data on children. Conclusion: Many Americans experienced sunburns and a minority engaged in protective behaviors. Females and older adults were most vigilant about sun protection. Substantial proportions of young women and adolescents recently used indoor tanning. Future efforts should promote protective hats, clothing, and shade; motivate males and younger populations to take precautions; and convince women and adolescents to reduce indoor tanning. (J Am Acad Dermatol 2011;65:S114-23.) C1 [Buller, David B.] Klein Buendel Inc, Golden, CO 80439 USA. [Cokkinides, Vilma] Amer Canc Soc, Atlanta, GA 30329 USA. [Hall, H. Irene; Saraiya, Mona] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hartman, Anne M.] NCI, Bethesda, MD 20892 USA. [Miller, Eric] Texas Dept State Hlth Serv, Austin, TX USA. [Paddock, Lisa] New Jersey State Canc Regist, Trenton, NJ USA. [Glanz, Karen] Univ Penn, Philadelphia, PA 19104 USA. RP Buller, DB (reprint author), Klein Buendel Inc, 1667 Cole Blvd,Suite 225, Golden, CO 80439 USA. EM dbuller@kleinbuendel.com FU Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC) FX Publication of this supplement to the JAAD was supported by the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC). NR 37 TC 95 Z9 96 U1 1 U2 15 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 NOV PY 2011 VL 65 IS 5 SU S BP S114 EP S123 DI 10.1016/j.jaad.2011.05.033 PG 10 WC Dermatology SC Dermatology GA 838DX UT WOS:000296268100014 PM 22018060 ER PT J AU Richards, TB Johnson, CJ Tatalovich, Z Cockburn, M Eide, MJ Henry, KA Lai, SM Cherala, SS Huang, YJ Ajani, UA AF Richards, Thomas B. Johnson, Christopher J. Tatalovich, Zaria Cockburn, Myles Eide, Melody J. Henry, Kevin A. Lai, Sue-Min Cherala, Sai S. Huang, Youjie Ajani, Umed A. TI Association between cutaneous melanoma incidence rates among white US residents and county-level estimates of solar ultraviolet exposure SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE dermatology/manpower; incidence; melanoma/epidemiology; population surveillance; registries; skin neoplasms/epidemiology; socioeconomic factors; solar ultraviolet rays/adverse effects ID UNITED-STATES; SKIN-CANCER; LATITUDE; RISK; SURVEILLANCE; RADIATION; PROGNOSIS; NEVI; UVB AB Background. Recent US studies have raised questions as to whether geographic differences in cutaneous melanoma incidence rates are associated with differences in solar ultraviolet (UV) exposure. Objectives: We sought to assess the association of solar UV exposure with melanoma incidence rates among US non-Hispanic whites. Methods: We assessed the association between county-level estimates of average annual solar UV exposure for 1961 to 1990 and county-level melanoma incidence rates during 2004 to 2006. We used Poisson multilevel mixed models to calculate incidence density ratios by cancer stage at diagnosis while controlling for individuals' age and sex and for county-level estimates of solar UV exposure, socioeconomic status, and physician density. Results: Age-adjusted rates of early- and late-stage melanoma were both significantly higher in high solar UV counties than in low solar UV counties. Rates of late-stage melanoma incidence were generally higher among men, but younger women had a higher rate of early-stage melanoma than their male counterparts. Adjusted rates of early-stage melanoma were significantly higher in high solar UV exposure counties among men aged 35 years or older and women aged 65 years or older. Limitations: The relationship between individual-level LTVexposure and risk for melanoma was not evaluated. Conclusions: County-level solar UV exposure was associated with the incidence of early-stage melanoma among older US adults but not among younger US adults. Additional studies are needed to determine whether exposure to artificial sources of UV exposure or other factors might be mitigating the relationship between solar UV exposure and risk for melanoma. (J Am Acad Dermatol 2011;65:S50-7.) C1 [Richards, Thomas B.; Ajani, Umed A.] Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Johnson, Christopher J.] Canc Data Registry Idaho, Boise, ID USA. [Tatalovich, Zaria] NCI, Rockville, MD USA. [Cockburn, Myles] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Eide, Melody J.] Henry Ford Hosp, Dept Dermatol, Detroit, MI 48202 USA. [Eide, Melody J.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Henry, Kevin A.] Univ Utah, Dept Geog, Salt Lake City, UT USA. [Lai, Sue-Min] Univ Kansas, Med Ctr, Dept Prevent Med & Publ Hlth, Kansas City, KS 66103 USA. [Cherala, Sai S.] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Huang, Youjie] Florida Dept Hlth, Tallahassee, FL USA. RP Richards, TB (reprint author), Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy NE,K-55, Atlanta, GA 30341 USA. EM TRichards@cdc.gov OI Cherala, Sai/0000-0002-3485-574X FU Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC); Dermatology Foundation FX Publication of this supplement to the JAAD was supported by the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention (CDC). Dr Eide was supported by a Dermatology Foundation Cancer Development Award in Health Care Policy. NR 31 TC 12 Z9 13 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 NOV PY 2011 VL 65 IS 5 SU S BP S50 EP S57 DI 10.1016/j.jaad.2011.04.035 PG 8 WC Dermatology SC Dermatology GA 838DX UT WOS:000296268100007 PM 22018067 ER PT J AU Majeed, F Kamal, AK AF Majeed, Farzin Kamal, Ayeesha Kamran TI Can Selective Serotonin Reuptake Inhibitors (SSRI) improve motor recovery after stroke? What is the role of Neuroplasticity? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Majeed, Farzin] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Majeed, F (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 2 Z9 3 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 NOV PY 2011 VL 61 IS 11 BP 1147 EP 1148 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 835NU UT WOS:000296043900029 PM 22126003 ER PT J AU Zhu, ZY Qin, HR Chen, WZ Zhao, Q Shen, XY Schutte, R Wang, YP Ofek, G Streaker, E Prabakaran, P Fouda, GG Liao, HX Owens, J Louder, M Yang, YP Klaric, KA Moody, MA Mascola, JR Scott, JK Kwong, PD Montefiori, D Haynes, BF Tomaras, GD Dimitrov, DS AF Zhu, Zhongyu Qin, Haiyan Rebekah Chen, Weizao Zhao, Qi Shen, Xiaoying Schutte, Robert Wang, Yanping Ofek, Gilad Streaker, Emily Prabakaran, Ponraj Fouda, Genevieve G. Liao, Hua-Xin Owens, John Louder, Mark Yang, Yongping Klaric, Kristina-Ana Moody, M. Anthony Mascola, John R. Scott, Jamie K. Kwong, Peter D. Montefiori, David Haynes, Barton F. Tomaras, Georgia D. Dimitrov, Dimiter S. TI Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies Identified from a Patient with 2F5-Like Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 NEUTRALIZING ANTIBODIES; PROXIMAL EXTERNAL REGION; GP41; AUTOREACTIVITY; INHIBITION; ENVELOPE; LIBRARY; DISPLAY; DESIGN AB The genes encoding broadly HIV-1-neutralizing human monoclonal antibodies (MAbs) are highly divergent from their germ line counterparts. We have hypothesized that such high levels of somatic hypermutation could pose a challenge for elicitation of the broadly neutralizing (bn) Abs and that identification of less somatically mutated bn Abs may help in the design of effective vaccine immunogens. In a quest for such bn Abs, phage-and yeast-displayed antibody libraries, constructed using peripheral blood mononuclear cells (PBMCs) from a patient with bn serum containing Abs targeting the epitope of the bn MAb 2F5, were panned against peptides containing the 2F5 epitope and against the HIV-1 gp140(JR-FL). Two MAbs (m66 and m66.6) were identified; the more mutated variant (m66.6) exhibited higher HIV-1-neutralizing activity than m66, although it was weaker than 2F5 in a TZM-bl cell assay. Binding of both MAbs to gp41 alanine substitution mutant peptides required the DKW664-666 core of the 2F5 epitope and two additional upstream residues (L-660,L-663). The MAbs have long (21-residue) heavy-chain third complementarity-determining regions (CDR-H3s), and m66.6 (but not m66) exhibited polyspecific reactivity to self- and non-self-antigens. Both m66 and m66.6 are significantly less divergent from their germ line Ab counterparts than 2F5-they have a total of 11 and 18 amino acid changes, respectively, from the closest VH and V kappa germ line gene products compared to 25 for 2F5. These new MAbs could help explore the complex maturation pathways involved in broad neutralization and its relationship with auto- and polyreactivity and may aid design of vaccine immunogens and development of therapeutics against HIV-1 infection. C1 [Dimitrov, Dimiter S.] NCI, CCRNP, CCR, NIH, Frederick, MD 21702 USA. [Shen, Xiaoying; Schutte, Robert; Fouda, Genevieve G.; Liao, Hua-Xin; Moody, M. Anthony; Montefiori, David; Haynes, Barton F.; Tomaras, Georgia D.] Human Vaccine Inst, Durham, NC USA. [Wang, Yanping; Streaker, Emily] SAIC, Frederick, MD USA. [Ofek, Gilad; Louder, Mark; Yang, Yongping; Mascola, John R.; Kwong, Peter D.] Vaccine Res Ctr, Bethesda, MD USA. [Klaric, Kristina-Ana; Scott, Jamie K.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [Klaric, Kristina-Ana; Scott, Jamie K.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. RP Dimitrov, DS (reprint author), NCI, CCRNP, CCR, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimiter.dimitrov@nih.gov RI Tomaras, Georgia/J-5041-2016 FU Bill and Melinda Gates Foundation; NIH; NCI [NO1-CO-12400]; NIAID; Canada Research Chair Program; NIH Center For HIV/AIDS Vaccine Immunology (CHAVI) [U19 AI067854] FX This research was supported by a Collaboration for AIDS Vaccine Discovery grant to B. F. Haynes from the Bill and Melinda Gates Foundation, the Intramural Research Program of the NIH, NCI, and NIAID, by federal funds from the NIH and NCI under contract NO1-CO-12400, by the NIH Center For HIV/AIDS Vaccine Immunology (CHAVI; grant U19 AI067854), and by funding from the Canada Research Chair Program. NR 24 TC 52 Z9 53 U1 2 U2 8 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 NOV PY 2011 VL 85 IS 21 BP 11401 EP 11408 DI 10.1128/JVI.05312-11 PG 8 WC Virology SC Virology GA 837ZL UT WOS:000296254400046 PM 21880764 ER PT J AU Tomaras, GD Binley, JM Gray, ES Crooks, ET Osawa, K Moore, PL Tumba, N Tong, T Shen, XY Yates, NL Decker, J Wibmer, CK Gao, F Alam, SM Easterbrook, P Karim, SA Kamanga, G Crump, JA Cohen, M Shaw, GM Mascola, JR Haynes, BF Montefiori, DC Morris, L AF Tomaras, Georgia D. Binley, James M. Gray, Elin S. Crooks, Emma T. Osawa, Keiko Moore, Penny L. Tumba, Nancy Tong, Tommy Shen, Xiaoying Yates, Nicole L. Decker, Julie Wibmer, Constantinos Kurt Gao, Feng Alam, S. Munir Easterbrook, Philippa Karim, Salim Abdool Kamanga, Gift Crump, John A. Cohen, Myron Shaw, George M. Mascola, John R. Haynes, Barton F. Montefiori, David C. Morris, Lynn TI Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; HUMAN MONOCLONAL-ANTIBODIES; HIV-INFECTED INDIVIDUALS; CORECEPTOR BINDING-SITE; SUBTYPE-C INFECTION; ENVELOPE GLYCOPROTEIN; VACCINE DESIGN; VIRAL ENVELOPE; ENV CLONES AB A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 "tier 2" viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein. C1 [Tomaras, Georgia D.; Shen, Xiaoying; Yates, Nicole L.; Gao, Feng; Alam, S. Munir; Crump, John A.; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Binley, James M.; Crooks, Emma T.; Osawa, Keiko; Tong, Tommy] Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. [Gray, Elin S.; Moore, Penny L.; Tumba, Nancy; Wibmer, Constantinos Kurt; Morris, Lynn] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Karim, Salim Abdool] Univ KwaZulu Natal, ZA-4013 Durban, Kwazulu Natal, South Africa. [Decker, Julie; Easterbrook, Philippa] Kings Coll London, Sch Med & Dent, Western Educ Ctr, London SE5 9RJ, England. [Kamanga, Gift] Kamuzu Cent Hosp, Tidziwe Ctr, Lilongwe, Malawi. [Crump, John A.] Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Cohen, Myron] Univ N Carolina, Inst Global Hlth & Infect Dis, Chapel Hill, NC USA. [Shaw, George M.] Univ Alabama Birmingham, Div Hematol Oncol, Birmingham, AL 35294 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Tomaras, Georgia D.; Shen, Xiaoying; Yates, Nicole L.; Gao, Feng; Alam, S. Munir; Crump, John A.; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Tomaras, Georgia D.; Shen, Xiaoying; Yates, Nicole L.; Gao, Feng; Alam, S. Munir; Crump, John A.; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Tomaras, Georgia D.; Shen, Xiaoying; Yates, Nicole L.; Gao, Feng; Alam, S. Munir; Crump, John A.; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Tomaras, Georgia D.; Shen, Xiaoying; Yates, Nicole L.; Gao, Feng; Alam, S. Munir; Crump, John A.; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP Tomaras, GD (reprint author), Duke Univ, Med Ctr, Duke Human Vaccine Inst, Box 2926, Durham, NC 27710 USA. EM gdt@duke.edu RI Abdool Karim, Salim Safurdeen/N-5947-2013; Tomaras, Georgia/J-5041-2016; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Moore, Penny/0000-0001-8719-4028; Wibmer, Constantinos Kurt/0000-0003-2329-2280; Gray, Elin/0000-0002-8613-3570 FU Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD-VIMC) [38619]; National Institutes of Health (NIH/NIAID/DAIDS); Center for HIV/AIDS Vaccine Immunology [AI067854-05]; NIAID, NIH [AI58C1-0763]; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD-VIMC grant 38619), the National Institutes of Health (NIH/NIAID/DAIDS), and the Center for HIV/AIDS Vaccine Immunology (AI067854-05). Additional funding was provided by grants AI58C1-0763 (NIAID, NIH; to J.M.B.), Torrey Pines Institute's AIDS and Infectious Disease Science Center (to J.M.B.), and the South African HIV/AIDS Research and Innovation Platform (SHARP) of the Department of Science and Technology (DST) (to L. M. and E. S. G.). This work was supported in part by the intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. NR 111 TC 93 Z9 95 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 21 BP 11502 EP 11519 DI 10.1128/JVI.05363-11 PG 18 WC Virology SC Virology GA 837ZL UT WOS:000296254400055 PM 21849452 ER PT J AU Bello, NF Wu, F Sette, P Dussupt, V Hirsch, VM Bouamr, F AF Bello, Nana F. Wu, Fan Sette, Paola Dussupt, Vincent Hirsch, Vanessa M. Bouamr, Fadila TI Distal Leucines Are Key Functional Determinants of Alix-Binding Simian Immunodeficiency Virus SIVsmE543 and SIVmac239 Type 3 L Domains SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-SORTING PATHWAY; LATE-BUDDING DOMAINS; UBIQUITIN LIGASES; PARTICLE RELEASE; HRS PROTEIN; TSG101; HIV-1; MOTIFS; GAG; NEDD4 AB In addition to PTAP L domains, primate lentiviruses carry Alix-binding motifs that include the recently described type 3 SREKPYKEVTEDLLHLNSLF sequence. We examined the requirements for the type 3 sequence motif in simian immunodeficiency virus SIVsmE543 and identified the 499LNSLF503 sequence as a key functional determinant. Mutation of distal leucines L-499 and L-502 (LL mutant) caused an inhibitory effect on Alix-dependent SIVsmE543 release that was quantitatively similar to that observed following disruption of the type 3 L domain or RNA interference (RNAi) depletion of Alix. Similar results were obtained with the SIVmac239 LL mutant. Thus, distal leucines are key determinants of SIVsmE543 and SIVmac239 type 3 L domains. C1 [Bello, Nana F.; Wu, Fan; Sette, Paola; Dussupt, Vincent; Hirsch, Vanessa M.; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM bouamrf@mail.nih.gov FU NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 30 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 21 BP 11532 EP 11537 DI 10.1128/JVI.05284-11 PG 6 WC Virology SC Virology GA 837ZL UT WOS:000296254400058 PM 21849430 ER PT J AU Zhu, M Hu, JP Perez, E Phillips, D Kim, W Ghaedian, R Napora, JK Zou, S AF Zhu, Min Hu, Jingping Perez, Evelyn Phillips, Dawn Kim, Wook Ghaedian, Reza Napora, Joshua K. Zou, Sige TI Effects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cranberry; Insulin release; Pancreatic beta-cell function; Pancreatic beta-cell mass; Aging ID BETA-CELL FUNCTION; BASAL INSULIN-SECRETION; DEPENDENT DIABETES-MELLITUS; CALORIC RESTRICTION; SKELETAL-MUSCLE; GLUCOSE-INTOLERANCE; PLASMA-GLUCOSE; AGE; RESISTANCE; ANTIOXIDANT AB The effects of long-term cranberry consumption on age-related changes in endocrine pancreas are not fully understood. Here we treated male Fischer 344 rats with either 2% whole cranberry powder supplemented or normal rodent chow from 6 to 22 month old. Both groups displayed an age-related decline in basal plasma insulin concentrations, but this age-related decline was delayed by cranberry. Cranberry supplementation led to increased beta-cell glucose responsiveness during the oral glucose tolerance test. Portal insulin concentration was 7.6-fold higher in rats fed cranberry, coupled with improved beta-cell function. However, insulin resistance values were similar in both groups. Total beta-cell mass and expression of pancreatic and duodenal homeobox 1 and insulin within islets were significantly enhanced in rats fed cranberry relative to controls. Furthermore, cranberry increased insulin release of an insulin-producing beta-cell line, revealing its insulinotropic effect. These findings suggest that cranberry is of particular benefit to beta-cell function in normal aging rats. C1 [Zhu, Min; Hu, Jingping; Perez, Evelyn; Phillips, Dawn; Zou, Sige] NIA, Lab Expt Gerontol, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Kim, Wook; Napora, Joshua K.] NIA, Clin Invest Lab, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Ghaedian, Reza] Decas Cranberry Prod Inc, Carver, MA USA. RP Zou, S (reprint author), NIA, Lab Expt Gerontol, NIH Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zous@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health; Cranberry Institute (East Wareham, MA) FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, and in part by a grant from Cranberry Institute (East Wareham, MA) to S.Z. NR 59 TC 12 Z9 12 U1 1 U2 6 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 NOV PY 2011 VL 66 IS 11 BP 1139 EP 1151 DI 10.1093/gerona/glr105 PG 13 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 836HN UT WOS:000296102100001 PM 21768504 ER PT J AU Smith, DL Mattison, JA Desmond, RA Gardner, JP Kimura, M Roth, GS Ingram, DK Allison, DB Aviv, A AF Smith, Daniel L., Jr. Mattison, Julie A. Desmond, Renee A. Gardner, Jeffrey P. Kimura, Masayuki Roth, George S. Ingram, Donald K. Allison, David B. Aviv, Abraham TI Telomere Dynamics in Rhesus Monkeys: No Apparent Effect of Caloric Restriction SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Telomere; Macaca mulatta; Aging; Caloric restriction; Rhesus monkeys ID T-CELL SENESCENCE; CARDIOVASCULAR-DISEASE; DIETARY RESTRICTION; INSULIN-RESISTANCE; NONHUMAN-PRIMATES; OXIDATIVE STRESS; LENGTH; MICE; AGE; LEUKOCYTES AB The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples. C1 [Smith, Daniel L., Jr.; Allison, David B.] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Smith, Daniel L., Jr.; Desmond, Renee A.; Allison, David B.] Univ Alabama, Nutr Obes Res Ctr, Birmingham, AL 35294 USA. [Mattison, Julie A.] NIA, Lab Expt Gerontol, NIH, Baltimore, MD USA. [Gardner, Jeffrey P.; Kimura, Masayuki; Aviv, Abraham] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Roth, George S.] GeroScience Inc, Pylesville, MD USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA. [Allison, David B.] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. RP Smith, DL (reprint author), Univ Alabama, Dept Nutr Sci, 1530 3rd Ave S,Webb 304A,Main Campus, Birmingham, AL 35294 USA. EM dsmithjr@uab.edu OI Allison, David/0000-0003-3566-9399 FU National Institutes of Health (NIH) [T32 DK062710, P30 DK056336, AG 021593, AG 020132]; National Institute on Aging, NIH FX This work was supported by National Institutes of Health (NIH) grants (T32 DK062710, P30 DK056336, AG 021593, and AG 020132); and the Intramural Program of the National Institute on Aging, NIH. NR 44 TC 12 Z9 12 U1 3 U2 15 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 NOV PY 2011 VL 66 IS 11 BP 1163 EP 1168 DI 10.1093/gerona/glr136 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 836HN UT WOS:000296102100003 PM 21860014 ER PT J AU Florez, H Ma, Y Crandall, JP Perreault, L Marcovina, SM Bray, GA Saudek, CD Barrett-Connor, E Knowler, WC AF Florez, Hermes Ma, Yong Crandall, Jill P. Perreault, Leigh Marcovina, Santica M. Bray, George A. Saudek, Christopher D. Barrett-Connor, Elizabeth Knowler, William C. CA Diabet Prevention Program Res Grp TI Parental Longevity and Diabetes Risk in the Diabetes Prevention Program SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Parental longevity; Diabetes risk; Diabetes Prevention Program ID GENOME-WIDE ASSOCIATION; LEIDEN LONGEVITY; CARDIOVASCULAR MORTALITY; NONAGENARIAN SIBLINGS; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; PREMATURE DEATH; ADULT ADOPTEES; DISEASE; AGE AB Background. Longevity clusters in families, and parental longevity may be associated with lower risk of chronic diseases in their children. It is unknown if diabetes risk is associated with parental longevity. Methods. We evaluated participants in the Diabetes Prevention Program with a parental history questionnaire at study entry. We classified them into five groups: premature death (parental death at age < 50 years), parental longevity (living to at least 80 years), and three intermediate groups (alive by age 49 but dying at age 50-59, 60-69, or 70-79). Those with alive parents and younger than 80 years were excluded. We analyzed separately effects of paternal (n = 2,165) and maternal (n = 1,739) longevity on diabetes incidence and risk after an average follow-up of 3.2 years. Results. At baseline, more diabetes risk factors (parental history of diabetes, coronary heart disease, higher body mass index, homeostasis model assessment for insulin resistance, and corrected insulin response) were found in participants whose parents died prematurely. Diabetes incidence was 9.5 cases/100 person-years in the 229 whose fathers died prematurely. In the 618 with paternal longevity, the rate was 6.6 cases/100 person-years (hazard ratio [95% confidence interval] = 0.68 [0.49-0.94]). The rates were 10.7 cases/100 person-years (n = 156) and 7.3 cases/100 person-years (n = 699, hazard ratio = 0.67 [95% confidence interval 0.47-0.95]) for those with maternal premature death or longevity, respectively. Associations with demographic and diabetes risk factors had minimal influence on the reduced risk found in those with paternal (adjusted hazard ratio = 0.78, 95% confidence interval 0.52-1.16) and maternal (adjusted hazard ratio = 0.64, 95% confidence interval 0.41-1.01) longevity. Conclusion. Parental longevity is associated with lower diabetes incidence in adults at high risk of type 2 diabetes. C1 [Florez, Hermes] Univ Miami, Miller Sch Med, Miami VAHS GRECC, Coral Gables, FL 33124 USA. [Crandall, Jill P.] Albert Einstein Coll Med, New York, NY USA. [Perreault, Leigh] Univ Colorado Denver, Sch Med, Denver, CO 80202 USA. [Marcovina, Santica M.] Univ Washington, Seattle, WA 98195 USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Saudek, Christopher D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, San Diego, CA 92103 USA. [Knowler, William C.] NIDDKD, Bethesda, MD 20892 USA. RP Florez, H (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and, Prevention; Office of Research on Women's Health; American Diabetes Association; Henry M. Jackson Foundation; National Institute of Diabetes and Digestive and Kidney Diseases; University of Miami [CTSA-K12/GRECC] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; and collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and, Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of centers, investigators, and staff can be found in the Supplementary Appendix.; The work was also supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the University of Miami CTSA-K12/GRECC program (H. F.). The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. NR 58 TC 10 Z9 10 U1 0 U2 2 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 NOV PY 2011 VL 66 IS 11 BP 1211 EP 1217 DI 10.1093/gerona/glr114 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 836HN UT WOS:000296102100009 PM 21852284 ER PT J AU Fielding, RA Rejeski, WJ Blair, S Church, T Espeland, MA Gill, TM Guralnik, JM Hsu, FC Katula, J King, AC Kritchevsky, SB McDermott, MM Miller, ME Nayfield, S Newman, AB Williamson, JD Bonds, D Romashkan, S Hadley, E Pahor, M AF Fielding, Roger A. Rejeski, W. Jack Blair, Steven Church, Tim Espeland, Mark A. Gill, Thomas M. Guralnik, Jack M. Hsu, Fang-Chi Katula, Jeffrey King, Abby C. Kritchevsky, Stephen B. McDermott, Mary M. Miller, Michael E. Nayfield, Susan Newman, Anne B. Williamson, Jeff D. Bonds, Denise Romashkan, Sergei Hadley, Evan Pahor, Marco CA LIFE Res Grp TI The Lifestyle Interventions and Independence for Elders Study: Design and Methods SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Disability; Physical activity; Exercise; Geriatrics; Physical function ID RANDOMIZED-CONTROLLED-TRIAL; LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; TASK-SWITCHING PERFORMANCE; ESTROGEN PLUS PROGESTIN; CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; QUALITY-OF-LIFE; OLDER-ADULTS; POSTMENOPAUSAL WOMEN AB Background. As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap. Methods. The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years. Results. LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness. Conclusions. Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women. C1 [Fielding, Roger A.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Exercise Physiol & Sarcopenia Lab, Boston, MA 02111 USA. [Rejeski, W. Jack; Katula, Jeffrey] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Blair, Steven] Univ S Carolina, Dept Exercise Sci, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Blair, Steven] Univ S Carolina, Dept Epidemiol & Biostat, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Church, Tim] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Espeland, Mark A.; Miller, Michael E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Gill, Thomas M.; Hsu, Fang-Chi] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [King, Abby C.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA. [Kritchevsky, Stephen B.; Williamson, Jeff D.] Wake Forest Univ, Bowman Gray Sch Med, Sect Gerontol & Geriatr Med, Dept Med,Sticht Ctr Aging, Winston Salem, NC USA. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Nayfield, Susan; Pahor, Marco] Univ Florida, Coll Med, Inst Aging, Gainesville, FL USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol & Med, Pittsburgh, PA 15260 USA. [Bonds, Denise] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Romashkan, Sergei] NIA, Clin Trials Branch, Bethesda, MD 20892 USA. [Hadley, Evan] NIA, Sect Geriatr & Gerontol, Bethesda, MD 20892 USA. RP Fielding, RA (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Exercise Physiol & Sarcopenia Lab, 711 Washington St, Boston, MA 02111 USA. EM roger.fielding@tufts.edu RI Buford, Thomas /B-1111-2011; Newman, Anne/C-6408-2013; Katula, Jeffrey/K-5905-2013; OI Buford, Thomas /0000-0002-9541-4358; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health (NIH)/National Institute on Aging Cooperative Agreement [UO1 AG22376]; National Institute on Aging, NIH; U.S. Department of Agriculture [58-1950-7-707]; Boston Claude D. Pepper Older Americans Independence Center [P30AG031679]; University of Florida Claude D. Pepper Older Americans Independence Center [P30 AG028740]; Pittsburgh Claude D. Pepper Older Americans Independence Center [P30 AG024827]; Claude D. Pepper Older Americans Independence Center [P30 AG21332, P30AG021342]; National Institute on Aging [K24 AG021507] FX The Lifestyle Interventions and Independence for Elders Study is funded by a National Institutes of Health (NIH)/National Institute on Aging Cooperative Agreement; (UO1 AG22376) and a supplement from the National Heart, Lung and Blood Institute (3U01AG022376-05A2S), and sponsored in part by the Intramural Research Program, National Institute on Aging, NIH.; Dr. Fielding's contribution is partially supported by the U.S. Department of Agriculture (58-1950-7-707). Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U. S. Dept of Agriculture. The Tufts Field Center is also partially supported by the Boston Claude D. Pepper Older Americans Independence Center (P30AG031679). The Administrative Coordinating Center and University of Florida Field Center are partially supported by the University of Florida Claude D. Pepper Older Americans Independence Center (P30 AG028740). The Pittsburgh Field Center is partially supported by the Pittsburgh Claude D. Pepper Older Americans Independence Center (P30 AG024827). The Wake Forest University Field Center is partially supported by the Claude D. Pepper Older Americans Independence Center (P30 AG21332). Dr. Gill is the recipient of a Midcareer Investigator Award in Patient-Oriented Research (K24 AG021507) from the National Institute on Aging. The Yale Field Center is partially supported by the Claude D. Pepper Older Americans Independence Center (P30AG021342). NR 106 TC 83 Z9 84 U1 5 U2 37 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 NOV PY 2011 VL 66 IS 11 BP 1226 EP 1237 DI 10.1093/gerona/glr123 PG 12 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 836HN UT WOS:000296102100011 PM 21825283 ER PT J AU Nielsen, JA Chambers, MA Romm, E Lee, LYH Berndt, JA Hudson, LD AF Nielsen, Joseph A. Chambers, Meredith A. Romm, Elena Lee, Laurel Yong-Hwa Berndt, Jo Ann Hudson, Lynn D. TI Mouse transmembrane BAX inhibitor Motif 3 (Tmbim3) encodes a 38 kDa transmembrane protein expressed in the central nervous system SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE BAX-inhibitor; Grina; Transmembrane protein ID APOPTOSIS; PREDICTION; SITES; DEATH AB Cell survival proteins play an important role throughout nervous system development, normal physiological processes, and pathological conditions. Transmembrane BAX inhibitor motif 3 (TMBIM3, also known as GRINA), is a member of a family of proteins that contain a conserved BAX inhibitor-1 motif. This family of proteins includes several members that have been shown to protect cells from apoptosis. In this study, the authors show that TMBIM3 is expressed in the brain including high levels in the hippocampus. Biochemical and sequence analysis of TMBIM3 demonstrates that the rat, murine, and human genes encode an approximately 38 kDa protein with a predicted seven transmembrane domain topology. A Tmbim3 knockout mouse line did not have an obvious phenotype, but may prove useful in future studies of this family of proteins. C1 [Nielsen, Joseph A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Nielsen, Joseph A.; Chambers, Meredith A.; Romm, Elena; Lee, Laurel Yong-Hwa; Berndt, Jo Ann; Hudson, Lynn D.] NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Nielsen, JA (reprint author), US FDA, Ctr Devices & Radiol Hlth, WO66 Room G431,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM joseph.nielsen@fda.hhs.gov FU National Institute of Neurological Disorders and Stroke (NINDS) FX The authors thank Dr. Chang-Yu Wang for the whole brain membrane fraction. The authors thank Dr. Dragan Maric for his FACS expertise and analysis of the Tmbim3 cell survival experiments, and Dr. Jim Pickle for assistance with floxing. The authors thank Dr. Sara Szuchet for initiating this project. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS). NR 17 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD NOV PY 2011 VL 357 IS 1-2 BP 73 EP 81 DI 10.1007/s11010-011-0877-3 PG 9 WC Cell Biology SC Cell Biology GA 834EF UT WOS:000295941500009 PM 21614515 ER PT J AU Didierlaurent, L Racine, PJ Houzet, L Chamontin, C Berkhout, B Mougel, M AF Didierlaurent, L. Racine, P. J. Houzet, L. Chamontin, C. Berkhout, B. Mougel, M. TI Role of HIV-1 RNA and protein determinants for the selective packaging of spliced and unspliced viral RNA and host U6 and 7SL RNA in virus particles SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TYPE-1 NUCLEOCAPSID PROTEIN; GENOMIC RNA; REVERSE TRANSCRIPTION; ZINC-FINGER; STEM-LOOP; BASIC RESIDUES; IN-VITRO; NUCLEAR EXPORT; INFECTED-CELLS; CELLULAR RNAS AB HIV-1 particles contain RNA species other than the unspliced viral RNA genome. For instance, viral spliced RNAs and host 7SL and U6 RNAs are natural components that are non-randomly incorporated. To understand the mechanism of packaging selectivity, we analyzed the content of a large panel of HIV-1 variants mutated either in the 5'UTR structures of the viral RNA or in the Gag-nucleocapsid protein (GagNC). In parallel, we determined whether the selection of host 7SL and U6 RNAs is dependent or not on viral RNA and/or GagNC. Our results reveal that the polyA hairpin in the 5'UTR is a major packaging determinant for both spliced and unspliced viral RNAs. In contrast, 5'UTR RNA structures have little influence on the U6 and 7SL RNAs, indicating that packaging of these host RNAs is independent of viral RNA packaging. Experiments with GagNC mutants indicated that the two zinc-fingers and N-terminal basic residues restrict the incorporation of the spliced RNAs, while favoring unspliced RNA packaging. GagNC through the zinc-finger motifs also restricts the packaging of 7SL and U6 RNAs. Thus, GagNC is a major contributor to the packaging selectivity. Altogether our results provide new molecular insight on how HIV selects distinct RNA species for incorporation into particles. C1 [Didierlaurent, L.; Racine, P. J.; Houzet, L.; Chamontin, C.; Mougel, M.] UMI&II, CPBS, CNRS, UMR5236, Montpellier, France. [Houzet, L.] NIAID, LMM, NIH, Bethesda, MD 20892 USA. [Berkhout, B.] Dept Med Microbiol CINIMA, Lab Expt Virol, Amsterdam, Netherlands. RP Mougel, M (reprint author), UMI&II, CPBS, CNRS, UMR5236, 1919 Rte Mende, Montpellier, France. EM marylene.mougel@univ-montp1.fr RI Mougel, Marylene/K-7958-2013 OI Mougel, Marylene/0000-0002-0345-1427 FU CNRS; ANRS; NWO-CW FX CNRS and ANRS; Fellowship from ANRS (to P.J.R.); NWO-CW (TOP grant to B. B.). Funding for open access charge: CNRS. NR 88 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2011 VL 39 IS 20 BP 8915 EP 8927 DI 10.1093/nar/gkr577 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 839CW UT WOS:000296343400029 PM 21791531 ER PT J AU Kessl, JJ Li, M Ignatov, M Shkriabai, N Eidahl, JO Feng, L Musier-Forsyth, K Craigie, R Kvaratskhelia, M AF Kessl, Jacques J. Li, Min Ignatov, Michael Shkriabai, Nikolozi Eidahl, Jocelyn O. Feng, Lei Musier-Forsyth, Karin Craigie, Robert Kvaratskhelia, Mamuka TI FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTEGRASE-BINDING DOMAIN; HIV-1 INTEGRASE; IN-VITRO; RETROVIRAL DNA; REVERSE TRANSCRIPTION; NUCLEOCAPSID PROTEIN; CRYSTAL-STRUCTURE; TERMINAL DOMAINS; CATALYTIC DOMAIN AB A tetramer of HIV-1 integrase (IN) stably associates with the viral DNA ends to form a fully functional concerted integration intermediate. LEDGF/p75, a key cellular binding partner of the lentiviral enzyme, also stabilizes a tetrameric form of IN. However, functional assays have indicated the importance of the order of viral DNA and LEDGF/p75 addition to IN for productive concerted integration. Here, we employed Forster Resonance Energy Transfer (FRET) to monitor assembly of individual IN subunits into tetramers in the presence of viral DNA and LEDGF/p75. The IN-viral DNA and IN-LEDGF/p75 complexes yielded significantly different FRET values suggesting two distinct IN conformations in these complexes. Furthermore, the order of addition experiments indicated that FRET for the preformed IN-viral DNA complex remained unchanged upon its subsequent binding to LEDGF/p75, whereas pre-incubation of LEDGF/p75 and IN followed by addition of viral DNA yielded FRET very similar to the IN-LEDGF/p75 complex. These findings provide new insights into the structural organization of IN subunits in functional concerted integration intermediates and suggest that differential multimerization of IN in the presence of various ligands could be exploited as a plausible therapeutic target for development of allosteric inhibitors. C1 [Kessl, Jacques J.; Shkriabai, Nikolozi; Eidahl, Jocelyn O.; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kessl, Jacques J.; Shkriabai, Nikolozi; Eidahl, Jocelyn O.; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Li, Min; Craigie, Robert] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ignatov, Michael; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Dept Chem, Columbus, OH 43210 USA. [Ignatov, Michael; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Dept Biochem, Columbus, OH 43210 USA. [Ignatov, Michael; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, 500 W 12Th Ave, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Kessl, Jacques/J-6073-2015 FU National Institutes of Health [AI062520, AI081581, AI077341, AI077387]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX The National Institutes of Health (grants AI062520, AI081581 and AI077341 to M. K., AI077387 to K.M.-F.); the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health and by the NIH AIDS Targeted Antiviral Program (to R. C.). Funding for open access charge: National Institutes of Health (grant AI062520). NR 70 TC 33 Z9 34 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2011 VL 39 IS 20 BP 9009 EP 9022 DI 10.1093/nar/gkr581 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 839CW UT WOS:000296343400037 PM 21771857 ER PT J AU Ackerman, ME Lai, JI Pastan, I Wittrup, KD AF Ackerman, Margaret E. Lai, Jennifer I. Pastan, Ira Wittrup, K. Dane TI Exploiting bias in a non-immune human antibody library to predict antigenicity SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Article DE antibody; antibody fragment; antigenicity; immunogenicity; protein library; protein selection; immune library; scFv ID YEAST SURFACE DISPLAY; B-CELL EPITOPES; AFFINITY ANTIBODIES; CYTOTOXIC ACTIVITY; CANCER-PATIENTS; COLON-CANCER; IMMUNOGENICITY; PROTEIN; RECOMBINANT; IMMUNOTOXIN AB Non-immune human antibody fragment libraries have generated antigen-binding proteins useful as prospective research, imaging, diagnostic and therapeutic agents. However, because the generation of such libraries relies on cloning antibody sequences from the circulating immune repertoire rather than truly naive, germline sequences, their composition may reflect the deletion of autoreactive sequences, making them less suited for isolating binding clones to human antigens, but perhaps useful in applications where an in vitro handle on representative circulating antibody diversity is desired. Here we demonstrate that a large non-immune human scFv library is relatively depleted of sequences capable of recognizing human antigens as compared with orthologs antigens. Additionally, because this non-naive, non-immune library may capture a representative section of antibody diversity, we explore its possible utility in conducting early pre-screens to predict the antigenicity of prospective therapeutics and find a correlation between the clinical immunogenicity of a small panel of protein therapeutics with their propensity for interacting with the library. C1 [Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Lebanon, NH 03766 USA. [Ackerman, Margaret E.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lai, Jennifer I.; Wittrup, K. Dane] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Wittrup, K. Dane] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ackerman, ME (reprint author), Dartmouth Coll, Thayer Sch Engn, Lebanon, NH 03766 USA. EM Margaret.E.Ackerman@Dartmouth.edu RI Ackerman, Margaret/B-5944-2012 FU MIT-Portugal FX This work was supported by funding from the MIT-Portugal Program. NR 52 TC 1 Z9 1 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD NOV PY 2011 VL 24 IS 11 BP 845 EP 853 DI 10.1093/protein/gzr046 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 836SW UT WOS:000296132800005 PM 21908549 ER PT J AU Yang, W AF Yang, Wei TI Surviving the sun: Repair and bypass of DNA UV lesions SO PROTEIN SCIENCE LA English DT Review DE CPD; 6-4 PP; unstacking; hysteresis; bending; ATPase; NER; TLS; photolyase; endonuclease ID NUCLEOTIDE EXCISION-REPAIR; CYCLOBUTANE PYRIMIDINE DIMER; ESCHERICHIA-COLI UVRA; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; DAMAGED DNA; XERODERMA-PIGMENTOSUM; POLYMERASE ETA; THERMUS-THERMOPHILUS; MOLECULAR-MECHANISM AB Structural studies of UV-induced lesions and their complexes with repair proteins reveal an intrinsic flexibility of DNA at lesion sites. Reduced DNA rigidity stems primarily from the loss of base stacking, which may manifest as bending, unwinding, base unstacking, or flipping out. The intrinsic flexibility at UV lesions allows efficient initial lesion recognition within a pool of millions to billions of normal DNA base pairs. To bypass the damaged site by translesion synthesis, the specialized DNA polymerase eta acts like a molecular "splint'' and reinforces B-form DNA by numerous protein-phosphate interactions. Photolyases and glycosylases that specifically repair UV lesions interact directly with UV lesions in bent DNA via surface complementation. UvrA and UvrB, which recognize a variety of lesions in the bacterial nucleotide excision repair pathway, appear to exploit hysteresis exhibited by DNA lesions and conduct an ATP-dependent stress test to distort and separate DNA strands. Similar stress tests are likely conducted in eukaryotic nucleotide excision repair. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 5,Rm B1-03, Bethesda, MD 20892 USA. EM Wei.Yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU NIDDK, NIH FX Grant sponsor: NIDDK, NIH. NR 68 TC 23 Z9 23 U1 4 U2 32 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2011 VL 20 IS 11 BP 1781 EP 1789 DI 10.1002/pro.723 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838FW UT WOS:000296273700004 PM 21898645 ER PT J AU Dickey, JS Zemp, FJ Martin, OA Kovalchuk, O AF Dickey, Jennifer S. Zemp, Franz J. Martin, Olga A. Kovalchuk, Olga TI The role of miRNA in the direct and indirect effects of ionizing radiation SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Review ID MICRORNA EXPRESSION PATTERNS; IN-VIVO; INTERCELLULAR COMMUNICATION; EPIGENETIC EFFECTORS; DNA-DAMAGE; CANCER; CELLS; IDENTIFICATION; IRRADIATION; GAMMA-H2AX AB This review focuses on a number of recent studies that have examined changes in microRNA (miRNA) expression profiles in response to ionizing radiation and other forms of oxidative stress. In both murine and human cells and tissues, a number of miRNAs display significant alterations in expression levels in response to both direct and indirect radiation exposure. In terms of direct irradiation, or exposure to agents that induce oxidative stress, miRNA array analyses indicate that a number of miRNAs are up- and down-regulated and, in particular, the let-7 family of miRNAs may well be critical in the cellular response to oxidative stress. In bystander cells that are not directly irradiated, but close to, or share media with directly irradiated cells or tissues, the miRNA expression profiles are also altered, but are somewhat distinct from the directly irradiated cells. Based on the results of these numerous studies, as well as our own data presented here, we conclude that miRNA regulation is a critical step in the cellular response to radiation and oxidative stress and that future studies should elucidate the mechanisms through which this altered regulation affects cell metabolism. C1 [Dickey, Jennifer S.] US FDA, Biochem Lab, Div Therapeut Prot, CDER, Bethesda, MD 20892 USA. [Zemp, Franz J.; Kovalchuk, Olga] Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. [Martin, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dickey, JS (reprint author), US FDA, Biochem Lab, Div Therapeut Prot, CDER, 29 Lincoln Dr,Bldg 29A,Room 2B-24, Bethesda, MD 20892 USA. EM Jennifer.dickey@fda.hhs.gov; Olga.martin@petermac.org NR 34 TC 41 Z9 41 U1 5 U2 18 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 NOV PY 2011 VL 50 IS 4 BP 491 EP 499 DI 10.1007/s00411-011-0386-5 PG 9 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 836EV UT WOS:000296093600001 PM 21928045 ER PT J AU Moncada-Velez, M Velez-Ortega, A Orrego, J Santisteban, I Jagadeesh, J Olivares, M Olaya, N Hershfield, M Candotti, F Franco, J AF Moncada-Velez, M. Velez-Ortega, A. Orrego, J. Santisteban, I. Jagadeesh, J. Olivares, M. Olaya, N. Hershfield, M. Candotti, F. Franco, J. TI Somatic Mosaicism Caused by Monoallelic Reversion of a Mutation in T Cells of a Patient with ADA-SCID and the Effects of Enzyme Replacement Therapy on the Revertant Phenotype SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID ADENOSINE-DEAMINASE DEFICIENCY; SEVERE COMBINED IMMUNODEFICIENCY; IN-VIVO REVERSION; LYMPHOCYTE SUBPOPULATIONS; INHERITED MUTATION; GENOTYPE; DISEASE AB Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B-SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naive phenotype) and NK cells, and sustained expansion of TCR gamma delta+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion. C1 [Orrego, J.; Olivares, M.; Franco, J.] Univ Antioquia, Dept Microbiol & Parasitol, Medellin, Colombia. [Moncada-Velez, M.; Velez-Ortega, A.] Univ Antioquia, Dept Biol, Medellin, Colombia. [Santisteban, I.; Hershfield, M.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Santisteban, I.; Hershfield, M.] Duke Univ, Med Ctr, Dept Biochemestry, Durham, NC USA. [Jagadeesh, J.; Candotti, F.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Olaya, N.] Univ Antioquia, Inst Patol, Medellin, Colombia. RP Franco, J (reprint author), Univ Antioquia, Dept Microbiol & Parasitol, Calle 62 52-59,Lab 530, Medellin, Colombia. EM jlfrancor@une.net.co OI Velez-Ortega, A. Catalina/0000-0001-9157-8390 FU Estrategia para Sostenibilidad [9889E01489]; Group of Primary Immunodeficiencies; Fundacion "Diana Garcia de Olarte" para las Inmunodeficiencias Primarias -FIP- (Medellin, Colombia) FX We deeply appreciate the commitment of our patient and his parents to perform these studies. Acknowledgments are made to Carlos J. Montoya, Olga L. Morales, Alejandra Wilches, Dagoberto Cabrera and Yadira Coll for their dedication to the care of our patient. We also thank the Grupo de Inmunologia Celular e Inmunogenetica (University of Antioquia, Medellin, Colombia) for their help with the HLA typing and Christiam Alvarez for his technical support. This work was supported by a grant from the "Estrategia para Sostenibilidad 2009-2011" 9889E01489 (CODI, UDEA) and the Group of Primary Immunodeficiencies and the Fundacion "Diana Garcia de Olarte" para las Inmunodeficiencias Primarias -FIP- (Medellin, Colombia). NR 29 TC 3 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD NOV PY 2011 VL 74 IS 5 BP 471 EP 481 DI 10.1111/j.1365-3083.2011.02593.x PG 11 WC Immunology SC Immunology GA 836BF UT WOS:000296081100007 PM 21671975 ER PT J AU Thoma, ME Gray, RH Kiwanuka, N Wang, MC Sewankambo, N Wawer, MJ AF Thoma, Marie E. Gray, Ronald H. Kiwanuka, Noah Wang, Mei-Cheng Sewankambo, Nelson Wawer, Maria J. TI The Natural History of Bacterial Vaginosis Diagnosed by Gram Stain Among Women in Rakai, Uganda SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID VAGINAL FLORA; MENSTRUAL-CYCLE; ASSOCIATIONS; MICROBIOME; BEHAVIORS; SYMPTOMS; HEALTH; HIV AB Background: Large datasets for investigating vaginal flora change at frequent, repeated intervals are limited and graphical methods for exploring such data are inadequate. We report 2-year weekly vaginal flora changes based on Gram stain using lasagna plots. Methods: Weekly vaginal flora patterns were evaluated among 211 sexually experienced women with >= 18 months of follow-up in Rakai, Uganda. Vaginal flora swabs were self-collected weekly and categorized by Nugent Gram stain criteria (0-3, normal; 4-6, intermediate; 7-10, bacterial vaginosis [BV]). Vaginal flora patterns were analyzed as the percentage of weekly observations with BV (longitudinal prevalence) and illustrated by lasagna plots. Characteristics of women were compared across tertiles of longitudinal prevalence of BV. Results: Ninety-five percent of women had at least 1 episode of BV over 2 years, with one-third of women spending more than half (52%-100%) of their time with BV. Vaginal pH >4.5 increased with increasing tertiles of longitudinal prevalence of BV (P < 0.001). Weekly fluctuation in vaginal flora states, as measured by a change in flora states from the before current visit, was highest in the middle (41.9%) compared with the lower (30.1%) and upper tertiles (27.8%, P < 0.001). HIV status and reported vaginal symptoms did not differ significantly across BV tertiles. Conclusions: Women exhibited different patterns of vaginal flora changes over time, which could not be described by baseline behaviors. Lasagna plots aided in describing the natural history of BV within and across women and may be applied to future BV natural history studies. C1 [Thoma, Marie E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, DESPR, NIH, Rockville, MD 20852 USA. [Thoma, Marie E.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Kiwanuka, Noah] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kiwanuka, Noah] Rakai Hlth Sci Program, Kalisizo, Uganda. [Wang, Mei-Cheng] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Sewankambo, Nelson] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. RP Thoma, ME (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, DESPR, NIH, 6100 Execut Blvd,Room 7B13E, Rockville, MD 20852 USA. EM thomame@mail.nih.gov OI Sewankambo, Nelson/0000-0001-9362-053X FU National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NIH, NICHD [R01AI47608]; NIH, National Institute for Allergy and Infectious Diseases (NIAID) [T32AI050056]; Center for Disease Control and Prevention (CDC) [R36PS001104] FX Supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH, NICHD grant R01AI47608 (to M.J.W.); the NIH, National Institute for Allergy and Infectious Diseases (NIAID) grant T32AI050056 (to J.M.Z.), the Cooperative Agreement number R36PS001104 (to M. E. T.) from the Center for Disease Control and Prevention (CDC). NR 27 TC 11 Z9 11 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD NOV PY 2011 VL 38 IS 11 BP 1040 EP 1045 DI 10.1097/OLQ.0b013e3182275499 PG 6 WC Infectious Diseases SC Infectious Diseases GA 838GE UT WOS:000296274600010 PM 21992981 ER PT J AU Jin, T AF Jin, Tian TI GPCR-controlled chemotaxis in Dictyostelium discoideum SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Article ID CAMP SIGNALING RESPONSE; CYCLIC 3',5'-AMP RELAY; HETEROTRIMERIC G-PROTEINS; DOMAIN-CONTAINING PROTEIN; SINGLE-MOLECULE ANALYSIS; G-BETA-GAMMA; LIVING CELLS; LEADING-EDGE; MEDIATES CHEMOTAXIS; CHEMOKINE RECEPTORS AB Dictyostelium discoideum has been chosen as the key model organism for the study of eukaryotic chemotaxis. Studies in this lower eukaryotic organism have allowed us to discover eukaryotic chemotaxis behavior and to gradually understand the mechanism of chemotaxis. Investigations in this simple organism often guide the direction of chemotaxis studies in areas such as forming concepts, discovering molecular components, revealing pathways and networks. The cooperation between experimental approaches and computational modeling has helped us to comprehend the signaling network as a system. To further reveal the relationships among the molecular mechanisms of individual signaling steps, a continuous interplay between model development and refinement and experimental testing and verification will be useful. This article focuses on a chemoattractant G-protein-coupled receptor (GPCR)/G-protein gradient sensing machinery, which ismonitored by PIP(3) responses and investigated by the interplay between live cell imaging experiments and computational modeling. We believe that such an approach will lead to a much better understanding of GPCR-controlled chemotaxis of all eukaryotic cells. (C) 2011 John Wiley & Sons, Inc. WIREs Syst Biol Med 2011 3 717-727 DOI: 10.1002/wsbm.143 C1 NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil, Rockville, MD USA. RP Jin, T (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil, Rockville, MD USA. EM tjin@niaid.nih.gov FU NIAID, NIH FX Jin is supported by intramural fund from NIAID, NIH. NR 72 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD NOV-DEC PY 2011 VL 3 IS 6 BP 717 EP 727 DI 10.1002/wsbm.143 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 838GQ UT WOS:000296275800007 PM 21381217 ER PT J AU Kitano, M Rahbari, R Patterson, EE Xiong, Y Prasad, NB Wang, YC Zeiger, MA Kebebew, E AF Kitano, Mio Rahbari, Reza Patterson, Erin E. Xiong, Yin Prasad, Nijaguna B. Wang, Yongchun Zeiger, Martha A. Kebebew, Electron TI Expression Profiling of Difficult-to-diagnose Thyroid Histologic Subtypes Shows Distinct Expression Profiles and Identify Candidate Diagnostic microRNAs SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID FINE-NEEDLE-ASPIRATION; PAPILLARY CARCINOMAS; SCIENCE CONFERENCE; MOLECULAR MARKERS; STEM-CELLS; CANCER; NODULES; BIOPSY; INDETERMINATE; TARGETS AB The incidence of thyroid cancer is increasing worldwide. The findings of up to 30% of thyroid fine-needle aspiration biopsies (FNAB) are inconclusive, primarily as a result of several thyroid histologic subtypes with overlapping cytologic features. MicroRNAs (miRNAs) are small noncoding RNAs and have been implicated in carcinogenesis. We hypothesized that there are miRNAs that are differentially expressed between benign and malignant thyroid tumors that are difficult to distinguish by FNAB. The expression of 1263 human miRNAs was profiled in 47 tumor samples representing difficult to diagnose histologic subtypes of thyroid neoplasm (21 benign, 26 malignant). Differentially expressed miRNAs were validated by quantitative real-time reverse transcriptase-polymerase chain reaction. The area under the receiver operating characteristic curve (AUC) was used to determine the diagnostic accuracy of differentially expressed miRNAs. Supervised hierarchical cluster analysis demonstrated grouping of 2 histologies (papillary and follicular thyroid carcinoma). A total of 34 miRNAs were differentially expressed in malignant compared to benign thyroid neoplasms (P < 0.05). A total of 25 of the 34 nonproprietary miRNAs were selected for validation, and 15 of the 25 miRNAs were differentially expressed between benign and malignant samples with P-value < 0.05. Seven miRNAs had AUC values of > 0.7. miR-7 and miR-126 had the highest diagnostic accuracy with AUCs values of 0.81 and 0.77, respectively. To our knowledge, this is the first study to evaluate the diagnostic accuracy of miRNAs in thyroid histologies that are difficult to distinguish as benign or malignant by FNAB. miR-126 and miR-7 had high diagnostic accuracy and could be helpful adjuncts to thyroid FNAB. C1 [Kitano, Mio; Rahbari, Reza; Patterson, Erin E.; Xiong, Yin; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Prasad, Nijaguna B.; Wang, Yongchun; Zeiger, Martha A.] Johns Hopkins Univ, Dept Surg, Endocrine Surg Sect, Sch Med Baltimore, Baltimore, MD USA. RP Kitano, M (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Intramural NIH HHS [ZIA BC011275-02] NR 70 TC 37 Z9 40 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2011 VL 18 IS 12 BP 3443 EP 3452 DI 10.1245/s10434-011-1766-4 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA 832XQ UT WOS:000295844400031 PM 21553140 ER PT J AU Hirasaka, K Lago, CU Kenaston, MA Fathe, K Nowinski, SM Nikawa, T Mills, EM AF Hirasaka, Katsuya Lago, Cory U. Kenaston, M. Alexander Fathe, Kristin Nowinski, Sara M. Nikawa, Takeshi Mills, Edward M. TI Identification of a Redox-Modulatory Interaction Between Uncoupling Protein 3 and Thioredoxin 2 in the Mitochondrial Intermembrane Space SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID OXYGEN SPECIES PRODUCTION; COMPLEX-III; RESPIRATORY-CHAIN; OXIDATIVE STRESS; HEART-MITOCHONDRIA; INSULIN-RESISTANCE; ENERGY-METABOLISM; ADIPOSE-TISSUE; LIVING CELLS; FATTY-ACIDS AB Uncoupling protein 3 (UCP3) is a member of the mitochondrial solute carrier superfamily that is enriched in skeletal muscle and controls mitochondrial reactive oxygen species (ROS) production, but the mechanisms underlying this function are unclear. Aims: The goal of this work focused on the identification of mechanisms underlying UCP3 functions. Results: Here we report that the N-terminal, intermembrane space (IMS)-localized hydrophilic domain of mouse UCP3 interacts with the N-terminal mitochondrial targeting signal of thioredoxin 2 (Trx2), a mitochondrial thiol reductase. Cellular immunoprecipitation and in vitro pull-down assays show that the UCP3-Trx2 complex forms directly, and that the Trx2 N-terminus is both necessary and sufficient to confer UCP3 binding. Mutation studies show that neither a catalytically inactivated Trx2 mutant, nor a mutant Trx2 bearing the N-terminal targeting sequence of cytochrome c oxidase (COXMTS-Trx2) bind UCP3. Biochemical analyses using permeabilized mitochondria, and live cell experiments using bimolecular fluorescence complementation show that the UCP3-Trx2 complex forms specifically in the IMS. Finally, studies in C2C12 myocytes stably overexpressing UCP3 (2.5-fold) and subjected to Trx2 knockdown show that Trx2 is required for the UCP3-dependent mitigation of complex III-driven mitochondrial ROS generation. UCP3 expression was increased in mice fed a high fat diet, leading to increased localization of Trx2 to the IMS. UCP3 overexpression also increased expression of the glucose transporter GLUT4 in a Trx2-dependent fashion. Innovation: This is the first report of a mitochondrial protein-protein interaction with UCP3 and the first demonstration that UCP3 binds directly, and in cells and tissues with mitochondrial thioredoxin 2. Conclusion: These studies identify a novel UCP3-Trx2 complex, a novel submitochondrial localization of Trx2, and a mechanism underlying UCP3-regulated mitochondrial ROS production. Antioxid. Redox Signal. 15, 2645-2661. C1 [Mills, Edward M.] Univ Texas Austin, Coll Pharm, Div Pharmacol Toxicol, Austin, TX 78714 USA. [Fathe, Kristin] Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78714 USA. [Hirasaka, Katsuya; Nikawa, Takeshi] Univ Tokushima, Dept Nutr Physiol, Inst Hlth Biosci, Tokushima 770, Japan. [Lago, Cory U.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Mills, EM (reprint author), Univ Texas Austin, Coll Pharm, Div Pharmacol Toxicol, 2409 Univ Ave,PHR 5-214, Austin, TX 78714 USA. EM ted_mills@mail.utexas.edu OI Hirasaka, Katsuya/0000-0003-2645-8450; Nowinski, Sara/0000-0002-4744-6101 FU National Institutes of Health [1R01DK089224]; JSPS FX This work was supported in part by Grant 1R01DK089224 (EMM) from the National Institutes of Health and a JSPS Postdoctoral Fellowships for Research Abroad (KH). We thank Dr. Casey W. Wright for providing the FG9 lentiviral vector. NR 54 TC 11 Z9 11 U1 2 U2 13 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD NOV PY 2011 VL 15 IS 10 BP 2645 EP 2661 DI 10.1089/ars.2011.3888 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 831MF UT WOS:000295734400001 PM 21619484 ER PT J AU Weir, D Faul, J Kardia, S Phillips, J AF Weir, David Faul, Jessica Kardia, Sharon Phillips, John TI A national resource for genetic research in behavioral & social science: The health and retirement study SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 41st Annual Meeting of the Behaviour-Genetics-Association CY JUN 06-09, 2011 CL Newport, RI SP Behav Genet Assoc C1 [Weir, David; Faul, Jessica; Kardia, Sharon] Univ Michigan, Ann Arbor, MI 48109 USA. [Phillips, John] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2011 VL 41 IS 6 SI SI BP 905 EP 905 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 826BO UT WOS:000295326600061 ER PT J AU Beydoun, HA Shroff, MR Mohan, R Beydoun, MA AF Beydoun, Hind A. Shroff, Monal R. Mohan, Ravinder Beydoun, May A. TI Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection among US men SO CANCER CAUSES & CONTROL LA English DT Article DE Vitamin A; Carotenoids; Prostate cancer; Prostate-specific antigen ID NUTRITION EXAMINATION SURVEY; ASCORBIC-ACID SUPPLEMENTATION; ANTIOXIDANT BETA-CAROTENE; ANTIGEN LEVELS; LUNG-CANCER; NATIONAL-HEALTH; LYCOPENE SUPPLEMENTATION; ALPHA-TOCOPHEROL; TOMATO PRODUCTS; RISK-FACTORS AB Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection were evaluated among 3,927 US men, 40-85 years of age, who participated in the 2001-2006 National Health and Nutrition Examination Surveys. Five recommended definitions of prostate cancer detection were adopted using total and free prostate-specific antigen (tPSA and fPSA) laboratory measurements. Men were identified as high risk based on alternative cutoffs, namely tPSA > 10 ng/ml, tPSA > 4 ng/ml, tPSA > 2.5 ng/ml, %fPSA < 25%, and %fPSA < 15%. %fPSA was defined as (fPSAA center dot tPSA)x 100%. Serum levels of vitamin A (retinol and retinyl esters) and carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein + zeaxanthin, lycopene) were defined as quartiles and examined as risk/protective factors for PSA biomarkers. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using binary logistic models. After adjustment for known demographic, socioeconomic, and lifestyle confounders, high serum levels of retinyl esters (tPSA > 10 ng/ml: Q4 vs. Q1 -> OR = 0.38, 95% CI: 0.14-1.00) and alpha-carotene (%fPSA < 15%: Q4 vs. Q1 -> OR = 0.49, 95% CI: 0.32-0.76) were associated with a lower odds, whereas high serum level of lycopene (tPSA > 2.5 ng/ml: Q4 vs. Q1 -> OR = 1.49, 95% CI: 1.01-2.14) was associated with a greater odds of prostate cancer detection. Apart from the three significant associations observed, no other exposure-outcome association was significant. Monitoring specific antioxidant levels may be helpful in the early detection of prostate cancer. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Shroff, Monal R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Mohan, Ravinder] Eastern Virginia Med Sch, Dept Family Med, Norfolk, VA 23501 USA. [Beydoun, May A.] NIA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 700 W Olney Rd,POB 1980, Norfolk, VA 23501 USA. EM baydouha@evms.edu FU NIH, National Institute on Aging FX This research was partly supported by the Intramural Research Program of the NIH, National Institute on Aging. We would like to thank Dr. Larry Brant and Dr. Joshua Goh for providing useful comments regarding the content of the manuscript. NR 51 TC 5 Z9 5 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2011 VL 22 IS 11 BP 1483 EP 1495 DI 10.1007/s10552-011-9822-8 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 834RP UT WOS:000295981400001 PM 21800039 ER PT J AU Purdue, MP Colt, JS Graubard, B Davis, F Ruterbusch, JJ DiGaetano, R Karami, S Wacholder, S Schwartz, K Chow, WH AF Purdue, Mark P. Colt, Joanne S. Graubard, Barry Davis, Faith Ruterbusch, Julie J. DiGaetano, Ralph Karami, Sara Wacholder, Sholom Schwartz, Kendra Chow, Wong-Ho TI A case-control study of reproductive factors and renal cell carcinoma among black and white women in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE Renal cell carcinoma; Reproductive factors; Case-control studies; Hysterectomy; Parity ID RISK-FACTORS; KIDNEY CANCER; HORMONAL FACTORS; PREGNANCY; COHORT; HYSTERECTOMY; HYPERTENSION; HAMSTERS; DISEASE AB Renal cell carcinoma (RCC) incidence is higher among blacks than whites in the United States and has been associated with the frequency and timing of childbirth among women in some epidemiologic studies. We investigated whether reproductive factors are associated with RCC, overall and by race, within a population-based case-control study. Between 2002 and 2007, 497 female cases of incident RCC (136 black, 361 white) and 546 female controls (273 black, 273 white) within the Detroit and Chicago metropolitan areas were enrolled. Information on reproductive history and other factors was collected through in-person interviews. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional logistic regression. Reduced RCC risk was observed among women aged a parts per thousand yen30 years at first live birth, relative to an age of < 20 years (OR 0.5, 95% CI 0.3-0.9). This association was present among both white (OR 0.4, 95% CI 0.2-0.9) and, though not statistically significant, black women (OR 0.6, 95% CI 0.2-1.8). In analyses restricted to clear cell adenocarcinoma, the most common RCC histological subtype, the association was particularly strong (OR 0.3, 95% CI 0.2-0.8). We did not observe clear evidence of association with RCC for other reproductive factors. Our findings further support an association between late maternal age at first birth and reduced RCC risk, and suggest that the association may be particularly strong for clear cell adenocarcinoma. C1 [Purdue, Mark P.; Colt, Joanne S.; Graubard, Barry; Karami, Sara; Wacholder, Sholom; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Davis, Faith] Univ Illinois, Chicago, IL USA. [Ruterbusch, Julie J.; Schwartz, Kendra] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Ruterbusch, Julie J.; Schwartz, Kendra] Wayne State Univ, Dept Family Med, Detroit, MI USA. [DiGaetano, Ralph] Westat Corp, Rockville, MD USA. [Schwartz, Kendra] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 8114, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU National Institutes of Health; National Cancer Institute [N02-CP-10128, N02-CP-11004, N02-CP-11161] FX We thank M. Dunn and K. Torres (Westat, Rockville, MD) for study coordination and S. Munuo (IMS, Silver Spring, MD) for computer support. Financial support: This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute under the following contracts: N02-CP-10128 (Westat, Inc.), N02-CP-11004 (Wayne State University), and N02-CP-11161 (University of Illinois at Chicago). NR 28 TC 8 Z9 8 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2011 VL 22 IS 11 BP 1537 EP 1544 DI 10.1007/s10552-011-9830-8 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 834RP UT WOS:000295981400007 PM 21866373 ER PT J AU Mondul, AM Weinstein, SJ Virtamo, J Albanes, D AF Mondul, Alison M. Weinstein, Stephanie J. Virtamo, Jarmo Albanes, Demetrius TI Serum total and HDL cholesterol and risk of prostate cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Cholesterol; HDL; Prospective studies; Prostatic neoplasms; Epidemiology; Risk; Molecular; Biomarker ID HIGH-DENSITY-LIPOPROTEIN; FOLLOW-UP; PLASMA-CHOLESTEROL; METABOLIC SYNDROME; LOWERING DRUGS; STATIN USE; COHORT; ASSOCIATION; MORTALITY; HYPERCHOLESTEROLEMIA AB Studies suggest a decreased risk of high-grade prostate cancer in men with lower circulating total cholesterol and that statins may protect against aggressive disease. Confirmation in additional populations and examination of associations for lipoprotein subfractions are needed. We examined prostate cancer risk and serum total and HDL cholesterol in the ATBC Study cohort (n = 29,093). Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041), non-aggressive (n = 829), aggressive (n = 461), advanced (n = 412), and high-grade (n = 231) prostate cancer by categories of total and HDL cholesterol. After excluding the first 10 years of follow-up, men with higher serum total cholesterol were at increased risk of overall (a parts per thousand yen240 vs. < 200 mg/dl: HR = 1.22, 95% CI 1.03-1.44, p-trend = 0.01) and advanced (a parts per thousand yen240 vs. < 200 mg/dl: HR = 1.85, 95% CI 1.13-3.03, p-trend = 0.05) prostate cancer. Higher HDL cholesterol was suggestively associated with a decreased risk of prostate cancer regardless of stage or grade. In this population of smokers, high serum total cholesterol was associated with higher risk of advanced prostate cancer, and high HDL cholesterol suggestively reduced the risk of prostate cancer overall. These results support previous studies and, indirectly, support the hypothesis that statins may reduce the risk of advanced prostate cancer by lowering cholesterol. C1 [Mondul, Alison M.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Dept Hlth & Human Serv, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20852 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00271, Finland. RP Mondul, AM (reprint author), NCI, Dept Hlth & Human Serv, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, 6120 Execut Blvd Ste 320, Rockville, MD 20852 USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU US Public Health Service; National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; National Cancer Institute FX This work was supported by US Public Health Service contracts from the National Cancer Institute, Department of Health and Human Services (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C); and by funding from the Intramural Research Program of the National Cancer Institute. NR 33 TC 41 Z9 41 U1 1 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2011 VL 22 IS 11 BP 1545 EP 1552 DI 10.1007/s10552-011-9831-7 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 834RP UT WOS:000295981400008 PM 21915616 ER PT J AU Faupel-Badger, JM Wang, YP Karumanchi, SA Stanczyk, F Pollak, M McElrath, T Hoover, RN Troisi, R AF Faupel-Badger, Jessica M. Wang, Yuping Karumanchi, S. Ananth Stanczyk, Frank Pollak, Michael McElrath, Thomas Hoover, Robert N. Troisi, Rebecca TI Associations of pregnancy characteristics with maternal and cord steroid hormones, angiogenic factors, and insulin-like growth factor axis SO CANCER CAUSES & CONTROL LA English DT Article DE African-American; Angiogenic factors; IGF; Leptin; Prolactin ID BREAST-CANCER RISK; SOLUBLE ENDOGLIN; ANTIANGIOGENIC FACTORS; TYROSINE KINASE-1; BIRTH-WEIGHT; PREECLAMPSIA; SERUM; ESTROGEN; METAANALYSIS; SFLT1 AB The objective of this study was to comprehensively profile biological factors in pregnancy that have been postulated to be important components of the in utero environment and may also have relevance to later susceptibility to cancer and other chronic diseases. Steroid sex hormones, IGFs, and angiogenic factors were measured in maternal and cord serum from term normotensive pregnancies. Spearman correlations and linear regression estimated relationships among the biological factors and clinical characteristics. The analytes were generally not correlated between maternal and fetal circulations. However, significant correlations were demonstrated among several analytes within maternal or cord samples. A few analytes were associated with clinical characteristics (e.g., maternal IGF-1 and IGFBP-3 were inversely correlated with offspring birth weight, while maternal leptin and cord testosterone were positively correlated with this characteristic). Maternal androgens were higher in African-Americans than whites, and maternal PlGF and soluble fms-like tyrosine kinase-1 (sFlt-1) were higher in male than female offspring. There were significant correlations among analytes, but the patterns differed depending on whether they were measured in the maternal or fetal circulation. The number and magnitude of correlations among analytes, however, should affect the design and interpretation of future studies. 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, Dept Obstet & Gynecol, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Karumanchi, S. Ananth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Stanczyk, Frank] Univ So Calif, Dept Obstet & Gynecol, Keck Sch Med, Los Angeles, CA 90089 USA. [Stanczyk, Frank] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Pollak, Michael] McGill Univ, Dept Med, Montreal, PQ, Canada. [McElrath, Thomas] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. 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, National Institutes of Health; Center for Cancer Training, NCI FX We thank Lisa Philibert, RN and Kimberly Mandino, RN for patient recruitment and clinical data collection for the study. We also thank Marianne Hyer for her contributions to data verification and analysis, and Dr. Jun Zhang for collaborating with us on the parent study. This research was supported by federal funds from the National Cancer Institute, National Institutes of Health. Dr. Faupel-Badger's research was supported by the Center for Cancer Training, Cancer Prevention Fellowship Program, NCI. NR 44 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2011 VL 22 IS 11 BP 1587 EP 1595 DI 10.1007/s10552-011-9835-3 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 834RP UT WOS:000295981400012 PM 21947778 ER PT J AU Chang, SE Horwitz, B Ostuni, J Reynolds, R Ludlow, CL AF Chang, Soo-Eun Horwitz, Barry Ostuni, John Reynolds, Richard Ludlow, Christy L. TI Evidence of Left Inferior Frontal-Premotor Structural and Functional Connectivity Deficits in Adults Who Stutter SO CEREBRAL CORTEX LA English DT Article DE DTI tractography; functional connectivity; motor; psychophysiological interaction (PPI); speech perception; speech production; stuttering ID POSITRON-EMISSION-TOMOGRAPHY; SPEECH MOTOR CONTROL; BASAL GANGLIA; NONSTUTTERING ADULTS; FLUENT SPEAKERS; HUMAN THALAMUS; CORTEX; FMRI; CEREBELLAR; AREAS AB The neurophysiological basis for stuttering may involve deficits that affect dynamic interactions among neural structures supporting fluid speech processing. Here, we examined functional and structural connectivity within corticocortical and thalamocortical loops in adults who stutter. For functional connectivity, we placed seeds in the left and right inferior frontal Brodmann area 44 (BA44) and in the ventral lateral nucleus (VLN) of the thalamus. Subject-specific seeds were based on peak activation voxels captured during speech and nonspeech tasks using functional magnetic resonance imaging. Psychophysiological interaction (PPI) was used to find brain regions with heightened functional connectivity with these cortical and subcortical seeds during speech and nonspeech tasks. Probabilistic tractography was used to track white matter tracts in each hemisphere using the same seeds. Both PPI and tractrography supported connectivity deficits between the left BA44 and the left premotor regions, while connectivity among homologous right hemisphere structures was significantly increased in the stuttering group. No functional connectivity differences between BA44 and auditory regions were found between groups. The functional connectivity results derived from the VLN seeds were less definitive and were not supported by the tractography results. Our data provide strongest support for deficient left hemisphere inferior frontal to premotor connectivity as a neural correlate of stuttering. C1 [Chang, Soo-Eun] Michigan State Univ, Dept Communicat Sci & Disorders, E Lansing, MI 48824 USA. [Chang, Soo-Eun; Ludlow, Christy L.] NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20852 USA. [Horwitz, Barry] NIDCD, Brain Imaging & Modeling Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20852 USA. [Ostuni, John] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20852 USA. [Reynolds, Richard] NIMH, NIH, Bethesda, MD 20852 USA. [Ludlow, Christy L.] James Madison Univ, Dept Commun Sci & Disorders, Harrisonburg, VA 22807 USA. RP Chang, SE (reprint author), Michigan State Univ, Dept Communicat Sci & Disorders, 112 Oyer Bldg, E Lansing, MI 48824 USA. EM schang7@msu.edu OI Ludlow, Christy/0000-0002-2015-6171 FU National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Deafness and other Communication Disorders (NIDCD); National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH) FX This work was supported by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Deafness and other Communication Disorders (NIDCD), and the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH). NR 69 TC 55 Z9 55 U1 3 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2011 VL 21 IS 11 BP 2507 EP 2518 DI 10.1093/cercor/bhr028 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 827FK UT WOS:000295413200008 PM 21471556 ER PT J AU Colt, JS Schwartz, K Graubard, BI Davis, F Ruterbusch, J DiGaetano, R Purdue, M Rothman, N Wacholder, S Chow, WH AF Colt, Joanne S. Schwartz, Kendra Graubard, Barry I. Davis, Faith Ruterbusch, Julie DiGaetano, Ralph Purdue, Mark Rothman, Nathaniel Wacholder, Sholom Chow, Wong-Ho TI Hypertension and Risk of Renal Cell Carcinoma Among White and Black Americans SO EPIDEMIOLOGY LA English DT Article ID POPULATION ATTRIBUTABLE RISK; KIDNEY CANCER; UNITED-STATES; ANTIHYPERTENSIVE MEDICATIONS; BLOOD-PRESSURE; DIURETICS; OBESITY; DENMARK; HISTORY; COHORT AB Background: Renal cell carcinoma and hypertension (a well-established renal cancer risk factor) are both more frequent among blacks than whites in the United States. The association between hypertension and renal cell carcinoma has not been examined in black Americans. We investigated the hypertension-renal cancer association by race, and we assessed the role of hypertension in the racial disparity of renal cancer incidence. Methods: Participants were enrolled in a population-based case-control study in Detroit and Chicago during 2002-2007 (number of cases: 843 whites, 358 blacks; number of controls: 707 whites, 519 blacks). Participants reported their history of hypertension and antihypertensive drug use. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for demographic characteristics, smoking, body mass index, and family history of cancer. Results: Hypertension doubled renal cancer risk (OR = 2.0 [CI = 1.7-2.5]) overall. For whites, the OR was 1.9 (CI = 1.5-2.4), whereas for blacks it was 2.8 (2.1-3.8) (P for interaction = 0.11). ORs increased with time after hypertension diagnosis (P for trend <0.001), reaching 4.1 (CI = 2.3-7.4) for blacks and 2.6 (CI = 1.7-4.1) for whites after 25 years. ORs for poorly controlled hypertension were 4.5 (CI = 2.3-8.8) for blacks and 2.1 (CI = 1.2-3.8) for whites. If these estimates correctly represent causal effects and if, hypothetically, hypertension could be prevented entirely among persons aged 50-79 years, the black/white disparity in renal cancer could be reversed among women and reduced by two-thirds among men. Conclusions: Hypertension is a risk factor for renal cancer among both blacks and whites, and might explain a substantial portion of the racial disparity in renal cancer incidence. Preventing and controlling hypertension might reduce renal cancer incidence, adding to the known benefits of blood pressure control for heart disease and stroke reduction, particularly among blacks. C1 [Colt, Joanne S.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH,Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Schwartz, Kendra; Ruterbusch, Julie] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Schwartz, Kendra; Ruterbusch, Julie] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Davis, Faith] Univ Illinois, Sch Publ Hlth, Dept Epidemiol & Biostat, Chicago, IL USA. [DiGaetano, Ralph] Westat Corp, Rockville, MD USA. RP Colt, JS (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH,Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,Room 8002, Bethesda, MD 20892 USA. EM coltj@mail.nih.gov FU National Institutes of Health; National Cancer Institute [N02-CP-10128, N02-CP-11004, N02-CP-11161] FX Supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute with contracts N02-CP-10128 (Westat, Inc.), N02-CP-11004 (Wayne State University), and N02-CP-11161 (University of Illinois at Chicago). NR 36 TC 33 Z9 34 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2011 VL 22 IS 6 BP 797 EP 804 DI 10.1097/EDE.0b013e3182300720 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 829YE UT WOS:000295622000006 PM 21881515 ER PT J AU Humblet, O Williams, PL Korrick, SA Sergeyev, O Emond, C Birnbaum, LS Burns, JS Altshul, L Patterson, DG Turner, WE Lee, MM Revich, B Hauser, R AF Humblet, Olivier Williams, Paige L. Korrick, Susan A. Sergeyev, Oleg Emond, Claude Birnbaum, Linda S. Burns, Jane S. Altshul, Larisa Patterson, Donald G., Jr. Turner, Wayman E. Lee, Mary M. Revich, Boris Hauser, Russ TI Dioxin and Polychlorinated Biphenyl Concentrations in Mother's Serum and the Timing of Pubertal Onset in Sons SO EPIDEMIOLOGY LA English DT Article ID TOXIC EQUIVALENCY FACTORS; SEXUAL-MATURATION; SPERM PRODUCTION; RUSSIAN BOYS; MALE-RAT; EXPOSURE; GROWTH; CHAPAEVSK; WEIGHT; PCBS AB Background: Animal studies have demonstrated that timing of pubertal onset can be altered by prenatal exposure to dioxins or polychlorinated biphenyls (PCBs), but studies of human populations have been quite limited. Methods: We assessed the association between maternal serum concentrations of dioxins and PCBs and the sons' age of pubertal onset in a prospective cohort of 489 mother-son pairs from Chapaevsk, Russia, a town contaminated with these chemicals during past industrial activity. The boys were recruited at ages 8 to 9 years, and 4 years of annual follow-up data were included in the analysis. Serum samples were collected at enrollment from both mothers and sons for measurement of dioxin and PCB concentrations using high-resolution mass spectrometry. The sons' pubertal onset-defined as pubertal stage 2 or higher for genitalia (G) or pubic hair (P), or testicular volume >3 mL-was assessed annually by the same physician. Results: In multivariate Cox models, elevated maternal serum PCBs were associated with earlier pubertal onset defined by stage G2 or higher (4th quartile hazard ratio = 1.7 [95% confidence interval = 1.1-2.5]), but not for stage P2 or higher or for testicular volume >3 mL. Maternal serum concentrations of dioxin toxic equivalents were not consistently associated with the sons' pubertal onset, although a dose-related delay in pubertal onset (only for G2 or higher) was seen among boys who breast-fed for 6 months or more. Conclusions: Maternal PCB serum concentrations measured 8 or 9 years after sons' births-which may reflect sons' prenatal and early-life exposures-were associated with acceleration in some, but not all, measures of pubertal onset. C1 [Humblet, Olivier; Korrick, Susan A.; Burns, Jane S.; Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Korrick, Susan A.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Korrick, Susan A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sergeyev, Oleg] Samara State Med Univ, Dept Phys Educ & Hlth, Samara, Russia. [Sergeyev, Oleg] Chapaevsk Med Assoc, Samara, Russia. [Emond, Claude] Univ Montreal, Fac Med, Dept Environm & Occupat Hlth, Montreal, PQ H3C 3J7, Canada. [Birnbaum, Linda S.] NCI, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Altshul, Larisa] Environm Hlth & Engn Inc, Needham, MA USA. [Patterson, Donald G., Jr.] EnviroSolut Consulting Inc, Jasper, GA USA. [Turner, Wayman E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Pediat Endocrinol Div, Dept Pediat & Cell Biol, Worcester, MA USA. [Revich, Boris] Russian Acad Sci, Ctr Demog & Human Ecol, Inst Forecasting, Moscow, Russia. RP Hauser, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg I,Room 1405, Boston, MA 02115 USA. EM rhauser@hohp.harvard.edu RI Sergeyev, Oleg/H-8854-2013; OI Sergeyev, Oleg/0000-0002-5745-3348; Lee, Mary/0000-0002-7204-4884 FU U.S. EPA [R82943701]; NIEHS [ES014370, ES00002, 5T32-ES07069-28]; NIEHS/NHGRI [5T32ES016645-02] FX This work was funded by U.S. EPA grant R82943701 and NIEHS grants ES014370, ES00002, and 5T32-ES07069-28. OH was supported by 5T32ES016645-02 from NIEHS/NHGRI. MML is a member of the UMass DERC (DK32520). CE is an International Consultant and the President of BioSimulation Consulting Inc. LA is a consultant for Environmental Health and Engineering, Inc. DGP is a consultant for Axys Analytical Solutions, Fluid Management Systems, Inc., and Exponent Inc. NR 41 TC 12 Z9 12 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2011 VL 22 IS 6 BP 827 EP 835 DI 10.1097/EDE.0b013e318230b0d1 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 829YE UT WOS:000295622000011 PM 21968773 ER PT J AU Shi, M Weinberg, CR AF Shi, Min Weinberg, Clarice R. TI How Much Are We Missing in SNP-by-SNP Analyses of Genome-wide Association Studies? SO EPIDEMIOLOGY LA English DT Article ID CLEFT-PALATE; HERITABILITY; PATHWAYS; LIP AB Genome-wide association studies have discovered common genetic variants associated with susceptibility for several complex diseases, but they have been unfruitful for many others. Typically, analysis is done "agnostically," by considering one single nucleotide polymorphism (SNP) at a time and controlling the overall type I error rate by correcting for multiple testing. Such one-at-atime analyses may be inadequate for screening genes under realistic causal models. We use oral clefting as a disease model to develop a range of toy example scenarios: risk might involve only genes, or genes and exposure, or genes, exposure, and their supermultiplicative interaction. These examples illustrate how dramatically important genetic variants can be obscured by a one-SNP-at-a-time analysis when multiple biologic pathways and multiple genes jointly influence etiology. These examples highlight the need for better methods for gene-by-environment and gene-by-gene analyses. C1 [Shi, Min; Weinberg, Clarice R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Shi, M (reprint author), NIEHS, Biostat Branch, A3-03 101-A315, Res Triangle Pk, NC 27709 USA. EM shi2@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01-ES040007, Z01-ES45002] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES040007; Z01-ES45002). NR 12 TC 6 Z9 6 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2011 VL 22 IS 6 BP 845 EP 847 DI 10.1097/EDE.0b013e31822ffbe7 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 829YE UT WOS:000295622000013 PM 21878815 ER PT J AU Orru, M Zanoveli, JM Quiroz, C Nguyen, HP Guitart, X Ferre, S AF Orru, Marco Zanoveli, Janaina Menezes Quiroz, Cesar Huu Phuc Nguyen Guitart, Xavier Ferre, Sergi TI Functional changes in postsynaptic adenosine A(2A) receptors during early stages of a rat model of Huntington disease SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Huntington disease; Transgenic rat; Adenosine A(2A) receptor; Locomotor activity; Cortical electrical stimulation ID BASAL GANGLIA; DOPAMINE-D-2 RECEPTORS; MOUSE MODELS; CELLS; NEUROTRANSMISSION; NEURONS AB Huntington disease (HD) is a neurodegenerative disorder involving preferential loss of striatal GABAergic medium spiny neurons. Adenosine A(2A) receptors (A(2A)Rs) are present in the striatum at both presynaptic and post-synaptic levels. Blocking pre-synaptic A(2A)Rs, localized in glutamatergic terminals that contact striatal GABAergic dynorphinergic neurons, reduces glutamate release, which could be beneficial in HD. On the other hand, blockade of post-synaptic A(2A)Rs, localized in striatal GABAergic enkephalinergic neurons, could exacerbate the motor dysfunction. To evaluate the function of pre- or post-synaptic A(2A)Rs in HD we used selective antagonists for these receptors in a transgenic rat model of HD. Locomotor activity after systemic administration of the postsynaptic A(2A)R antagonist KW-6002 was used to investigate the function of postsynaptic A(2A)Rs. The role of pre-synaptic A(2A)Rs was instead evaluated by measuring the reduction of the electromyographic response of mastication muscles during electrical stimulation of the orofacial motor cortex after the systemic administration of the presynaptic A(2A)R antagonist SCH-442416. The ability of KW-6002 to produce locomotor activation was lost at 6 and 12 month-old of age in heterozygous and homozygous transgenic rats, but not in wild-type littermates. Nevertheless, no significant changes were observed up to 12 months of age in the potency of SCH-442416 to decrease the electromyographic response after cortical electrical stimulation. These results agree with a selective impairment of the striatal GABAergic enkephalinergic neuronal function during pre-symptomatic stages in HD. Since presynaptic A(2A)R function is not impaired, this receptor could probably be used as a target for the symptomatic treatment of the disease. Published by Elsevier Inc. C1 [Orru, Marco; Zanoveli, Janaina Menezes; Quiroz, Cesar; Guitart, Xavier; Ferre, Sergi] Natl Inst Drug Abuse, CNS Receptor Receptor Interact Unit, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Huu Phuc Nguyen] Univ Tubingen, Dept Med Genet, D-72076 Tubingen, Germany. RP Ferre, S (reprint author), Natl Inst Drug Abuse, CNS Receptor Receptor Interact Unit, IRP, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Nguyen, Huu Phuc/F-5390-2015 OI Ferre, Sergi/0000-0002-1747-1779; Nguyen, Huu Phuc/0000-0001-6139-788X FU NIDA; CHDI Foundation; CAPES/Brazil [BEX 4135/09-1] FX Work funded by the intramural funds of NIDA and by CHDI Foundation. JMZ was a postdocotoral student financially supported by CAPES/Brazil (Process number: BEX 4135/09-1). NR 31 TC 7 Z9 7 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 NOV PY 2011 VL 232 IS 1 BP 76 EP 80 DI 10.1016/j.expneurol.2011.08.005 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 833UW UT WOS:000295911400009 PM 21867705 ER PT J AU Qiu, P Cui, XZ Barochia, A Li, Y Natanson, C Eichacker, PQ AF Qiu, Ping Cui, Xizhong Barochia, Amisha Li, Yan Natanson, Charles Eichacker, Peter Q. TI The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE anti-TNF; clinical trial; drug development; sepsis; therapy ID TUMOR-NECROSIS-FACTOR; HUMAN SEPTIC SHOCK; FACTOR-ALPHA; ENDOTHELIAL-CELLS; ESCHERICHIA-COLI; FACTOR CHALLENGES; CECAL LIGATION; CYTOKINE; EFFICACY; ENDOTOXIN AB Introduction: Septic shock is highly lethal and its incidence is increasing. Although TNF-alpha plays a key role in sepsis pathogenesis, past efforts to therapeutically inhibit it had limited success. However, there is continued interest in such therapies and there are now ongoing Phase II sepsis trials testing the effects of AZD9773, a TNF-directed polyclonal antibody fragment preparation. Experience with anti-inflammatory agents suggested that their efficacy may relate to sepsis-associated risk of death. Areas covered: An overview of the biology of TNF and experimental data implicating TNF as a key mediator in sepsis pathogenesis; a review of the earlier clinical experience with anti-TNF therapies demonstrating that when examined across 12 trials, these agents had a highly consistent overall effect which although not reaching significance, was on the side of benefit; a review of data showing that sepsis-associated risk of death may influence the efficacy of anti-inflammatory agents like anti-TNF ones and a review of the rational and clinical experience to date with AZD9773 and its precursor, CytoFab. Expert opinion: Discusses variables that may need to be accounted for to maximize the success of clinical trials in sepsis testing agents that modulate host inflammation. C1 [Qiu, Ping; Cui, Xizhong; Barochia, Amisha; Li, Yan; Natanson, Charles; Eichacker, Peter Q.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU NIH Clinical Center FX We confirm that this research was supported by the intramural program of the NIH Clinical Center. The authors have no other competing interests to declare. NR 54 TC 31 Z9 33 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD NOV PY 2011 VL 20 IS 11 BP 1555 EP 1564 DI 10.1517/13543784.2011.623125 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 831GU UT WOS:000295718200008 PM 21961576 ER PT J AU Esser, D Kouril, T Zaparty, M Sierocinski, P Chan, PP Lowe, T Van der Oost, J Albers, SV Schomburg, D Makarova, KS Siebers, B AF Esser, Domink Kouril, Theresa Zaparty, Melanie Sierocinski, Pawel Chan, Patricia P. Lowe, Todd Van der Oost, John Albers, Sonja-Verena Schomburg, Dietmar Makarova, Kira S. Siebers, Bettina TI Functional curation of the Sulfolobus solfataricus P2 and S. acidocaldarius 98-3 complete genome sequences SO EXTREMOPHILES LA English DT Article DE Archaea; Thermoacidophiles; Genome analysis; Genomics ID NONAUTONOMOUS MOBILE ELEMENTS; ARCHAEAL GENOMES; GENUS SULFOLOBUS; TEMPERATURE; MODEL AB The thermoacidophiles Sulfolobus solfataricus P2 and S. acidocaldarius 98-3 are considered key model organisms representing a major phylum of the Crenarchaeota. Because maintaining current, accurate genome information is indispensable for modern biology, we have updated gene function annotation using the arCOGs database, plus other available functional, structural and phylogenetic information. The goal of this initiative is continuous improvement of genome annotation with the support of the Sulfolobus research community. C1 [Esser, Domink; Kouril, Theresa; Siebers, Bettina] Univ Duisburg Essen, Biofilm Ctr, Fac Chem, D-45141 Essen, Germany. [Zaparty, Melanie] Univ Regensburg, Inst Mol & Cellular Anat, D-93053 Regensburg, Germany. [Sierocinski, Pawel; Van der Oost, John] Wageningen Univ, Microbiol Lab, NL-6703 HB Wageningen, Netherlands. [Chan, Patricia P.; Lowe, Todd] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA USA. [Albers, Sonja-Verena] Max Planck Inst Terr Microbiol, D-35043 Marburg, Germany. [Schomburg, Dietmar] Tech Univ Carolo Wilhelmina Braunschweig, Dept Bioinformat & Biochem, D-38106 Braunschweig, Germany. [Makarova, Kira S.] NIH, Natl Biotechnol Ctr, Bethesda, MD 20894 USA. RP Siebers, B (reprint author), Univ Duisburg Essen, Biofilm Ctr, Fac Chem, Univ Str 5, D-45141 Essen, Germany. EM bettina.siebers@uni-due.de RI Albers, Sonja-Verena/H-1213-2012; OI Albers, Sonja-Verena/0000-0003-2459-2226 FU BMBF; NWO FX The project has been performed in the course of the transnational SysMO initiative within the Sulfolobus Systems Biology "SulfoSYS" project. Partners gratefully acknowledge financial support from their respective national funding agencies (BMBF, NWO) as well as partner universities. NR 21 TC 10 Z9 10 U1 3 U2 9 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 1431-0651 J9 EXTREMOPHILES JI Extremophiles PD NOV PY 2011 VL 15 IS 6 BP 711 EP 712 DI 10.1007/s00792-011-0392-1 PG 2 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 835CP UT WOS:000296011800009 PM 21912952 ER PT J AU Pathmajeyan, MS Patel, SA Carroll, JA Seib, T Striebel, JF Bridges, RJ Chesebro, B AF Pathmajeyan, Melissa S. Patel, Sarjubhai A. Carroll, James A. Seib, Todd Striebel, James F. Bridges, Richard J. Chesebro, Bruce TI Increased Excitatory Amino Acid Transport into Murine Prion Protein Knockout Astrocytes Cultured In Vitro SO GLIA LA English DT Article DE prion protein; excitatory amino acid transporters; astrocyte; excitotoxicity; NMDA receptor ID DEPENDENT GLUTAMATE TRANSPORTERS; MICE LACKING; CYCLIC-AMP; REACTIVE ASTROCYTES; NMDA RECEPTORS; MESSENGER-RNA; HIGH-AFFINITY; UP-REGULATION; TIME-COURSE; EXPRESSION AB Prion protein (PrP) is expressed on a wide variety of cells and plays an important role in the pathogenesis of transmissible spongiform encephalopathies. However, its normal function remains unclear. Mice that do not express PrP exhibit deficits in spatial memory and abnormalities in excitatory neurotransmission suggestive that PrP may function in the glutamatergic synapse. Here, we show that transport of D-aspartate, a nonmetabolized L-glutamate analog, through excitatory amino acid transporters (EAATs) was faster in astrocytes from PrP knockout (PrPKO) mice than in astrocytes from C57BL/10SnJ wild-type (WT) mice. Experiments using EAAT subtype-specific inhibitors demonstrated that in both WT and PrPKO astrocytes, the majority of transport was mediated by EAAT1. Furthermore, PrPKO astrocytes were more effective than WT astrocytes at alleviating L-glutamate-mediated excitotoxic damage in both WT and PrPKO neuronal cultures. Thus, in this in vitro model, PrPKO astrocytes exerted a functional influence on neuronal survival and may therefore influence regulation of glutamatergic neurotransmission in vivo. (C) 2011 Wiley-Liss, Inc. C1 [Pathmajeyan, Melissa S.; Carroll, James A.; Striebel, James F.; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Pathmajeyan, Melissa S.; Patel, Sarjubhai A.; Seib, Todd; Bridges, Richard J.] Univ Montana, Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Pathmajeyan, Melissa S.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM bchesebro@nih.gov FU NIAID Division of Intramural Research at NIH; National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX Grant sponsor: NIAID Division of Intramural Research at NIH.; The authors gratefully acknowledge David Patterson for assistance with statistics, Sharon Jetter for assistance in maintaining the mouse colonies, Brent Race for SNP analysis, Ron Messer for assistance with FACS analysis, Anita Mora for assistance with graphics, Michael Kavanaugh for helpful discussions, and Gerald S. Baron, Karin Peterson, and Suzette Priola for critical reading of the manuscript. This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 60 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD NOV PY 2011 VL 59 IS 11 BP 1684 EP 1694 DI 10.1002/glia.21215 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 833KQ UT WOS:000295884500011 PM 21766339 ER PT J AU Kadakia, MB Fox, CS Scirica, BM Murphy, SA Bonaca, MP Morrow, DA AF Kadakia, Mitul B. Fox, Caroline S. Scirica, Benjamin M. Murphy, Sabina A. Bonaca, Marc P. Morrow, David A. TI Central obesity and cardiovascular outcomes in patients with acute coronary syndrome: observations from the MERLIN-TIMI 36 trial SO HEART LA English DT Article ID BODY-MASS INDEX; ACUTE MYOCARDIAL-INFARCTION; META-REGRESSION ANALYSIS; WAIST CIRCUMFERENCE; ABDOMINAL OBESITY; METABOLIC SYNDROME; HEART-ASSOCIATION; UNSTABLE ANGINA; ARTERY-DISEASE; ADIPOSE-TISSUE AB Objective Despite the association of obesity with incident cardiovascular disease, obese patients with acute coronary syndrome (ACS) appear to have more favourable short-term outcomes. A study was undertaken to determine whether this 'obesity paradox' persists in the long term and to examine the specific relationship of central obesity with outcomes after ACS. Methods The relationship was investigated between two measures of obesity-body mass index (BMI) and waist circumference (WC)-and 30-day and 1-year outcomes after ACS. 6560 patients with non-ST elevation ACS in the MERLIN-TIMI 36 trial were followed for 1 year. Patients were stratified into three BMI groups (<25, 25-30, >= 30 kg/m(2)) and gender-specific tertiles of WC. The primary endpoint was cardiovascular death, myocardial infarction or recurrent ischaemia. Results Patients with BMI >= 30 kg/m(2) had a significantly lower risk of the primary endpoint than those with BMI <25 kg/m(2) (HR 0.64; 95% CI 0.51 to 0.81, p<0.0001) at 30 days. However, after the 30-day acute phase, landmark analysis from 30 days to 1 year showed no difference in risk between BMI groups (HR 1.09; 95% CI 0.92 to 1.29, p=0.34). WC tertiles demonstrated a similar relationship. When BMI groups were stratified by WC there was a trend towards more adverse outcomes in higher WC groups among those in lower BMI groups. The group with the lowest BMI and highest WC had the highest risk (HR 2.8; 95% CI 0.93 to 8.3; p=0.067). Conclusions Obesity is associated with more favourable short-term outcomes after ACS. However, in the longer term the obesity paradox is no longer present and may reverse. Those with WC out of proportion to BMI suggestive of significant central adiposity may be at highest risk following ACS. C1 [Kadakia, Mitul B.] Hosp Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19103 USA. [Kadakia, Mitul B.; Scirica, Benjamin M.; Murphy, Sabina A.; Bonaca, Marc P.; Morrow, David A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, NHBLIs Framingham Heart Study, Framingham, MA USA. [Kadakia, Mitul B.; Fox, Caroline S.; Scirica, Benjamin M.; Murphy, Sabina A.; Bonaca, Marc P.; Morrow, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Kadakia, MB (reprint author), Hosp Univ Penn, Div Cardiovasc Med, 3400 Spruce St, Philadelphia, PA 19103 USA. EM kadakia@post.harvard.edu FU CV Therapeutics (now Gilead Science Inc); Novartis Pharmaceuticals Corporation; AstraZeneca Pharmaceuticals LP; Daiichi-Sankyo Inc; Merck Co Inc; Johnson and Johnson Pharmaceutical Research & Development LLC; Bayer HealthCare Pharmaceuticals; Bristol-Myers-Squibb Company; CV Therapeutics FX MERLIN-TIMI 36 was supported by CV Therapeutics (now Gilead Science Inc).; BMS has received grants for clinical research via the TIMI Study Group and Brigham and Women's Hospital from CV Therapeutics, Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP, Daiichi-Sankyo Inc, Merck & Co Inc, Johnson and Johnson Pharmaceutical Research & Development LLC, Bayer HealthCare Pharmaceuticals and Bristol-Myers-Squibb Company and has served as a consultant for AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, CV Therapeutics, Cogentus, Shionogi & Co Ltd, Gilead Sciences Inc, Merck & Co Inc and Schering-Plough Corporation. DAM has received grants for clinical research via the TIMI Study Group and Brigham & Women's Hospital from CV Therapeutics, served as a consultant for Menarini Group and received honoraria for educational presentations from CV Therapeutics. MBK, CSF, MPB and SAM do not report any potential conflicts. NR 33 TC 30 Z9 32 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD NOV PY 2011 VL 97 IS 21 BP 1782 EP 1787 DI 10.1136/heartjnl-2011-300231 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 829VK UT WOS:000295612600013 PM 21865203 ER PT J AU Im, KM Kirchhoff, T Wang, XS Green, T Chow, CY Vijai, J Korn, J Gaudet, MM Fredericksen, Z Pankratz, VS Guiducci, C Crenshaw, A McGuffog, L Kartsonaki, C Morrison, J Healey, S Sinilnikova, OM Mai, PL Greene, MH Piedmonte, M Rubinstein, WS Hogervorst, FB Rookus, MA Collee, JM Hoogerbrugge, N van Asperen, CJ Meijers-Heijboer, HEJ van Roozendaal, CE Caldes, T Perez-Segura, P Jakubowska, A Lubinski, J Huzarski, T Blecharz, P Nevanlinna, H Aittomaki, K Lazaro, C Blanco, I Barkardottir, RB Montagna, M D'Andrea, E Devilee, P Olopade, OI Neuhausen, SL Peissel, B Bonanni, B Peterlongo, P Singer, CF Rennert, G Lejbkowicz, F Andrulis, IL Glendon, G Ozcelik, H Toland, AE Caligo, MA Beattie, MS Chan, S Domchek, SM Nathanson, KL Rebbeck, TR Phelan, C Narod, S John, EM Hopper, JL Buys, SS Daly, MB Southey, MC Terry, MB Tung, N Hansen, TVO Osorio, A Benitez, J Duran, M Weitzel, JN Garber, J Hamann, U Peock, S Cook, M Oliver, CT Frost, D Platte, R Evans, DG Eeles, R Izatt, L Paterson, J Brewer, C Hodgson, S Morrison, PJ Porteous, M Walker, L Rogers, MT Side, LE Godwin, AK Schmutzler, RK Wappenschmidt, B Laitman, Y Meindl, A Deissler, H Varon-Mateeva, R Preisler-Adams, S Kast, K Venat-Bouvet, L Stoppa-Lyonnet, D Chenevix-Trench, G Easton, DF Klein, RJ Daly, MJ Friedman, E Dean, M Clark, AG Altshuler, DM Antoniou, AC Couch, FJ Offit, K Gold, B AF Im, Kate M. Kirchhoff, Tomas Wang, Xianshu Green, Todd Chow, Clement Y. Vijai, Joseph Korn, Joshua Gaudet, Mia M. Fredericksen, Zachary Pankratz, V. Shane Guiducci, Candace Crenshaw, Andrew McGuffog, Lesley Kartsonaki, Christiana Morrison, Jonathan Healey, Sue Sinilnikova, Olga M. Mai, Phuong L. Greene, Mark H. Piedmonte, Marion Rubinstein, Wendy S. Hogervorst, Frans B. Rookus, Matti A. Collee, J. Margriet Hoogerbrugge, Nicoline van Asperen, Christi J. Meijers-Heijboer, Hanne E. J. van Roozendaal, Cees E. Caldes, Trinidad Perez-Segura, Pedro Jakubowska, Anna Lubinski, Jan Huzarski, Tomasz Blecharz, Pawel Nevanlinna, Heli Aittomaki, Kristiina Lazaro, Conxi Blanco, Ignacio Barkardottir, Rosa B. Montagna, Marco D'Andrea, Emma Devilee, Peter Olopade, Olufunmilayo I. Neuhausen, Susan L. Peissel, Bernard Bonanni, Bernardo Peterlongo, Paolo Singer, Christian F. Rennert, Gad Lejbkowicz, Flavio Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Toland, Amanda Ewart Caligo, Maria Adelaide Beattie, Mary S. Chan, Salina Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Timothy R. Phelan, Catherine Narod, Steven John, Esther M. Hopper, John L. Buys, Saundra S. Daly, Mary B. Southey, Melissa C. Terry, Mary-Beth Tung, Nadine Hansen, Thomas V. O. Osorio, Ana Benitez, Javier Duran, Mercedes Weitzel, Jeffrey N. Garber, Judy Hamann, Ute Peock, Susan Cook, Margaret Oliver, Clare T. Frost, Debra Platte, Radka Evans, D. Gareth Eeles, Ros Izatt, Louise Paterson, Joan Brewer, Carole Hodgson, Shirley Morrison, Patrick J. Porteous, Mary Walker, Lisa Rogers, Mark T. Side, Lucy E. Godwin, Andrew K. Schmutzler, Rita K. Wappenschmidt, Barbara Laitman, Yael Meindl, Alfons Deissler, Helmut Varon-Mateeva, Raymonda Preisler-Adams, Sabine Kast, Karin Venat-Bouvet, Laurence Stoppa-Lyonnet, Dominique Chenevix-Trench, Georgia Easton, Douglas F. Klein, Robert J. Daly, Mark J. Friedman, Eitan Dean, Michael Clark, Andrew G. Altshuler, David M. Antoniou, Antonis C. Couch, Fergus J. Offit, Kenneth Gold, Bert TI Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers SO HUMAN GENETICS LA English DT Article ID TAY-SACHS DISEASE; BREAST-CANCER; POSITIVE SELECTION; GENETIC-VARIATION; POPULATION; FREQUENCY; GENOME; JEWS; ASSOCIATION; SIGNATURES AB Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews. C1 [Gold, Bert] NCI, Frederick, MD 21702 USA. [Im, Kate M.; Dean, Michael; Gold, Bert] NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. [Kirchhoff, Tomas; Vijai, Joseph; Klein, Robert J.; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, Program Canc Prevent & Populat Res,Program Canc P, New York, NY 10021 USA. [Wang, Xianshu; Fredericksen, Zachary; Pankratz, V. Shane; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Collee, J. Margriet; Montagna, Marco] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02138 USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Daly, Mark J.; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Ctr Human Genet Res, Boston, MA 02114 USA. [Chow, Clement Y.; Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Healey, Sue; Chenevix-Trench, Georgia; Antoniou, Antonis C.] Queensland Inst Med Res, Genet & Populat Hlth Div, Brisbane, Qld 4006, Australia. [Sinilnikova, Olga M.] Ctr Hosp Univ Lyon, Unite Mixte Genet Constitut Canc Frequents, Ctr Lyon Berard, Lyon, France. [Sinilnikova, Olga M.] Univ Lyon, Ctr Leon Berard, Lyon, France. [Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Rockville, MD USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rubinstein, Wendy S.] NorthShore Univ Hlth Syst, Evanston, IL USA. [Hogervorst, Frans B.] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Dept Clin Genet, Family Canc Clin, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Hereditary Canc Clin, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Meijers-Heijboer, Hanne E. J.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Leiden, Netherlands. [van Roozendaal, Cees E.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Caldes, Trinidad; Perez-Segura, Pedro] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Blecharz, Pawel] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Krakow, Poland. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, FIN-00290 Helsinki, Finland. [Lazaro, Conxi; Blanco, Ignacio] Catalan Inst Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain. [Barkardottir, Rosa B.] Landspitali LSH, Dept Pathol, Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Montagna, Marco; D'Andrea, Emma] IRCCS, Immunol & Mol Oncol Unit, Ist Oncol Veneto IOV, Padua, Italy. [D'Andrea, Emma] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. Peter MacCallum Canc Ctr, Kathleen Cuningham Fdn Consortium Res Familial Br, Melbourne, Vic, Australia. [Devilee, Peter] Leiden Univ, Dept Human Genet & Pathol, Med Ctr, Leiden, Netherlands. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Dept Med, Chicago, IL 60637 USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Milan, Italy. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Dept Expt Oncol & Mol Med, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Singer, Christian F.] Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Singer, Christian F.] Univ Vienna, Comprehens Canc Med Ctr, Vienna, Austria. [Rennert, Gad; Lejbkowicz, Flavio] Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi] Technion Israel Inst Technol, Fac Med, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Genet Network, Toronto, ON, Canada. Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Toland, Amanda Ewart] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Caligo, Maria Adelaide] Univ Pisa, Sect Genet Oncol, Dept Lab Med, Pisa, Italy. Santa Chiara Univ Hosp, Pisa, Italy. Lund Univ, Dept Oncol, Lund, Sweden. [Beattie, Mary S.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Chan, Salina] Univ Calif San Francisco, Canc Risk Program, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. Univ Cambridge, Dept Oncol, Cambridge, England. [Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Phelan, Catherine] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Narod, Steven] Womens Coll Res Inst, Toronto, ON, Canada. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Hopper, John L.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic 3010, Australia. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Terry, Mary-Beth] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Tung, Nadine] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Hansen, Thomas V. O.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Osorio, Ana] Copenhagen Univ Hosp, Dept Clin Biochem, Rigshosp, Copenhagen, Denmark. [Osorio, Ana] Spanish Natl Canc Res Ctr, Human Genet Grp, Canc Genet Programme, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Spanish Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Genet Grp & Genotyping Unit, Human Canc Genet Programme, Madrid, Spain. [Duran, Mercedes] Univ Valladolid IBGM UVA, Inst Biol & Mol Genet, Valladolid, Spain. [Weitzel, Jeffrey N.] City Hope Canc Ctr, Div Clin Canc Genet, Duarte, CA USA. [Garber, Judy] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamann, Ute] Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Surrey, England. [Izatt, Louise] Royal Marsden NHS Fdn Trust, Surrey, England. [Paterson, Joan] Guys & St Thomas NHS Fdn Trust, London, England. [Brewer, Carole] Addenbrookes Hosp, Dept Clin Genet, E Anglian Reg Genet Serv, Cambridge, England. [Hodgson, Shirley] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Morrison, Patrick J.] Univ London, Dept Clin Genet, London, England. [Porteous, Mary] Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Walker, Lisa] Western Gen Hosp, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Rogers, Mark T.] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Side, Lucy E.] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales. [Godwin, Andrew K.] Great Ormond St Hosp Sick Children, NE Thames Reg Genet Serv, London WC1N 3JH, England. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Kansas, Med Ctr, Dept Pathol & Lab, Kansas City, KS 66103 USA. [Venat-Bouvet, Laurence] Univ Hosp Cologne, Cologne, Germany. [Stoppa-Lyonnet, Dominique] Ctr Hosp Univ Dupuytren, Dept Med Oncol, Limoges, France. [Laitman, Yael; Friedman, Eitan] Univ Paris 05, INSERM, U509, Serv Genet Oncol,Inst Curie, Paris, France. [Meindl, Alfons] Chaim Sheba Med Ctr, Susan Levy Gertner Oncogenet Unit, Inst Genet, IL-52621 Tel Hashomer, Israel. [Deissler, Helmut] Tech Univ Munich, Munich, Germany. [Varon-Mateeva, Raymonda] Univ Hosp Ulm, Ulm, Germany. [Preisler-Adams, Sabine] Charite Campus Virchow Klinikum, Inst Human Genet, Berlin, Germany. [Kast, Karin] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Gold, Bert] Tech Univ Dresden, Dept Obstet & Gynaecol, Univ Hosp Carl Gustav, Dresden, Germany. RP Gold, B (reprint author), NCI, Box B,Boyles St Ft Detrick, Frederick, MD 21702 USA. EM golda@mail.nih.gov RI Osorio, Ana/I-4324-2014; Bernard, Loris/K-5953-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Ligtenberg, Marjolijn/N-9666-2013; Ripamonti, Carla Barbara/D-2247-2017; Peissel, Bernard/E-8187-2017; Oosterwijk, Jan C./G-5770-2011; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Dean, Michael/G-8172-2012; D'Andrea, Emma/B-4374-2013; Andrulis, Irene/E-7267-2013; Joseph, Vijai/J-9158-2013; Klein, Robert/K-1888-2013; Altshuler, David/A-4476-2009 OI Evans, Gareth/0000-0002-8482-5784; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Bossi, Paolo/0000-0003-0135-0224; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Ligtenberg, Marjolijn/0000-0003-1290-1474; Ripamonti, Carla Barbara/0000-0002-2892-8164; Peissel, Bernard/0000-0001-9233-3571; Nordling, Margareta/0000-0002-4047-4994; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Blanco, Ignacio/0000-0002-7414-7481; montagna, marco/0000-0002-4929-2150; Dean, Michael/0000-0003-2234-0631; Joseph, Vijai/0000-0002-7933-151X; Klein, Robert/0000-0003-3539-5391; Altshuler, David/0000-0002-7250-4107 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Starr Foundation; Breast Cancer Research Foundation; Sabin Family Fund; CRUK; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-en"; NHMRC; National Breast Cancer Foundation; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Italian citizens; Fondazione IRCCS Istituto Nazionale Tumori; Komen Foundation; National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; ISCIII [RD06/0020/0021]; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; OSU Comprehensive Cancer Center; Cancer Care Ontario; US National Cancer Institute, National Institutes of Health [RFA CA-06-503]; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385]; NIHR; Biomedical Research Centre, Manchester; Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; NEYE foundation; [NIHCA116167] FX This work was supported in part by federal funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also acknowledge the support of the Starr Foundation, the Breast Cancer Research Foundation and the Sabin Family Fund. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the US government. The authors wish to thank Dr. Colm O'hUigin, who provided valuable comments on an early version of this manuscript.; UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye and Patricia Harrington for their contributions toward the UKFOCR.; The GEMO study (Cancer Genetics Network "Groupe Genetique et Cancer'', Federation Nationale des Centres de Lutte Contre le Cancer, France) is supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association "Le cancer du sein, parlons-en!'' Award.; For kConFab, we wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinic and the Clinical Follow Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.; The CONSIT TEAM study (Consorzio degli Studi Italiani Tumori Ereditari Alla Mammella), acknowledges Marco Pierotti, Siranoush Manoukian, Daniela Zaffaroni, Carla B. Ripamonti and Paolo Radice of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy and Loris Bernard of the Cogentech, Consortium for Genomic Technologies, Milan, Italy. We thank all patients and families who participated in this study. This study was supported by funds from Italian citizens who allocated the 5 9 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1,000').; For the Mayo Study, the authors would like to acknowledge funding from the Breast Cancer Research Foundation, Komen Foundation, and NIHCA116167.; The Cancer Prevention Institute of California was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registry (CFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the CFR.; The SWE-BRCA study acknowledge the study collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie StenmarkAskmalm and Sigrun Liedgren Linko "ping University Hospital; A angstrom ke Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Gronberg, Eva-Lena Stattin and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. The HCSC study was supported by RD06/0020/0021 from ISCIII.; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Collaborating Centers are Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hogervorst, S. Verhoef, M. Verheus, L.J. van 't Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collee, A. M.W. van den Ouweland, A. Jager, M.J. Hooning, M. M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M. P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E. B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A. H. van der Hout, M.J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756.; The Ohio State University Clinical Cancer Genetics (OSU CCG) study is supported by the OSU Comprehensive Cancer Center. We thank Leigha Senter and Kevin Sweet for patient accrual, sample ascertainment and database management. The Human Genetics Sample bank processed the samples.; This work was supported by Cancer Care Ontario and the US National Cancer Institute, National Institutes of Health under RFA #CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the BCFR. We wish to thank Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.; Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins, Kashmir Randhawa. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell, Nafisa Patel. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D'Mello are also supported by Cancer Research UK Grant C5047/A8385.; CBCS: We thank Bent Ejlertsen, Mette K. Andersen, Anne-Marie Gerdes and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE foundation for financial support. NR 38 TC 8 Z9 8 U1 2 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD NOV PY 2011 VL 130 IS 5 BP 685 EP 699 DI 10.1007/s00439-011-1003-z PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 834DP UT WOS:000295939900009 PM 21597964 ER PT J AU Clore, GM AF Clore, G. Marius TI Exploring translocation of proteins on DNA by NMR SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Protein-DNA interactions; Sliding; Direct transfer; Target search process; Paramagnetic relaxation enhancement; z-Exchange spectroscopy; Lineshape analysis ID PARAMAGNETIC RELAXATION ENHANCEMENT; LAC REPRESSOR HEADPIECE; DIFFUSION-DRIVEN MECHANISMS; BINDING DOMAIN; HETERONUCLEAR CORRELATION; EXCHANGE SPECTROSCOPY; OPERATOR INTERACTION; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; NUCLEIC-ACIDS AB While an extensive body of knowledge has accumulated on the structures of transcription factors, DNA and their complexes from both NMR and crystallography, much less is known at a molecular level regarding the mechanisms whereby transcription factors locate their specific DNA target site within an overwhelming sea of non-specific DNA sites. Indirect kinetic data suggested that three processes are involved in the search procedure: jumping by dissociation of the protein from the DNA followed by re-association at another site, direct transfer from one DNA molecule or segment to another, and one-dimensional sliding. In this brief perspective I summarize recent NMR developments from our laboratory that have permitted direct characterization of the species and molecular mechanisms involved in the target search process, including the detection of highly transient sparsely-populated states. The main tool in these studies involves the application of paramagnetic relaxation enhancement, supplemented by z-exchange spectroscopy, lineshape analysis and residual dipolar couplings. These studies led to the first direct demonstration of rotation-coupled sliding of a protein along the DNA and the direct transfer of a protein from one DNA molecule to another without dissociating into free solution. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS [Z01 DK029023-17] NR 56 TC 15 Z9 15 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD NOV PY 2011 VL 51 IS 3 BP 209 EP 219 DI 10.1007/s10858-011-9555-8 PG 11 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TY UT WOS:000295988200001 PM 21847629 ER PT J AU Tang, M Sperling, LJ Berthold, DA Schwieters, CD Nesbitt, AE Nieuwkoop, AJ Gennis, RB Rienstra, CM AF Tang, Ming Sperling, Lindsay J. Berthold, Deborah A. Schwieters, Charles D. Nesbitt, Anna E. Nieuwkoop, Andrew J. Gennis, Robert B. Rienstra, Chad M. TI High-resolution membrane protein structure by joint calculations with solid-state NMR and X-ray experimental data SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Membrane protein; Solid-state NMR; X-ray reflections; High resolution; Joint calculation ID ANGLE-SPINNING NMR; DISULFIDE BOND FORMATION; RESIDUAL DIPOLAR COUPLINGS; M2 PROTON CHANNELS; HYBRID SOLUTION; REFINEMENT PROTOCOL; CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; LIPID-BILAYERS; BINDING-SITE AB X-ray diffraction and nuclear magnetic resonance spectroscopy (NMR) are the staple methods for revealing atomic structures of proteins. Since crystals of biomolecular assemblies and membrane proteins often diffract weakly and such large systems encroach upon the molecular tumbling limit of solution NMR, new methods are essential to extend structures of such systems to high resolution. Here we present a method that incorporates solid-state NMR restraints alongside of X-ray reflections to the conventional model building and refinement steps of structure calculations. Using the 3.7 crystal structure of the integral membrane protein complex DsbB-DsbA as a test case yielded a significantly improved backbone precision of 0.92 in the transmembrane region, a 58% enhancement from using X-ray reflections alone. Furthermore, addition of solid-state NMR restraints greatly improved the overall quality of the structure by promoting 22% of DsbB transmembrane residues into the most favored regions of Ramachandran space in comparison to the crystal structure. This method is widely applicable to any protein system where X-ray data are available, and is particularly useful for the study of weakly diffracting crystals. C1 [Tang, Ming; Sperling, Lindsay J.; Berthold, Deborah A.; Nesbitt, Anna E.; Nieuwkoop, Andrew J.; Gennis, Robert B.; Rienstra, Chad M.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Schwieters, Charles D.] Ctr Informat Technol, Div Computat Biosci, NIH, Bethesda, MD 20892 USA. RP Rienstra, CM (reprint author), Univ Illinois, Dept Chem, 600 S Mathews Ave, Urbana, IL 61801 USA. EM rienstra@scs.illinois.edu RI Tang, Ming/A-5348-2010 OI Tang, Ming/0000-0001-7479-6206 FU National Institutes of Health [R01GM075937, S10RR025037, R01GM073770, NRSA F32GM095344]; Molecular Biophysics Training Grant [PHS 5 T32 GM008276]; Ullyot Fellowship FX This research was supported by the National Institutes of Health (R01GM075937, S10RR025037, and R01GM073770 ARRA supplement to Chad M. Rienstra, and NRSA F32GM095344 to Anna E. Nesbitt), the Molecular Biophysics Training Grant (PHS 5 T32 GM008276) and Ullyot Fellowship to Lindsay J. Sperling, and the NIH Intramural Research Program of CIT to Charles D. Schwieters. The authors thank the School of Chemical Sciences NMR Facility at the University of Illinois at Urbana-Champaign for assistance with data acquisition and Mike Hallock for helpful assistance with structure calculations. NR 47 TC 34 Z9 34 U1 2 U2 18 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD NOV PY 2011 VL 51 IS 3 BP 227 EP 233 DI 10.1007/s10858-011-9565-6 PG 7 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TY UT WOS:000295988200003 PM 21938394 ER PT J AU Venditti, V Fawzi, NL Clore, GM AF Venditti, Vincenzo Fawzi, Nicolas L. Clore, G. Marius TI Automated sequence- and stereo-specific assignment of methyl-labeled proteins by paramagnetic relaxation and methyl-methyl nuclear overhauser enhancement spectroscopy SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Paramagnetic relaxation enhancement; Methyl-TROSY; H-1-C-13 HMQC; Paramagnetic spin-labeling; Methyl group labeling ID MOLECULAR-WEIGHT PROTEINS; N-TERMINAL DOMAIN; ENZYME I; BIOLOGICAL MACROMOLECULES; ESCHERICHIA-COLI; NMR-SPECTROSCOPY; SIDE-CHAINS; COMPLEXES; SPECTRA; PROTEASOME AB Methyl-transverse relaxation optimized spectroscopy is rapidly becoming the preferred NMR technique for probing structure and dynamics of very large proteins up to similar to 1 MDa in molecular size. Data interpretation, however, necessitates assignment of methyl groups which still presents a very challenging and time-consuming process. Here we demonstrate that, in combination with a known 3D structure, paramagnetic relaxation enhancement (PRE), induced by nitroxide spin-labels incorporated at only a few surface-exposed engineered cysteines, provides fast, straightforward and robust access to methyl group resonance assignments, including stereoassignments for the methyl groups of leucine and valine. Neither prior assignments, including backbone assignments, for the protein, nor experiments that transfer magnetization between methyl groups and the protein backbone, are required. PRE-derived assignments are refined by 4D methyl-methyl nuclear Overhauser enhancement data, eliminating ambiguities and errors that may arise due to the high sensitivity of PREs to the potential presence of sparsely-populated transient states. C1 [Venditti, Vincenzo; Fawzi, Nicolas L.; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Venditti, Vincenzo/A-9411-2013; Fawzi, Nicolas/E-2555-2013; Clore, G. Marius/A-3511-2008 OI Fawzi, Nicolas/0000-0001-5483-0577; Clore, G. Marius/0000-0003-3809-1027 FU NIH, NIDDK; Office of the Director of the NIH FX We thank Drs. Mark Fleissner, Kalman Hideg, Tamas Kalai and Wayne Hubbell for generously providing the reagent for generating the R1p paramagnetic side chain. This work was supported by funds from the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 35 TC 22 Z9 22 U1 2 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD NOV PY 2011 VL 51 IS 3 BP 319 EP 328 DI 10.1007/s10858-011-9559-4 PG 10 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TY UT WOS:000295988200012 PM 21935714 ER PT J AU Saio, T Ogura, K Shimizu, K Yokochi, M Burke, TR Inagaki, F AF Saio, Tomohide Ogura, Kenji Shimizu, Kazumi Yokochi, Masashi Burke, Terrence R., Jr. Inagaki, Fuyuhiko TI An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Ligand screening; Fragment-based drug design (FBDD); Protein-ligand structure; Lanthanide-binding peptide tag (LBT); Paramagnetic relaxation enhancement (PRE); Pseudo-contact shift (PCS) ID GRB2 SH2 DOMAIN; MOLECULAR-STRUCTURE DETERMINATION; PROTEIN-PROTEIN COMPLEXES; HIGH-AFFINITY INHIBITOR; XPLOR-NIH; DIPOLAR COUPLINGS; BINDING-AFFINITY; DRUG DISCOVERY; SPECTROSCOPY; RESTRAINTS AB A nuclear magnetic resonance-based ligand screening strategy utilizing a paramagnetic lanthanide probe is presented. By fixing a paramagnetic lanthanide ion to a target protein, a pseudo-contact shift (PCS) and a paramagnetic relaxation enhancement (PRE) can be observed for both the target protein and its bound ligand. Based on PRE and PCS information, the bound ligand is then screened from the compound library and the structure of the ligand-protein complex is determined. PRE is an isotropic paramagnetic effect observed within 30 from the lanthanide ion, and is utilized for the ligand screening in the present study. PCS is an anisotropic paramagnetic effect providing long-range (similar to 40 ) distance and angular information on the observed nuclei relative to the paramagnetic lanthanide ion, and utilized for the structure determination of the ligand-protein complex. Since a two-point anchored lanthanide-binding peptide tag is utilized for fixing the lanthanide ion to the target protein, this screening method can be generally applied to non-metal-binding proteins. The usefulness of this strategy was demonstrated in the case of the growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain and its low- and high-affinity ligands. C1 [Saio, Tomohide; Ogura, Kenji; Shimizu, Kazumi; Yokochi, Masashi; Inagaki, Fuyuhiko] Hokkaido Univ, Fac Adv Life Sci, Dept Biol Struct, Sapporo, Hokkaido 0010021, Japan. [Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Inagaki, F (reprint author), Hokkaido Univ, Fac Adv Life Sci, Dept Biol Struct, N-21,W-11,Kita Ku, Sapporo, Hokkaido 0010021, Japan. EM ff-inagaki@mvf.biglobe.ne.jp RI Burke, Terrence/N-2601-2014 NR 47 TC 27 Z9 28 U1 1 U2 37 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD NOV PY 2011 VL 51 IS 3 BP 395 EP 408 DI 10.1007/s10858-011-9566-5 PG 14 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 834TY UT WOS:000295988200019 PM 21927934 ER PT J AU Adjemian, J Farnon, EC Tschioko, F Wamala, JF Byaruhanga, E Bwire, GS Kansiime, E Kagirita, A Ahimbisibwe, S Katunguka, F Jeffs, B Lutwama, JJ Downing, R Tappero, JW Formenty, P Amman, B Manning, C Towner, J Nichol, ST Rollin, PE AF Adjemian, Jennifer Farnon, Eileen C. Tschioko, Florimond Wamala, Joseph F. Byaruhanga, Emmanuel Bwire, Godfrey S. Kansiime, Edgar Kagirita, Atek Ahimbisibwe, Sam Katunguka, F. Jeffs, Ben Lutwama, Julius J. Downing, Robert Tappero, Jordan W. Formenty, Pierre Amman, Brian Manning, Craig Towner, Jonathan Nichol, Stuart T. Rollin, Pierre E. TI Outbreak of Marburg Hemorrhagic Fever Among Miners in Kamwenge and Ibanda Districts, Uganda, 2007 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VIRUS AB Marburg hemorrhagic fever was detected among 4 miners in Ibanda District, Uganda, from June through September, 2007. Infection was likely acquired through exposure to bats or bat secretions in a mine in Kamwenge District, Uganda, and possibly human-to-human transmission between some patients. We describe the epidemiologic investigation and the health education response. C1 [Adjemian, Jennifer] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Farnon, Eileen C.; Amman, Brian; Manning, Craig; Towner, Jonathan; Nichol, Stuart T.; Rollin, Pierre E.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Tschioko, Florimond] WHO, Reg Off Africa, Brazzaville, Congo. [Wamala, Joseph F.; Bwire, Godfrey S.; Kansiime, Edgar; Kagirita, Atek; Ahimbisibwe, Sam; Katunguka, F.] Minist Hlth, Kampala, Uganda. [Byaruhanga, Emmanuel] Ibanda Hosp, Ibanda, Uganda. [Jeffs, Ben] Med Sans Frontieres, Barcelona, Spain. [Lutwama, Julius J.] Uganda Virus Res Inst, Entebbe, Uganda. [Downing, Robert; Tappero, Jordan W.] Ctr Dis Control & Prevent, Entebbe, Uganda. [Formenty, Pierre] WHO, CH-1211 Geneva, Switzerland. RP Adjemian, J (reprint author), NIAID, Lab Clin Infect Dis, NIH, Qrts 15 B-1,8 West Dr,MSC 2665, Bethesda, MD 20892 USA. EM jennifer.adjemian@nih.gov FU Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia FX This work was supported by the Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia. NR 12 TC 33 Z9 33 U1 1 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S796 EP S799 DI 10.1093/infdis/jir312 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400007 PM 21987753 ER PT J AU Aleksandrowicz, P Marzi, A Biedenkopf, N Beimforde, N Becker, S Hoenen, T Feldmann, H Schnittler, HJ AF Aleksandrowicz, Paulina Marzi, Andrea Biedenkopf, Nadine Beimforde, Nadine Becker, Stephan Hoenen, Thomas Feldmann, Heinz Schnittler, Hans-Joachim TI Ebola Virus Enters Host Cells by Macropinocytosis and Clathrin-Mediated Endocytosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID BARRIER FUNCTION; CELLULAR ENTRY; GLYCOPROTEINS; PARTICLES; INFECTION; MARBURG; DYNAMIN; MACROPHAGES; ACTIVATION; INHIBITORS AB Virus entry into host cells is the first step of infection and a crucial determinant of pathogenicity. Here we show that Ebola virus-like particles (EBOV-VLPs) composed of the glycoprotein GP(1,2) and the matrix protein VP40 use macropinocytosis and clathrin-mediated endocytosis to enter cells. EBOV-VLPs applied to host cells induced actin-driven ruffling and enhanced FITC-dextran uptake, which indicated macropinocytosis as the main entry mechanism. This was further supported by inhibition of entry through inhibitors of actin polymerization (latrunculin A), Na(+)/H(+)-exchanger (EIPA), and PI3-kinase (wortmannin). A fraction of EBOV-VLPs, however, colocalized with clathrin heavy chain (CHC), and VLP uptake was reduced by CHC small interfering RNA transfection and expression of the dominant negative dynamin II-K44A mutant. In contrast, we found no evidence that EBOV-VLPs enter cells via caveolae. This work identifies macropinocytosis as the major, and clathrin-dependent endocytosis as an alternative, entry route for EBOV particles. Therefore, EBOV seems to utilize different entry pathways depending on both cell type and virus particle size. C1 [Aleksandrowicz, Paulina; Beimforde, Nadine; Schnittler, Hans-Joachim] Univ Munster, Inst Anat & Vaskulaere Biol, D-48149 Munster, Germany. [Aleksandrowicz, Paulina] Tech Univ Dresden, Inst Physiol, Dresden, Germany. [Aleksandrowicz, Paulina] Tech Univ Dresden, MTZ Imaging Facil, Dresden, Germany. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Biedenkopf, Nadine; Becker, Stephan; Hoenen, Thomas] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [Feldmann, Heinz] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. RP Schnittler, HJ (reprint author), Univ Munster, Inst Anat & Vaskulaere Biol, Vesaliusweg 2-4, D-48149 Munster, Germany. EM hans.schnittler@uni-muenster.de RI Becker, Stephan/A-1065-2010; OI Becker, Stephan/0000-0002-2794-5659; Hoenen, Thomas/0000-0002-5829-6305 FU Deutsche Forschungsgemeinschaft [SCHN 430/3-3, SCH 430/6-1]; Schering foundation; Public Health Agency of Canada; National Institutes of Health; Center for Regenerative Therapy Dresden FX This work was supported by the Deutsche Forschungsgemeinschaft (SCHN 430/3-3 and SCH 430/6-1), the Schering foundation (N. B., T. H.), the Public Health Agency of Canada, the Intramural Research Program of the National Institutes of Health, and the Center for Regenerative Therapy Dresden. NR 51 TC 64 Z9 69 U1 0 U2 37 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S957 EP S967 DI 10.1093/infdis/jir326 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400030 PM 21987776 ER PT J AU de Wit, E Munster, VJ Metwally, SA Feldmann, H AF de Wit, Emmie Munster, Vincent J. Metwally, Samia A. Feldmann, Heinz TI Assessment of Rodents as Animal Models for Reston Ebolavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MOUSE MODEL; HEMORRHAGIC-FEVER; VIRUS; PHILIPPINES; FILOVIRUS; INFECTION; HOST AB The emergence of Reston ebolavirus (REBOV) in domestic swine in the Philippines has caused a renewed interest in REBOV pathogenicity. Here, the use of different rodent species as animal disease models for REBOV was investigated. BALB/c and STAT1(-/-) mice, Hartley guinea pigs, and Syrian hamsters were inoculated intraperitoneally with REBOV strain Pennsylvania or Reston08-A. Although virus replication occurred in guinea pigs, hamsters, and STAT1(-/-) mice, progression to disease was only observed in STAT1(-/-) mice. Moreover, REBOV Pennsylvania was more pathogenic than REBOV Reston08-A in this model. Thus, STAT1(-/-) mice may be used for research of REBOV pathogenicity and intervention strategies. C1 [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Metwally, Samia A.] USDA, Food & Agr Org Reference Ctr Vesicular Dis, Anim & Plant Hlth Inspect Serv,Foreign Anim Dis D, Natl Vet Serv Labs,Plum Isl Anim Dis Ctr, Greenport, NY USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 18 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 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S968 EP S972 DI 10.1093/infdis/jir330 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400031 PM 21987777 ER PT J AU Ebihara, H Rockx, B Marzi, A Feldmann, F Haddock, E Brining, D LaCasse, RA Gardner, D Feldmann, H AF Ebihara, Hideki Rockx, Barry Marzi, Andrea Feldmann, Friederike Haddock, Elaine Brining, Douglas LaCasse, Rachel A. Gardner, Don Feldmann, Heinz TI Host Response Dynamics Following Lethal Infection of Rhesus Macaques With Zaire ebolavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID DISSEMINATED INTRAVASCULAR COAGULATION; HEMORRHAGIC-FEVER; DENDRITIC CELLS; VIRUS-INFECTION; PROTEIN-C; POSTEXPOSURE PROTECTION; NONHUMAN-PRIMATES; ADAPTIVE IMMUNITY; MARBURG VIRUSES; PATHOGENESIS AB To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechanisms underlying disseminated intravascular coagulation in EHF patients. Furthermore, monitoring of expression levels for cytokines/chemokines suggested a mixed anti-inflammatory response syndrome (MARS), which indicates that a catastrophic uncontrolled immunological status contributes to the development of fatal hemorrhagic fever. These results highlight the pathological analogies between EHF and severe sepsis and not only contribute to our understanding of the pathogenic process, but will also help to establish novel postexposure treatment modalities. C1 [Ebihara, Hideki; Rockx, Barry; Marzi, Andrea; Haddock, Elaine; Feldmann, Heinz] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. [Feldmann, Friederike] NIAID, Off Res Operat, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. [Brining, Douglas; LaCasse, Rachel A.; Gardner, Don] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Ebihara, H (reprint author), NIAID, Virol Lab, NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 48 TC 39 Z9 39 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S991 EP S999 DI 10.1093/infdis/jir336 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400035 PM 21987781 ER PT J AU Falzarano, D Feldmann, F Grolla, A Leung, A Ebihara, H Strong, JE Marzi, A Takada, A Jones, S Gren, J Geisbert, J Jones, SM Geisbert, TW Feldmann, H AF Falzarano, Darryl Feldmann, Friederike Grolla, Allen Leung, Anders Ebihara, Hideki Strong, James E. Marzi, Andrea Takada, Ayato Jones, Shane Gren, Jason Geisbert, Joan Jones, Steven M. Geisbert, Thomas W. Feldmann, Heinz TI Single Immunization With a Monovalent Vesicular Stomatitis Virus-Based Vaccine Protects Nonhuman Primates Against Heterologous Challenge With Bundibugyo ebolavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ATTENUATED RECOMBINANT VACCINE; MARBURG VIRUS; HEMORRHAGIC-FEVER; INFECTION; FILOVIRUSES; ANTIBODIES; LIVE AB The recombinant vesicular stomatitis virus (rVSV) vector-based monovalent vaccine platform expressing a filovirus glycoprotein has been demonstrated to provide protection from lethal challenge with Ebola (EBOV) and Marburg (MARV) viruses both prophylactically and after exposure. This platform provides protection between heterologous strains within a species; however, protection from lethal challenge between species has been largely unsuccessful. To determine whether the rVSV-EBOV vaccines have the potential to provide protection against a newly emerging, phylogenetically related species, cynomolgus macaques were vaccinated with an rVSV vaccine expressing either the glycoprotein of Zaire ebolavirus (ZEBOV) or Cote d'Ivoire ebolavirus (CIEBOV) and then challenged with Bundibugyo ebolavirus (BEBOV), which was recently proposed as a new EBOV species following an outbreak in Uganda in 2007. A single vaccination with the ZEBOV-specific vaccine provided cross-protection (75% survival) against subsequent BEBOV challenge, whereas vaccination with the CIEBOV-specific vaccine resulted in an outcome similar to mock-immunized animals (33% and 25% survival, respectively). This demonstrates that monovalent rVSV-based vaccines may be useful against a newly emerging species; however, heterologous protection across species remains challenging and may depend on enhancing the immune responses either through booster immunizations or through the inclusion of multiple immunogens. C1 [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Falzarano, Darryl; Feldmann, Friederike; Grolla, Allen; Leung, Anders; Ebihara, Hideki; Strong, James E.; Marzi, Andrea; Jones, Shane; Gren, Jason; Jones, Steven M.; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Falzarano, Darryl; Jones, Steven M.; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. [Takada, Ayato] Hokkaido Univ, Dept Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan. [Geisbert, Joan; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX USA. [Geisbert, Joan; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA. [Strong, James E.; Jones, Steven M.] Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT USA. EM feldmannh@niaid.nih.gov RI Takada, Ayato/A-6679-2012 FU National Microbiology Laboratory, Public Health Agency of Canada; Manitoba Health Research Council; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the National Microbiology Laboratory, Public Health Agency of Canada; the Manitoba Health Research Council (to D. F.); and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 30 TC 21 Z9 21 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S1082 EP S1089 DI 10.1093/infdis/jir350 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400045 PM 21987745 ER PT J AU Geisbert, TW Feldmann, H AF Geisbert, Thomas W. Feldmann, Heinz TI Recombinant Vesicular Stomatitis Virus-Based Vaccines Against Ebola and Marburg Virus Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; HEMORRHAGIC-FEVER; POSTEXPOSURE PROTECTION; GUINEA-PIGS; VECTORS; LIVE; GLYCOPROTEINS; CHALLENGE; IMMUNOGENICITY; VACCINATION AB The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections. C1 [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, 301 Univ Blvd, Galveston, TX 77550 USA. EM tom.geisbert@utmb.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01 AI082197]; National Microbiology Laboratory of the Public Health Agency of Canada FX This work is supported by the intramural and extramural research programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant number U01 AI082197 to T. W. G.); and the National Microbiology Laboratory of the Public Health Agency of Canada. NR 50 TC 55 Z9 59 U1 6 U2 50 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S1075 EP S1081 DI 10.1093/infdis/jir349 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400044 PM 21987744 ER PT J AU Gunther, S Feldmann, H Geisbert, TW Hensley, LE Rollin, PE Nichol, ST Stroher, U Artsob, H Peters, CJ Ksiazek, TG Becker, S ter Meulen, J Olschlager, S Schmidt-Chanasit, J Sudeck, H Burchard, GD Schmiedel, S AF Guenther, Stephan Feldmann, Heinz Geisbert, Thomas W. Hensley, Lisa E. Rollin, Pierre E. Nichol, Stuart T. Stroeher, Ute Artsob, Harvey Peters, Clarence J. Ksiazek, Thomas G. Becker, Stephan ter Meulen, Jan Oelschlaeger, Stephan Schmidt-Chanasit, Jonas Sudeck, Hinrich Burchard, Gerd D. Schmiedel, Stefan TI Management of Accidental Exposure to Ebola Virus in the Biosafety Level 4 Laboratory, Hamburg, Germany SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VESICULAR-STOMATITIS-VIRUS; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; POSTEXPOSURE PROTECTION; RISK-FACTORS; INFECTION; TRANSMISSION; INTERFERON; SUDAN; 1-BETA-D-RIBOFURANOSYL-1,2,4-TRIAZOLE-3-CARBOXAMIDE AB A needlestick injury occurred during an animal experiment in the biosafety level 4 laboratory in Hamburg, Germany, in March 2009. The syringe contained Zaire ebolavirus (ZEBOV) mixed with Freund's adjuvant. Neither an approved treatment nor a postexposure prophylaxis (PEP) exists for Ebola hemorrhagic fever. Following a risk-benefit assessment, it was recommended the exposed person take an experimental vaccine that had shown PEP efficacy in ZEBOV-infected nonhuman primates (NHPs) [12]. The vaccine, which had not been used previously in humans, was a live-attenuated recombinant vesicular stomatitis virus (recVSV) expressing the glycoprotein of ZEBOV. A single dose of 5 x 10(7) plaque-forming units was injected 48 hours after the accident. The vaccinee developed fever 12 hours later and recVSV viremia was detectable by polymerase chain reaction (PCR) for 2 days. Otherwise, the person remained healthy, and ZEBOV RNA, except for the glycoprotein gene expressed in the vaccine, was never detected in serum and peripheral blood mononuclear cells during the 3-week observation period. C1 [Guenther, Stephan; Oelschlaeger, Stephan; Schmidt-Chanasit, Jonas] Bernhard Nocht Inst Trop Med, Dept Virol, D-20359 Hamburg, Germany. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Geisbert, Thomas W.] Boston Univ, Sch Med, Natl Emerging Infect Dis Labs Inst, Boston, MA 02118 USA. [Hensley, Lisa E.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Rollin, Pierre E.; Nichol, Stuart T.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Stroeher, Ute; Artsob, Harvey] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Peters, Clarence J.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX USA. [Ksiazek, Thomas G.] Univ Texas Med Branch, Galveston Natl Lab, Dept Pathol, Galveston, TX USA. [Becker, Stephan] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [ter Meulen, Jan] Merck Res Labs, Vaccine Res, West Point, PA USA. [Sudeck, Hinrich] Bundeswehrkrankenhaus Hamburg, Hamburg, Germany. [Burchard, Gerd D.; Schmiedel, Stefan] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. RP Gunther, S (reprint author), Bernhard Nocht Inst Trop Med, Dept Virol, Bernhard Nocht Str 74, D-20359 Hamburg, Germany. EM guenther@bni.uni-hamburg.de RI Becker, Stephan/A-1065-2010; OI Becker, Stephan/0000-0002-2794-5659; Schmidt-Chanasit, Jonas/0000-0003-4433-0231 NR 32 TC 71 Z9 75 U1 0 U2 30 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S785 EP S790 DI 10.1093/infdis/jir298 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400005 PM 21987751 ER PT J AU Kortepeter, MG Lawler, JV Honko, A Bray, M Johnson, JC Purcell, BK Olinger, GG Rivard, R Hepburn, MJ Hensley, LE AF Kortepeter, Mark G. Lawler, James V. Honko, Anna Bray, Mike Johnson, Joshua C. Purcell, Bret K. Olinger, Gene G. Rivard, Robert Hepburn, Matthew J. Hensley, Lisa E. TI Real-time Monitoring of Cardiovascular Function in Rhesus Macaques Infected With Zaire ebolavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; VIRUS INFECTION; POSTEXPOSURE PROTECTION; MARBURG VIRUSES; SEVERE SEPSIS; SEPTIC SHOCK; GUINEA-PIGS; PATHOGENESIS; MONKEYS; CONGO AB Nine rhesus macaques were implanted with multisensor telemetry devices and internal jugular vein catheters before being infected with Zaire ebolavirus. All animals developed viremia, fever, a hemorrhagic rash, and typical changes of Ebola hemorrhagic fever in clinical laboratory tests. Three macaques unexpectedly survived this usually lethal disease, making it possible to compare physiological parameters in lethally challenged animals and survivors. After the onset of fever, lethal illness was characterized by a decline in mean arterial blood pressure, an increase in pulse and respiratory rate, lactic acidosis, and renal failure. Survivors showed less pronounced change in these parameters. Four macaques were randomized to receive supplemental volumes of intravenous normal saline when they became hypotensive. Although those animals had less severe renal compromise, no apparent survival benefit was observed. This is the first report of continuous physiologic monitoring in filovirus-infected nonhuman primates and the first to attempt cardiovascular support with intravenous fluids. C1 [Kortepeter, Mark G.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Dept Prevent Med, Bethesda, MD 20814 USA. [Kortepeter, Mark G.; Honko, Anna; Johnson, Joshua C.; Purcell, Bret K.; Olinger, Gene G.; Hensley, Lisa E.] USA, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. [Lawler, James V.] NIAID, Integrated Res Facil, Div Clin Res, NIH, Ft Detrick, MD USA. [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Rivard, Robert; Hepburn, Matthew J.] USA, Med Res Inst Infect Dis, Div Med, Ft Detrick, MD 21702 USA. RP Kortepeter, MG (reprint author), Uniformed Serv Univ Hlth Sci, Clin Res Program, F Edward Hebert Sch Med, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd,Bldg 28,Rm 201, Bethesda, MD 20814 USA. EM mkortepeter@idcrp.org OI Olinger, Gene/0000-0001-7338-0292; Johnson, Joshua/0000-0002-5677-3841; Honko, Anna/0000-0001-9165-148X FU Defense Threat Reduction Agency [4.10033_07_RD_B] FX This work was supported by the Defense Threat Reduction Agency (Project #4.10033_07_RD_B). NR 25 TC 18 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S1000 EP S1010 DI 10.1093/infdis/jir337 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400036 PM 21987736 ER PT J AU Kortepeter, MG Bausch, DG Bray, M AF Kortepeter, Mark G. Bausch, Daniel G. Bray, Mike TI Basic Clinical and Laboratory Features of Filoviral Hemorrhagic Fever SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VIRUS-INFECTED PATIENTS; EBOLA-VIRUS; CONGO; KIKWIT; RESPONSES; EPIDEMIC; OUTBREAK; SUDAN; ZAIRE; PATHOGENESIS AB The filoviruses Marburg and Ebola cause severe hemorrhagic fever (HF) in humans. Beginning with the 1967 Marburg outbreak, 30 epidemics, isolated cases, and accidental laboratory infections have been described in the medical literature. We reviewed those reports to determine the basic clinical and laboratory features of filoviral HF. The most detailed information was found in descriptions of patients treated in industrialized countries; except for the 2000 outbreak of Ebola Sudan HF in Uganda, reports of epidemics in central Africa provided little controlled or objective clinical data. Other than the case fatality rate, there were no clear differences in the features of the various filovirus infections. This compilation will be of value to medical workers responding to epidemics and to investigators attempting to develop animal models of filoviral HF. By identifying key unanswered questions and gaps in clinical data, it will help guide clinical research in future outbreaks. C1 [Kortepeter, Mark G.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Bausch, Daniel G.] Tulane Sch Publ Hlth & Trop Med, Dept Trop Med, New Orleans, LA USA. [Bray, Mike] NIAID, Div Clin Res, Bethesda, MD 20892 USA. RP Kortepeter, MG (reprint author), Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mkortepeter@idcrp.org NR 54 TC 100 Z9 109 U1 1 U2 30 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S810 EP S816 DI 10.1093/infdis/jir299 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400010 PM 21987756 ER PT J AU Kuhl, A Hoffmann, M Muller, MA Munster, VJ Gnirss, K Kiene, M Tsegaye, TS Behrens, G Herrler, G Feldmann, H Drosten, C Pohlmann, S AF Kuehl, Annika Hoffmann, Markus Mueller, Marcel A. Munster, Vincent J. Gnirss, Kerstin Kiene, Miriam Tsegaye, Theodros Solomon Behrens, Georg Herrler, Georg Feldmann, Heinz Drosten, Christian Poehlmann, Stefan TI Comparative Analysis of Ebola Virus Glycoprotein Interactions With Human and Bat Cells SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ROUSETTUS-AEGYPTIACUS; HEMORRHAGIC-FEVER; MARBURG VIRUSES; INFECTION; PATHOGENESIS; PROTEIN; IDENTIFICATION; REPLICATION; EXPRESSION; PARTICLES AB Infection with Ebola virus (EBOV) causes hemorrhagic fever in humans with high case-fatality rates. The EBOV-glycoprotein (EBOV-GP) facilitates viral entry and promotes viral release from human cells. African fruit bats are believed not to develop disease upon EBOV infection and have been proposed as a natural reservoir of EBOV. We compared EBOV-GP interactions with human cells and cells from African fruit bats. We found that susceptibility to EBOV-GP-dependent infection was not limited to bat cells from potential reservoir species, and we observed that GP displayed similar biological properties in human and bat cells. The only exception was GP localization, which was to a greater extent intracellular in bat cells as compared to human cells. Collectively, our results suggest that GP interactions with fruit bat and human cells are similar and do not limit EBOV tropism for certain bat species. C1 [Poehlmann, Stefan] German Primate Ctr, Infect Biol Unit, D-37077 Gottingen, Germany. [Kuehl, Annika; Gnirss, Kerstin; Kiene, Miriam; Tsegaye, Theodros Solomon; Poehlmann, Stefan] Hannover Med Sch, Inst Virol, Hannover, Germany. [Hoffmann, Markus; Herrler, Georg] Univ Vet Med Hannover, Inst Virol, Hannover, Germany. [Mueller, Marcel A.; Drosten, Christian] Univ Bonn, Med Ctr, Inst Virol, D-5300 Bonn, Germany. [Munster, Vincent J.; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Behrens, Georg] Hannover Med Sch, Clin Immunol & Rheumatol, Hannover, Germany. RP Pohlmann, S (reprint author), German Primate Ctr, Infect Biol Unit, Kellnerweg 4, D-37077 Gottingen, Germany. EM s.poehlmann@dpz.eu RI Behrens, Georg/Q-4486-2016; OI Tsegaye, Theodros Solomon/0000-0002-1573-4600; Pohlmann, Stefan/0000-0001-6086-9136; Mueller, Marcel/0000-0003-2242-5117; Munster, Vincent/0000-0002-2288-3196 FU German Federal Ministry of Education and Research (BMBF) [01KIO701, 01KIO703]; International Research Training Group [1273]; Hannover Biomedical Research School; European Community [223498]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the German Federal Ministry of Education and Research (BMBF) via the project Ecology and Pathogenesis of SARS, an Archetypical Zoonosis (project codes 01KIO701, 01KIO703); International Research Training Group 1273 and Hannover Biomedical Research School (S.P. and G.B.); the European Community's Seventh Framework Programme FP7 EMPERIE, (project code 223498); and in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 28 Z9 30 U1 2 U2 44 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S840 EP S849 DI 10.1093/infdis/jir306 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400014 PM 21987760 ER PT J AU Kuhl, A Banning, C Marzi, A Votteler, J Steffen, I Bertram, S Glowacka, I Konrad, A Sturzl, M Guo, JT Schubert, U Feldmann, H Behrens, G Schindler, M Pohlmann, S AF Kuehl, Annika Banning, Carina Marzi, Andrea Votteler, Joerg Steffen, Imke Bertram, Stephanie Glowacka, Ilona Konrad, Andreas Stuerzl, Michael Guo, Ju-Tao Schubert, Ulrich Feldmann, Heinz Behrens, Georg Schindler, Michael Poehlmann, Stefan TI The Ebola Virus Glycoprotein and HIV-1 Vpu Employ Different Strategies to Counteract the Antiviral Factor Tetherin SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RETROVIRUS RELEASE; RESTRICTION FACTOR; PARTICLE RELEASE; INHIBITS HIV-1; CELL-SURFACE; DC-SIGNR; PROTEIN; BST-2/TETHERIN; REPLICATION; MECHANISM AB The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking the Ebola virus (EBOV), a hemorrhagic fever virus. The HIV-1 viral protein U (Vpu) and the EBOV-glycoprotein (EBOV-GP) both inhibit tetherin. Here, we compared tetherin counteraction by EBOV-GP and Vpu. We found that EBOV-GP but not Vpu counteracted tetherin from different primate species, indicating that EBOV-GP and Vpu target tetherin differentially. Tetherin interacted with the GP2 subunit of EBOV-GP, which might encode the determinants for tetherin counteraction. Vpu reduced cell surface expression of tetherin while EBOV-GP did not, suggesting that both proteins employ different mechanisms to counteract tetherin. Finally, Marburg virus (MARV)-GP also inhibited tetherin and downregulated tetherin in a cell type-dependent fashion, indicating that tetherin antagonism depends on the cellular source of tetherin. Collectively, our results indicate that EBOV-GP counteracts tetherin by a novel mechanism and that tetherin inhibition is conserved between EBOV-GP and MARV-GP. C1 [Poehlmann, Stefan] German Primate Ctr, Dept Infect Biol, D-37077 Gottingen, Germany. [Kuehl, Annika; Steffen, Imke; Bertram, Stephanie; Glowacka, Ilona; Poehlmann, Stefan] Hannover Med Sch, Inst Virol, Hamburg, Germany. [Banning, Carina; Schindler, Michael] Leibniz Inst Expt Virol & Immunol, Heinrich Pette Inst, Hamburg, Germany. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Votteler, Joerg; Schubert, Ulrich] Univ Erlangen Nurnberg, Inst Virol, D-8520 Erlangen, Germany. [Konrad, Andreas; Stuerzl, Michael] Univ Erlangen Nurnberg, Div Mol & Expt Surg, Dept Surg, D-8520 Erlangen, Germany. [Guo, Ju-Tao] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Behrens, Georg] Hannover Med Sch, Clin Immunol & Rheumatol, Hamburg, Germany. RP Pohlmann, S (reprint author), German Primate Ctr, Dept Infect Biol, Kellnerweg 4, D-37077 Gottingen, Germany. EM s.poehlmann@dpz.eu RI Sturzl, Michael/B-3019-2015; Schindler, Michael/C-1647-2015; Behrens, Georg/Q-4486-2016; OI Sturzl, Michael/0000-0002-9276-2824; Schindler, Michael/0000-0001-8989-5813; Pohlmann, Stefan/0000-0001-6086-9136 FU Hannover Biomedical Research School; Deutsche AIDS Gesellschaft; Deutsche Forschungsgemeinschaft (DFG); Heinrich Pette Institute; Free and Hanseatic City of Hamburg; Federal Ministry of Health; Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported by the Hannover Biomedical Research School (A. K.), Deutsche AIDS Gesellschaft (S. P., G. B.), Deutsche Forschungsgemeinschaft (DFG), and the Heinrich Pette Institute, which is a member of the Leibniz Gemeinschaft (WGL), and is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health (C. B., M. S.), and Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (A. M., H. F.). NR 50 TC 34 Z9 35 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S850 EP S860 DI 10.1093/infdis/jir378 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400015 PM 21987761 ER PT J AU Marzi, A Ebihara, H Callison, J Groseth, A Williams, KJ Geisbert, TW Feldmann, H AF Marzi, Andrea Ebihara, Hideki Callison, Julie Groseth, Allison Williams, Kinola J. Geisbert, Thomas W. Feldmann, Heinz TI Vesicular Stomatitis Virus-Based Ebola Vaccines With Improved Cross-Protective Efficacy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID NONHUMAN-PRIMATES; HEMORRHAGIC-FEVER; FILOVIRUS VACCINE; MARBURG VIRUSES; UNITED-STATES; RESTON VIRUS; INFECTION; PARTICLES; GLYCOPROTEINS; IMMUNIZATION AB For Ebola virus (EBOV), 4 different species are known: Zaire, Sudan, Cote d'Ivoire, and Reston ebolavirus. The newly discovered Bundibugyo ebolavirus has been proposed as a 5th species. So far, no cross-neutralization among EBOV species has been described, aggravating progress toward cross-species protective vaccines. With the use of recombinant vesicular stomatitis virus (rVSV)-based vaccines, guinea pigs could be protected against Zaire ebolavirus (ZEBOV) infection only when immunized with a vector expressing the homologous, but not a heterologous, EBOV glycoprotein (GP). However, infection of guinea pigs with nonadapted wild-type strains of the different species resulted in full protection of all animals against subsequent challenge with guinea pig-adapted ZEBOV, showing that cross-species protection is possible. New vectors were generated that contain EBOV viral protein 40 (VP40) or EBOV nucleoprotein (NP) as a second antigen expressed by the same rVSV vector that encodes the heterologous GP. After applying a 2-dose immunization approach, we observed an improved cross-protection rate, with 5 of 6 guinea pigs surviving the lethal ZEBOV challenge if vaccinated with rVSV-expressing SEBOV-GP and -VP40. Our data demonstrate that cross-protection between the EBOV species can be achieved, although EBOV-GP alone cannot induce the required immune response. C1 [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Marzi, Andrea; Ebihara, Hideki; Groseth, Allison; Williams, Kinola J.; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Williams, Kinola J.; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Williams, Kinola J.] Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU National Institutes of Health (NIH); Public Health Agency of Canada; Department of Health and Human Services [U01 AI082197]; Natural Science and Engineering Council of Canada (NSERC) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), the Public Health Agency of Canada and the Department of Health and Human Services (grant U01 AI082197 to Thomas W. Geisbert). A. M. and A. G. were funded by the Natural Science and Engineering Council of Canada (NSERC). NR 38 TC 29 Z9 33 U1 3 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S1066 EP S1074 DI 10.1093/infdis/jir348 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400043 PM 21987743 ER PT J AU Nakayama, E Tomabechi, D Matsuno, K Kishida, N Yoshida, R Feldmann, H Takada, A AF Nakayama, Eri Tomabechi, Daisuke Matsuno, Keita Kishida, Noriko Yoshida, Reiko Feldmann, Heinz Takada, Ayato TI Antibody-Dependent Enhancement of Marburg Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; GLYCOPROTEIN; STRAINS; DISEASE; PARTICLES; OUTBREAK; EPITOPES; BINDING; PROTEIN; ANGOLA AB Methods. To investigate this antibody-dependent enhancement (ADE) in MARV infection, we produced mouse antisera and monoclonal antibodies (mAbs) to the GPs of MARV strains Angola and Musoke. Results. The infectivity of vesicular stomatitis virus pseudotyped with Angola GP in K562 cells was significantly enhanced in the presence of Angola GP antisera, whereas only minimal ADE activity was seen with Musoke GP antisera. This difference correlated with the percentage of hybridoma clones producing infectivity-enhancing mAbs. Using mAbs to MARV GP, we identified 3 distinct ADE epitopes in the mucinlike region on Angola GP. Interestingly, some of these antibodies bound to both Angola and Musoke GPs but showed significantly higher ADE activity for strain Angola. ADE activity depended on epitopes in the mucinlike region and glycine at amino acid position 547, present in the Angola but absent in the Musoke GP. Conclusions. These results suggest a possible link between ADE and MARV pathogenicity and provide new insights into the mechanisms underlying ADE entry of filoviruses. C1 [Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Dept Global Epidemiol, Kita Ku, Sapporo, Hokkaido 0010020, Japan. [Kishida, Noriko] Natl Inst Infect Dis, Ctr Influenza Virus Res, Lab Influenza Virus Surveillance, Tokyo, Japan. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Dept Global Epidemiol, Kita Ku, Kita 20,Nishi 10, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp RI Takada, Ayato/A-6679-2012; YOSHIDA, Reiko/F-6883-2012 FU Japan Society for the Promotion of Science; Takeda Science Foundation; Ministry of Education, Culture, Sports, Science and Technology, Japan [F-001, 05021011]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; [19041001] FX This work was supported by Research Fellowships for Young Scientists from the Japan Society for the Promotion of Science, the Takeda Science Foundation, a Grant-in-Aid for Scientific Research on Priority Areas (grant 19041001), and, in part, by the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases (grant 05021011) and the Global COE Program "Establishment of International Collaboration Centers for Zoonosis Control" (grant F-001) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (http://www.mext.go.jp/english/index.htm). Filovirus work at the Rocky Mountain Laboratories is funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 30 TC 23 Z9 24 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S978 EP S985 DI 10.1093/infdis/jir334 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400033 PM 21987779 ER PT J AU Raymond, J Bradfute, S Bray, M AF Raymond, JoLynne Bradfute, Steven Bray, Mike TI Filovirus Infection of STAT-1 Knockout Mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID EBOLA-VIRUS INFECTION; T-CELL RESPONSES; HEMORRHAGIC-FEVER; MOUSE MODEL; IN-VITRO; APOPTOSIS; PATHOGENESIS; PROTECTION; DEFICIENCY; IMMUNITY AB We evaluated the susceptibility to Ebola and Marburg virus infection of mice that cannot respond to interferon (IFN)-alpha/beta and IFN-gamma because of deletion of the STAT-1 gene. A mouse-adapted Zaire ebolavirus (ZEBOV) caused rapidly lethal disease; wild-type ZEBOV and Sudan Ebolavirus and 4 different Marburg virus strains produced severe, but more slowly progressive illness; and Reston Ebolavirus caused mild disease that was late in onset. The virulence of each agent was mirrored by the pace and severity of pathologic changes in the liver and lymphoid tissues. A virus-like particle vaccine elicited strong antibody responses but did not protect against mouse-adapted ZEBOV challenge. C1 [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Raymond, JoLynne] Armed Forces Inst Pathol, Dept Vet Pathol, Washington, DC 20306 USA. [Bradfute, Steven] USA, Med Res Inst Infect Dis, Frederick, MD USA. RP Bray, M (reprint author), NIAID, Div Clin Res, NIH, Room 1229F,6700 Rockledge Dr, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 14 TC 32 Z9 32 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S986 EP S990 DI 10.1093/infdis/jir335 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400034 PM 21987780 ER PT J AU Tsuda, Y Safronetz, D Brown, K LaCasse, R Marzi, A Ebihara, H Feldmann, H AF Tsuda, Yoshimi Safronetz, David Brown, Kyle LaCasse, Rachel Marzi, Andrea Ebihara, Hideki Feldmann, Heinz TI Protective Efficacy of a Bivalent Recombinant Vesicular Stomatitis Virus Vaccine in the Syrian Hamster Model of Lethal Ebola Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HANTAVIRUS PULMONARY SYNDROME; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; MARBURG VIRUS; GLYCOPROTEINS; PATHOGENESIS; PARTICLES; LIVE AB Background. Outbreaks of filoviral hemorrhagic fever occur sporadically and unpredictably across wide regions in central Africa and overlap with the occurrence of other infectious diseases of public health importance. Methods. As a proof of concept we developed a bivalent recombinant vaccine based on vesicular stomatitis virus (VSV) expressing the Zaire ebolavirus (ZEBOV) and Andes virus (ANDV) glycoproteins (VSVDG/Dual) and evaluated its protective efficacy in the common lethal Syrian hamster model. Hamsters were vaccinated with VSVDG/Dual and were lethally challenged with ZEBOV or ANDV. Time to immunity and postexposure treatment were evaluated by immunizing hamsters at different times prior to and post ZEBOV challenge. Results. A single immunization with VSVDG/Dual conferred complete and sterile protection against lethal ZEBOV and ANDV challenge. Complete protection was achieved with an immunization as close as 3 days prior to ZEBOV challenge, and 40% of the animals were even protected when treated with VSVDG/Dual one day postchallenge. In comparison to the monovalent VSV vaccine, the bivalent vaccine has slightly reduced postexposure efficacy most likely due to its restricted lymphoid organ replication. Conclusions. Bivalent VSV vectors are a feasible approach to vaccination against multiple pathogens. C1 [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Brown, Kyle] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Brown, Kyle; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [LaCasse, Rachel] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT USA. EM feldmannh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 36 TC 11 Z9 13 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S1090 EP S1097 DI 10.1093/infdis/jir379 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400046 PM 21987746 ER PT J AU Wolf, K Beimforde, N Falzarano, D Feldmann, H Schnittler, HJ AF Wolf, Kristin Beimforde, Nadine Falzarano, Darryl Feldmann, Heinz Schnittler, Hans-Joachim TI The Ebola Virus Soluble Glycoprotein (sGP) Does Not Affect Lymphocyte Apoptosis and Adhesion to Activated Endothelium SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VIRION GLYCOPROTEINS; HEMORRHAGIC-FEVER; DENDRITIC CELLS; MARBURG VIRUSES; IN-VITRO; INFECTION; PATHOGENESIS; MACROPHAGES; FILOVIRUSES; EXPRESSION AB Ebola virus infection is associated with the release of a soluble glycoprotein (sGP) from infected cells. The sGP has been proposed to modulate Ebola virus pathogenesis in primates but little is known about the role of this protein during infection and disease manifestation. So far sGP has been shown to revert the effect of tumor necrosis factor alpha (TNF-alpha) on endothelial permeability, indicating that the function of sGP might be antiinflammatory. Since bystander apoptosis of lymphocytes has been demonstrated in Ebola virus infections, we aimed to investigate the ability of sGP to modulate lymphocyte apoptosis and adhesion of lymphocytes to activated endothelium. Recombinant sGP alone or together with TNF-alpha and the death receptors TRAIL and FAS neither increased nor decreased apoptosis of Jurkat cells, a well-established human lymphocytic cell line. In addition, Jurkat cell adhesion to native or activated human umbilical vein endothelial cells was also found to be not altered by sGP. C1 [Beimforde, Nadine; Schnittler, Hans-Joachim] Univ Munster, Inst Anat, D-48149 Munster, Germany. [Wolf, Kristin] Tech Univ Dresden, Inst Physiol, Dresden, Germany. [Falzarano, Darryl; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Falzarano, Darryl; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Falzarano, Darryl; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Schnittler, HJ (reprint author), Univ Munster, Inst Anat, Vesaliusweg 2-4, D-48149 Munster, Germany. EM hans.schnittler@uni-muenster.de FU Deutsche Forschungsgemeinschaft [SCHN 430/3-3, SCH 430/6-1]; National Microbiology Laboratory of the Public Health Agency of Canada FX This work was supported by the Deutsche Forschungsgemeinschaft (SCHN 430/3-3 and SCH 430/6-1) and the National Microbiology Laboratory of the Public Health Agency of Canada. NR 36 TC 3 Z9 3 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 SU 3 BP S947 EP S952 DI 10.1093/infdis/jir322 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 834VD UT WOS:000295991400028 PM 21987774 ER PT J AU Turkbey, B Mani, H Shah, V Rastinehad, AR Bernardo, M Pohida, T Pang, YX Daar, D Benjamin, C McKinney, YL Trivedi, H Chua, C Bratslavsky, G Shih, JH Linehan, WM Merino, MJ Choyke, PL Pinto, PA AF Turkbey, Baris Mani, Haresh Shah, Vijay Rastinehad, Ardeshir R. Bernardo, Marcelino Pohida, Thomas Pang, Yuxi Daar, Dagane Benjamin, Compton McKinney, Yolanda L. Trivedi, Hari Chua, Celene Bratslavsky, Gennady Shih, Joanna H. Linehan, W. Marston Merino, Maria J. Choyke, Peter L. Pinto, Peter A. TI Multiparametric 3T Prostate Magnetic Resonance Imaging to Detect Cancer: Histopathological Correlation Using Prostatectomy Specimens Processed in Customized Magnetic Resonance Imaging Based Molds SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostatectomy; magnetic resonance imaging; magnetic resonance spectroscopy; pathology ID PHASED-ARRAY COIL; ENDORECTAL COIL; RADICAL PROSTATECTOMY; LOCALIZATION; MRI; QUALITY AB Purpose: We determined the prostate cancer detection rate of multiparametric magnetic resonance imaging at 3T. Precise one-to-one histopathological correlation with magnetic resonance imaging was possible using prostate magnetic resonance imaging based custom printed specimen molds after radical prostatectomy. Materials and Methods: This institutional review board approved prospective study included 45 patients (mean age 60.2 years, range 49 to 75) with a mean prostate specific antigen of 6.37 ng/ml (range 2.3 to 23.7) who had biopsy proven prostate cancer (mean Gleason score of 6.7, range 6 to 9). Before prostatectomy all patients underwent prostate magnetic resonance imaging using endorectal and surface coils on a 3T scanner, which included triplane T2-weighted magnetic resonance imaging, apparent diffusion coefficient maps of diffusion weighted magnetic resonance imaging, dynamic contrast enhanced magnetic resonance imaging and spectroscopy. The prostate specimen was whole mount sectioned in a customized mold, allowing geometric alignment to magnetic resonance imaging. Tumors were mapped on magnetic resonance imaging and histopathology. Sensitivity, specificity, positive predictive value and negative predictive value of magnetic resonance imaging for cancer detection were calculated. In addition, the effects of tumor size and Gleason score on the sensitivity of multiparametric magnetic resonance imaging were evaluated. Results: The positive predictive value of multiparametric magnetic resonance imaging to detect prostate cancer was 98%, 98% and 100% in the overall prostate, peripheral zone and central gland, respectively. The sensitivity of magnetic resonance imaging sequences was higher for tumors larger than 5 mm in diameter as well as for those with higher Gleason scores (greater than 7, p < 0.05). Conclusions: Prostate magnetic resonance imaging at 3T allows for the detection of prostate cancer. A multiparametric approach increases the predictive power of magnetic resonance imaging for diagnosis. In this study accurate correlation between multiparametric magnetic resonance imaging and histopathology was obtained by the patient specific, magnetic resonance imaging based mold technique. C1 [Rastinehad, Ardeshir R.; Benjamin, Compton; Trivedi, Hari; Chua, Celene; Bratslavsky, Gennady; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Shah, Vijay; Bernardo, Marcelino; Daar, Dagane; McKinney, Yolanda L.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Mani, Haresh; Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Pohida, Thomas] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shah, Vijay; Bernardo, Marcelino] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,Room 2-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 21 TC 193 Z9 198 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2011 VL 186 IS 5 BP 1818 EP 1824 DI 10.1016/j.juro.2011.07.013 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 835FX UT WOS:000296022200024 PM 21944089 ER PT J AU Loeb, S Carter, HB Berndt, SI Ricker, W Schaeffer, EM AF Loeb, Stacy Carter, H. Ballentine Berndt, Sonja I. Ricker, Winnie Schaeffer, Edward M. TI Complications After Prostate Biopsy: Data From SEER-Medicare SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; biopsy; infection; complications ID ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; NEEDLE-BIOPSY; CANCER; PROPHYLAXIS; POPULATION; INFECTION; MORTALITY AB Purpose: More than 1 million prostate biopsies are performed annually among Medicare beneficiaries. We determined the risk of serious complications requiring hospitalization. We hypothesized that with emerging multidrug resistant organisms there may be an increasing risk of infectious complications. Materials and Methods: In a 5% random sample of Medicare participants in SEER (Surveillance, Epidemiology and End Results) regions from 1991 to 2007 we compared 30-day hospitalization rates and ICD-9 primary diagnosis codes for admissions between 17,472 men who underwent prostate biopsy and a random sample of 134,977 controls. Multivariate logistic and Poisson regression were used to examine the risk and predictors of serious infectious and noninfectious complications with time. Results: The 30-day hospitalization rate was 6.9% within 30 days of prostate biopsy, which was substantially higher than the 2.7% in the control population. After adjusting for age, race, SEER region, year and comorbidities prostate biopsy was associated with a 2.65-fold (95% CI 2.47-2.84) increased risk of hospitalization within 30 days compared to the control population (p <0.0001). The risk of infectious complications requiring hospitalization after biopsy was significantly greater in more recent years (p(trend) = 0.001). Among men undergoing biopsy, later year, nonwhite race and higher comorbidity scores were significantly associated with an increased risk of infectious complications. Conclusions: The risk of hospitalization within 30 days of prostate biopsy was significantly higher than in a control population. Infectious complications after prostate biopsy have increased in recent years while the rate of serious noninfectious complications is relatively stable. Careful patient selection for prostate biopsy is essential to minimize the potential harms. C1 [Loeb, Stacy; Carter, H. Ballentine; Schaeffer, Edward M.] Johns Hopkins Med Inst, Brady Urol Inst, Baltimore, MD 21287 USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ricker, Winnie] Informat Management Serv Inc, Rockville, MD USA. RP Loeb, S (reprint author), Johns Hopkins Med Inst, Brady Urol Inst, 600 N Wolfe St,Marburg 143, Baltimore, MD 21287 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 FU Division of Cancer Epidemiology and Genetics; Howard Hughes Medical Institute, National Institutes of Health; AUA Astellas; Patrick C. Walsh Prostate Cancer Research Foundation FX Supported by the Division of Cancer Epidemiology and Genetics Intramural Research Program, and the Howard Hughes Medical Institute, National Institutes of Health, an AUA Astellas Rising Star Award and the Patrick C. Walsh Prostate Cancer Research Foundation (EMS). NR 21 TC 236 Z9 241 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2011 VL 186 IS 5 BP 1830 EP 1834 DI 10.1016/j.juro.2011.06.057 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 835FX UT WOS:000296022200026 PM 21944136 ER PT J AU Castaneda, RT Boddington, S Henning, TD Wendland, M Mandrussow, L Liu, SY Daldrup-Link, H AF Castaneda, Rosalinda T. Boddington, Sophie Henning, Tobias D. Wendland, Mike Mandrussow, Lydia Liu, Siyuan Daldrup-Link, Heike TI Labeling human embryonic stem-cell-derived cardiomyocytes for tracking with MR imaging SO PEDIATRIC RADIOLOGY LA English DT Article DE Human embryonic stem cells; Cardiomyocytes; Iron oxides; SPIO; MR imaging; Cell labeling; Children ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; CONTRAST AGENTS; MYOCARDIAL-INFARCTION; BONE-MARROW; PROTAMINE SULFATE; INDOCYANINE GREEN; STROMAL CELLS; FERUMOXIDES; DELIVERY AB Background Human embryonic stem cells (hESC) can generate cardiomyocytes (CM), which offer promising treatments for cardiomyopathies in children. However, challenges for clinical translation result from loss of transplanted cell from target sites and high cell death. An imaging technique that noninvasively and repetitively monitors transplanted hESC-CM could guide improvements in transplantation techniques and advance therapies. Objective To develop a clinically applicable labeling technique for hESC-CM with FDA-approved superparamagnetic iron oxide nanoparticles (SPIO) by examining labeling before and after CM differentiation. Materials and methods Triplicates of hESC were labeled by simple incubation with 50 mu g/ml of ferumoxides before or after differentiation into CM, then imaged on a 7T MR scanner using a T2-weighted multi-echo spin-echo sequence. Viability, iron uptake and T2-relaxation times were compared between groups using t-tests. Results hESC-CM labeled before differentiation demonstrated significant MR effects, iron uptake and preserved function. hESC-CM labeled after differentiation showed no significant iron uptake or change in MR signal (P < 0.05). Morphology, differentiation and viability were consistent between experimental groups. Conclusion hESC-CM should be labeled prior to CM differentiation to achieve a significant MR signal. This technique permits monitoring delivery and engraftment of hESC-CM for potential advancements of stem cell-based therapies in the reconstitution of damaged myocardium. C1 [Castaneda, Rosalinda T.; Daldrup-Link, Heike] Lucile Packard Childrens Hosp, Stanford Sch Med, Stanford, CA 94305 USA. [Boddington, Sophie; Wendland, Mike; Mandrussow, Lydia] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, UCSF Med Ctr, San Francisco, CA 94143 USA. [Henning, Tobias D.] Univ Hosp Cologne, Dept Radiol & Neuroradiol, Cologne, Germany. [Liu, Siyuan] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. RP Daldrup-Link, H (reprint author), Lucile Packard Childrens Hosp, Stanford Sch Med, 725 Welch Rd,Rm 1665, Stanford, CA 94305 USA. EM rcastan@stanford.edu; heiked@stanford.edu RI Liu, Siyuan/D-2227-2012; Daldrup-Link, Heike/D-9829-2012 OI Daldrup-Link, Heike/0000-0002-4929-819X FU California Institute for Regenerative Medicine (CIRM) [RS1-00381-1] FX This study was supported by a research grant from the California Institute for Regenerative Medicine (CIRM), grant # RS1-00381-1. NR 62 TC 5 Z9 7 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD NOV PY 2011 VL 41 IS 11 BP 1384 EP 1392 DI 10.1007/s00247-011-2130-3 PG 9 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 835AK UT WOS:000296005400006 PM 21594541 ER PT J AU Preston, KL Epstein, DH AF Preston, Kenzie L. Epstein, David H. TI Stress in the daily lives of cocaine and heroin users: relationship to mood, craving, relapse triggers, and cocaine use SO PSYCHOPHARMACOLOGY LA English DT Article DE Stress; Cocaine; Craving; Addiction; Human; Ecological momentary assessment ID ECOLOGICAL MOMENTARY ASSESSMENT; DEPENDENT INDIVIDUALS; DAILY-LIFE; SMOKING LAPSES; REAL-TIME; SMOKERS AB Quantitative real-time data on the stress experienced by drug misusers in their daily lives may provide additional insight into stress's role in drug use. The purpose of this study is to evaluate stress in relation to craving, mood, relapse-trigger exposure, and cocaine use in cocaine-dependent outpatients. Methadone-maintained cocaine- and heroin-abusing outpatients (N = 114) provided ecological momentary assessment data on handheld computers. Ratings of stress were compared to those of craving and mood and past-hour exposure to putative drug-use triggers in randomly prompted entries and in the 5 h prior to participant-initiated cocaine use reports. Stress had significant positive relationships with current ratings of craving for cocaine, heroin, and tobacco and with ratings of tiredness, boredom, and irritation, and had significant negative relationships with ratings of happiness and relaxation. Stress was significantly greater in entries in which participants also reported past-hour exposure to negative-mood triggers, most of the drug-exposure triggers, or any trigger involving thoughts about drugs (e.g., tempted out of the blue). The linear increase in stress during the 5-h preceding individual episodes of cocaine use was not significant (p = 0.12), though there was a trend for such an increase before the use episodes that participants attributed to stressful states when they occurred (p = 0.87). The findings suggest a complex role of stress in addiction. Stress reported in real time in the natural environment showed strong cross-sectional momentary relationships with craving, mood, and exposure to drug-use trigger. However, the prospective association between stress ratings and cocaine-use episodes was, at best, weak. C1 [Preston, Kenzie L.; Epstein, David H.] NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, NIDA Intramural Res Program,NIH,Dept Hlth & Human, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, NIDA Intramural Res Program,NIH,Dept Hlth & Human, Room 01B 602,251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU National Institute on Drug Abuse (NIDA), National Institutes of Health; NIDA Intramural Research Program; Genes and Environment Initiative [Z01-DA000499] FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health. We wish to thank the NIDA IRP Archway Clinic staff for data collection.; This research was supported by the NIDA Intramural Research Program and Genes and Environment Initiative Cooperative Agreement Z01-DA000499. NR 33 TC 41 Z9 41 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 29 EP 37 DI 10.1007/s00213-011-2183-x PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000003 PM 21336579 ER PT J AU Sinha, R Shaham, Y Heilig, M AF Sinha, Rajita Shaham, Yavin Heilig, Markus TI Translational and reverse translational research on the role of stress in drug craving and relapse SO PSYCHOPHARMACOLOGY LA English DT Review DE Corticotropin-releasing factor; Craving; Extinction; NK1 receptor; Noradrenaline; Reinstatement; Relapse; Reverse translational research; Stress; Substance P; Translational research; Yohimbine ID CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED PLACE PREFERENCE; COCAINE-SEEKING BEHAVIOR; CUE-INDUCED REINSTATEMENT; NK1 RECEPTOR ANTAGONIST; VENTRAL TEGMENTAL AREA; YOHIMBINE-INDUCED INCREASES; MIDBRAIN DOPAMINE NEURONS; SUBSTANCE-P RECEPTORS; REAL-TIME REPORTS AB High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown. Here, we address this topic by discussing recent results on the effect of alpha-2 adrenoceptors and substance P-NK1 receptor antagonists on stress-induced reinstatement in mice and rats and stress-induced craving and potentially stress-induced relapse in humans. We also discuss brain sites and circuits involved in stress-induced reinstatement of drug seeking in rats and those activated during stress-induced craving in humans. There is evidence that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced drug seeking in rats and stress-induced craving in humans. Whether these drugs would also prevent stress-induced drug relapse in humans and whether similar or different brain mechanisms are involved in stress-induced reinstatement in non-humans and stress-induced drug craving and relapse in humans are subjects for future research. C1 [Shaham, Yavin] NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD USA. [Sinha, Rajita] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, IRP, NIH,DHHS, Bethesda, MD USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Heilig, Markus/0000-0003-2706-2482 FU NIDA; NIAAA; NIH FX The writing of this review was supported in part by the Intramural Research Programs of NIDA (YS) and NIAAA (MH), and extramural NIH grants (RS). NR 201 TC 55 Z9 55 U1 2 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 69 EP 82 DI 10.1007/s00213-011-2263-y PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000007 PM 21494792 ER PT J AU Jobes, ML Ghitza, UE Epstein, DH Phillips, KA Heishman, SJ Preston, KL AF Jobes, Michelle L. Ghitza, Udi E. Epstein, David H. Phillips, Karran A. Heishman, Stephen J. Preston, Kenzie L. TI Clonidine blocks stress-induced craving in cocaine users SO PSYCHOPHARMACOLOGY LA English DT Article DE Clonidine; Cocaine; Stress-induced craving; Cue-induced craving; Imagery scripts; Reinstatement ID INDUCED REINSTATEMENT; HEROIN-SEEKING; RATS; LOFEXIDINE; ADDICTION; RELAPSE; ABUSE; CUES; VALIDATION; ABSTINENCE AB Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement. The objective of this study is to test the effect of clonidine on stress- and cue-induced craving in human cocaine users. Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. In a single test session, each participant received clonidine or placebo followed 3 h later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving were collected. Subjective responsivity ("crave cocaine" Visual Analog Scale) to stress scripts was significantly attenuated in the 0.1- and 0.2-mg clonidine groups; for drug-cue scripts, this attenuation occurred only in the 0.2-mg group. Other subjective measures of craving showed similar patterns of effects but Dose x Script interactions were not significant. Clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with preclinical findings, although this was significant on only one of several measures. Our results, though modest and preliminary, converge with other evidence to suggest that alpha-2 adrenergic agonists may help prevent relapse in drug abusers experiencing stress or situations that remind them of drug use. C1 [Jobes, Michelle L.; Epstein, David H.; Phillips, Karran A.; Heishman, Stephen J.; Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Jobes, ML (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jobesm@nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU National Institute on Drug Abuse (NIDA), National Institutes of Health FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health. NR 35 TC 35 Z9 36 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 83 EP 88 DI 10.1007/s00213-011-2230-7 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000008 PM 21399902 ER PT J AU Le, AD Funk, D Juzytsch, W Coen, K Navarre, BM Cifani, C Shaham, Y AF Le, A. D. Funk, Douglas Juzytsch, Walter Coen, Kathleen Navarre, Brittany M. Cifani, Carlo Shaham, Yavin TI Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Alpha-1 adrenoceptors; Alpha-2 adrenoceptors; Diet; Alcohol self-administration; Noradrenaline; Reinstatement; Relapse; Stress ID CORTICOTROPIN-RELEASING-FACTOR; ANXIOGENIC DRUG YOHIMBINE; COCAINE-INDUCED REINSTATEMENT; CONDITIONED PLACE PREFERENCE; MEDIAL PREFRONTAL CORTEX; STRIA TERMINALIS; BED NUCLEUS; INDUCED INCREASES; NORADRENERGIC MECHANISMS; NOREPINEPHRINE RELEASE AB Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking. C1 [Le, A. D.; Funk, Douglas; Juzytsch, Walter; Coen, Kathleen] Ctr Addict & Mental Hlth, Neurobiol Alcohol Lab, Toronto, ON M5S 2S1, Canada. [Le, A. D.] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Le, A. D.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Navarre, Brittany M.; Cifani, Carlo; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP Le, AD (reprint author), Ctr Addict & Mental Hlth, Neurobiol Alcohol Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM Anh_le@camh.net RI shaham, yavin/G-1306-2014; OI Cifani, Carlo/0000-0001-6180-828X FU NIAAA [AA13108]; National Institute on Drug Abuse FX This work was supported by a grant from the NIAAA (AA13108) to A. D. Le and by the Intramural Research Program of the National Institute on Drug Abuse. We thank Dr. Donna Calu and Ms. Thi Kuch for their help in conducting exp. 2. NR 75 TC 50 Z9 50 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 89 EP 99 DI 10.1007/s00213-011-2178-7 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000009 PM 21318567 ER PT J AU Schank, JR Pickens, CL Rowe, KE Cheng, K Thorsell, A Rice, KC Shaham, Y Heilig, M AF Schank, Jesse R. Pickens, Charles L. Rowe, Kelly E. Cheng, Kejun Thorsell, Annika Rice, Kenner C. Shaham, Yavin Heilig, Markus TI Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429 SO PSYCHOPHARMACOLOGY LA English DT Article DE Substance P; Neurokinin; Alcohol; Stress; Relapse; Reinstatement; Fear conditioning ID CORTICOTROPIN-RELEASING-FACTOR; SUBSTANCE-P; RECEPTOR ANTAGONIST; INDUCED RELAPSE; PRIMING INJECTIONS; COCAINE SEEKING; RAPHE NUCLEUS; MICE LACKING; ANXIETY; DEPENDENCE AB Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined. Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats. L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding. At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution. To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse. C1 [Schank, Jesse R.; Rowe, Kelly E.; Thorsell, Annika; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Pickens, Charles L.; Shaham, Yavin] NIDA, Behav Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Branch, NIH, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), 10 Ctr Dr,10-1E 5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI shaham, yavin/G-1306-2014; OI Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 NR 49 TC 36 Z9 36 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 111 EP 119 DI 10.1007/s00213-011-2201-z PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000011 PM 21340476 ER PT J AU Ross, SA Davis, CD AF Ross, Sharon A. Davis, Cindy D. TI MicroRNA, Nutrition, and Cancer Prevention SO ADVANCES IN NUTRITION LA English DT Article AB MicroRNA (miRNA) are small noncoding RNA molecules that are involved in post-transcriptional gene silencing. Alterations in miRNA expression are observed in and may underlie many different human diseases, including cancer. In fact, miRNA have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Genetic and epigenetic alterations may explain aberrant miRNA expression in cancer cells and may also contribute to cancer risk. It is now thought that by circulating through the bloodstream, miRNA can exert their effects at distant sites as well as within the cells of origin. Recent evidence suggests that nutrients and other bioactive food components protect against cancer through modulation of miRNA expression. Moreover, dietary factors have been shown to modify miRNA expression and their mRNA targets in various cancer processes, including apoptosis, cell cycle regulation, differentiation, inflammation, angiogenesis, and metastasis as well as pathways in stress response. Herein, we provide a brief overview of dietary modulation of miRNA expression and its potential role in cancer prevention. Understanding the affect of dietary factors on miRNA expression and function may provide insight on prevention strategies to reduce the burden of cancer. Adv. Nutr. 2: 472-485, 2011. C1 [Ross, Sharon A.; Davis, Cindy D.] NCI, Nutr Sci Res Grp, Bethesda, MD 20892 USA. RP Ross, SA (reprint author), NCI, Nutr Sci Res Grp, Bethesda, MD 20892 USA. EM rosssha@mail.nih.gov NR 104 TC 44 Z9 46 U1 0 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 J9 ADV NUTR JI Adv. Nutr. PD NOV PY 2011 VL 2 IS 6 BP 472 EP 485 DI 10.3945/an.111.001206 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA V27BV UT WOS:000208589600004 PM 22332090 ER PT J AU Dolja, VV Koonin, EV AF Dolja, Valerian V. Koonin, Eugene V. TI Common origins and host-dependent diversity of plant and animal viromes SO CURRENT OPINION IN VIROLOGY LA English DT Article ID STRAND RNA VIRUSES; DNA-REPLICATION; INITIATOR PROTEINS; MOVEMENT PROTEINS; EVOLUTION; LIFE; GEMINIVIRUSES; POLYMERASES; SEQUENCE; IMMUNITY AB Many viruses infecting animals and plants share common cores of homologous genes involved in the key processes of viral replication. In contrast, genes that mediate virus-host interactions including in many cases capsid protein (CP) genes are markedly different. There are three distinct scenarios for the origin of related viruses of plants and animals: first, evolution from a common ancestral virus predating the divergence of plants and animals; second, horizontal transfer of viruses, for example, through insect vectors; third, parallel origin from related genetic elements. We present evidence that each of these scenarios contributed, to a varying extent, to the evolution of different groups of viruses. C1 [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Dolja, Valerian V.] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS [ZIA LM000073-16] NR 57 TC 20 Z9 20 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD NOV PY 2011 VL 1 IS 5 BP 322 EP 331 DI 10.1016/j.coviro.2011.09.007 PG 10 WC Virology SC Virology GA 051FU UT WOS:000312112400002 PM 22408703 ER PT J AU Faria, NR Suchard, MA Rambaut, A Lemey, P AF Faria, Nuno Rodrigues Suchard, Marc A. Rambaut, Andrew Lemey, Philippe TI Toward a quantitative understanding of viral phylogeography SO CURRENT OPINION IN VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFLUENZA-A H5N1; HIV-1; COMPARTMENTALIZATION; EVOLUTION; EMERGENCE; MODELS; HISTORY; TISSUES; ORIGIN AB Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave in the genomes of fast evolving viruses. Recent Bayesian inference methods that consider phylogenetic diffusion of discretely and continuously distributed traits offer a unique opportunity to explore genotypic and phenotypic evolution in greater detail. To provide a taste of the recent advances in viral diffusion approaches, we highlight key findings arising at the intrahost, local and global epidemiological scales. We also outline future areas of research and discuss how these may contribute to a quantitative understanding of the phylodynamics of RNA viruses. C1 [Faria, Nuno Rodrigues; Lemey, Philippe] Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA. [Rambaut, Andrew] Univ Edinburgh, Ashworth Labs, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lemey, P (reprint author), Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. EM philippe.Lemey@rega.kuleuven.be RI Faria, Nuno/I-2975-2012; OI Faria, Nuno/0000-0001-8839-2798; Rodrigues Faria, Nuno/0000-0002-9747-8822; Rambaut, Andrew/0000-0003-4337-3707 FU Fundacao para a Ciencia e Tecnologia [SFRH/BD/64530/2009]; European Commission (EC Grant CHAIN 7FP) [223131]; European Research Council under the European Community's Seventh Framework Programme (FP7)/ERC Grant [260864]; US National Science Foundation [DMS 0856099]; US National Institutes of Health [R01 GM086887, R01 HG006139, NS063897] FX NRF is supported by Fundacao para a Ciencia e Tecnologia under grant agreement No. SFRH/BD/64530/2009. The research leading to these results has received funding from the European Commission (EC Grant CHAIN 7FP, 223131), the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement No. 260864, the US National Science Foundation (DMS 0856099) and the US National Institutes of Health (R01 GM086887, R01 HG006139 and NS063897). NR 58 TC 26 Z9 26 U1 0 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD NOV PY 2011 VL 1 IS 5 BP 423 EP 429 DI 10.1016/j.coviro.2011.10.003 PG 7 WC Virology SC Virology GA 051FU UT WOS:000312112400016 PM 22440846 ER PT J AU Mukhopadhyay, P Horvath, B Zsengeller, Z Zielonka, J Tanchian, G Kechrid, M Patel, V Stillman, IE Parikh, SM Joseph, J Kalyanaraman, B Pacher, P AF Mukhopadhyay, Partha Horvath, Bela Zsengeller, Zsuzsanna Zielonka, Jacek Tanchian, Galin Kechrid, Malek Patel, Vivek Stillman, Isaac E. Parikh, Samir M. Joseph, Joy Kalyanaraman, Balaraman Pacher, Pal TI Mitochondrial-Targeted Antioxidants Represent a Promising Approach for Prevention Of SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Mukhopadhyay, Partha; Horvath, Bela; Tanchian, Galin; Kechrid, Malek; Patel, Vivek; Pacher, Pal] NIAAA, NIH, Bethesda, MD 20892 USA. [Zsengeller, Zsuzsanna; Stillman, Isaac E.; Parikh, Samir M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Milwaukee, WI USA. RI Horvath, Bela/A-7368-2009; Zielonka, Jacek/N-9546-2014 OI Zielonka, Jacek/0000-0002-2524-0145 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S93 EP S93 DI 10.1016/j.freeradbiomed.2011.10.457 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600236 ER PT J AU Nagababu, E Salgado, MT Lima, SD Lima, M Silber, HA Rifkind, JM AF Nagababu, Enika Salgado, Maria T. Lima, Sandra D. Lima, Michael Silber, Harry A. Rifkind, Joseph M. TI Effect of Intermittent Pneumatic Compression of Legs On Blood Nitric Oxide and Brachial Artery Diameter SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Nagababu, Enika; Salgado, Maria T.; Rifkind, Joseph M.] NIA, Bethesda, MD 20892 USA. [Lima, Sandra D.; Lima, Michael; Silber, Harry A.] Johns Hopkins Med Inst, Baltimore, MD USA. 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S160 EP S161 DI 10.1016/j.freeradbiomed.2011.10.222 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600423 ER PT J AU Noyes, A Stefaniuk, C Cheng, YZ Kennison, JA Kassis, JA AF Noyes, Amanda Stefaniuk, Catherine Cheng, Yuzhong Kennison, James A. Kassis, Judith A. TI Modulation of the Activity of a Polycomb-Group Response Element in Drosophila by a Mutation in the Transcriptional Activator Woc SO G3-GENES GENOMES GENETICS LA English DT Article DE polycomb repression; polycomb response elements; PRE; woc ID ENGRAILED GENE; GROUP PROTEINS; MELANOGASTER; BINDING; EXPRESSION; COMPLEX; DNA; BOUNDARIES; LOCUS; PRES AB Polycomb group response elements (PRE) are cis-regulatory elements that bind Polycomb group proteins. We are studying a 181-bp PRE from the Drosophila engrailed gene. This PRE causes pairing-sensitive silencing of mini-white in transgenes. Here we show that the 181-bp PRE also represses mini-white expression in flies with only one copy of the transgene. To isolate mutations that alter the activity of the 181-bp PRE, we screened for dominant suppressors of PRE-mediated mini-white repression. Dominant suppressors of mini-white repression were rare; we recovered only nine mutations out of 68,274 progeny screened. Two of the nine mutations isolated are due to the same single amino acid change in the transcriptional activator Woc (without children). Reversion experiments show that these are dominant gain-of-function mutations in woc. We suggest that Woc can interfere with the activity of the PRE. Our data have implications for how Polycomb group proteins act to either partially repress or completely silence their target genes. C1 [Noyes, Amanda; Stefaniuk, Catherine; Cheng, Yuzhong; Kennison, James A.; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Kassis, JA (reprint author), NICHD, PGD, NIH, 6 Ctr Dr,MSC 2785, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Kassis, Judith/0000-0001-9268-3213 FU National Institute of Child Health and Human Development, National Institutes of Health FX We thank Pamela Geyer and Emily Kuhn for the EK710 plasmid and the Cre recombinase flies; Mike Goldberg and Rick Padgett for woc mutants; Sarah DeVido for making the P[L181PRE] clone and for localization of many of the insertion sites; and Kristofor Langlais for statistical analysis of the qRT-PCR data. Many of the stocks used in these experiments were obtained from the Bloomington Stock Center. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 38 TC 3 Z9 3 U1 0 U2 0 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD NOV 1 PY 2011 VL 1 IS 6 BP 471 EP 478 DI 10.1534/g3.111.001230 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 055IP UT WOS:000312409400007 PM 22384357 ER PT J AU Cheng, YC O'Connell, JR Cole, JW Stine, OC Dueker, N McArdle, PF Sparks, MJ Shen, J Laurie, CC Nelson, S Doheny, KF Ling, H Pugh, EW Brott, TG Brown, RD Meschia, JF Nalls, M Rich, SS Worrall, B Anderson, CD Biffi, A Cortellini, L Furie, KL Rost, NS Rosand, J Manolio, TA Kittner, SJ Mitchell, BD AF Cheng, Yu-Ching O'Connell, Jeffrey R. Cole, John W. Stine, O. Colin Dueker, Nicole McArdle, Patrick F. Sparks, Mary J. Shen, Jess Laurie, Cathy C. Nelson, Sarah Doheny, Kimberly F. Ling, Hua Pugh, Elizabeth W. Brott, Thomas G. Brown, Robert D., Jr. Meschia, James F. Nalls, Michael Rich, Stephen S. Worrall, Bradford Anderson, Christopher D. Biffi, Alessandro Cortellini, Lynelle Furie, Karen L. Rost, Natalia S. Rosand, Jonathan Manolio, Teri A. Kittner, Steven J. Mitchell, Braxton D. TI Genome-Wide Association Analysis of Ischemic Stroke in Young Adults SO G3-GENES GENOMES GENETICS LA English DT Article DE epidemiology; genetics; brain infarction; FMNL2 ID VARIANTS; RISK; CLASSIFICATION; DISEASE; IMPUTATION; INFARCTION; SUBTYPE; LINKAGE; LOCI; TOOL AB Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15-49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 x 10(-8)), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 x 10(-7)) and rs1986743 (in ARL6IP6; P = 2.7 x 10(-7)), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults. C1 [Cheng, Yu-Ching; O'Connell, Jeffrey R.; McArdle, Patrick F.; Mitchell, Braxton D.] Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21201 USA. [Cole, John W.; Sparks, Mary J.; Kittner, Steven J.] Univ Maryland, Dept Neurol, Sch Med, Baltimore, MD 21201 USA. [Stine, O. Colin; Dueker, Nicole] Univ Maryland, Dept Epidemiol & Publ Hlth, Sch Med, Baltimore, MD 21201 USA. [Cole, John W.; Kittner, Steven J.] Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD 21201 USA. [Shen, Jess; Laurie, Cathy C.; Nelson, Sarah] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doheny, Kimberly F.; Ling, Hua; Pugh, Elizabeth W.] Johns Hopkins Univ, Ctr Inherited Dis Res, Sch Med, Baltimore, MD 21224 USA. [Brott, Thomas G.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Nalls, Michael] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Mitchell, Braxton D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Rich, Stephen S.; Worrall, Bradford] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Worrall, Bradford] Univ Virginia, Dept Neurol, Charlottesville, VA 22908 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Furie, Karen L.; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Mitchell, BD (reprint author), Univ Maryland, Dept Med, Sch Med, 660 W Redwood St,Howard Hall,Room 492, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu OI Anderson, Christopher/0000-0002-0053-2002; Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) [U01 HG-004436]; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK-072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; GEI [U01 HG-004438-01]; 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 NS-45012, U01 NS-069208-01]; National Institute on Aging, NIH [Z01 AG-000954-06, Z01 AG-000015-50]; NIH-NINDS [R01 NS-42733, R01 NS-39987, K23 NS-064052, R01 NS-063925, P50 NS-051343]; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke; Keane Stroke Genetics Research Fund; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research FX GEOS was supported by the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) Grant U01 HG-004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK-072488); and by 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) and funded by GEI Grant U01 HG-004438-01. Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG-004446; Bruce S. Weir, P. I.). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control, and by National Institute of Neurological Disorders and Stroke (NINDS) and NIH Office of Research on Women's Health Grants R01 NS-45012 and U01 NS-069208-01. The ISGS/SWISS study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (J. F. Meschia, P. I.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (J. F. Meschia, P. I.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). GASROS was supported by American Heart Association/Bugher Foundation Centers for Stroke Prevention Research Grant 0775010N; NIH-NINDS Grants K23 NS-064052 (N. S. Rost), R01 NS-063925 (J. Rosand), and P50 NS-051343 (J. Rosand and K. L. Furie); the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke; and the Keane Stroke Genetics Research Fund. Drs. A. Biffi, N. S. Rost, and C. D. Anderson were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research. NR 31 TC 12 Z9 12 U1 0 U2 0 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD NOV 1 PY 2011 VL 1 IS 6 BP 505 EP 513 DI 10.1534/g3.111.001164 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 055IP UT WOS:000312409400011 PM 22384361 ER PT J AU Lin, SW Fan, JH Dawsey, SM Taylor, PR Qiao, YL Abnet, CC AF Lin, Shih-Wen Fan, Jin-Hu Dawsey, Sanford M. Taylor, Philip R. Qiao, You-Lin Abnet, Christian C. TI Serum thyroglobulin, a biomarker for iodine deficiency, is not associated with increased risk of upper gastrointestinal cancers in a large Chinese cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China ID NUTRITION INTERVENTION TRIAL; GASTRIC-CANCER; GENERAL-POPULATION; HELICOBACTER-PYLORI; ESOPHAGEAL; DISEASE; SUPPLEMENTATION; THYROTROPIN; MORTALITY; LINXIAN AB Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and nonsignificantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. Our study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from similar to 200 subjects of each case type and 400 noncases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex-and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted hazard ratios of 0.88 (95% confidence interval 0.50-1.52), 1.14 (0.63-2.05) and 0.78 (0.47-1.31) for GNCA, GCA and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers. C1 [Lin, Shih-Wen] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lin, Shih-Wen] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. RP Lin, SW (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3019,MSC 7232, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov; qiaoy@cicams.ac.cn RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics NR 25 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2011 VL 129 IS 9 BP 2284 EP 2289 DI 10.1002/ijc.25789 PG 6 WC Oncology SC Oncology GA 824VO UT WOS:000295230500023 PM 21105043 ER PT J AU Vavere, AL Simon, GG George, RT Rochitte, CE Arai, AE Miller, JM Di Carli, M Zadeh, AA Dewey, M Niinuma, H Laham, R Rybicki, FJ Schuijf, JD Paul, N Hoe, J Kuribyashi, S Sakuma, H Nomura, C Yaw, TS Kofoed, KF Yoshioka, K Clouse, ME Brinker, J Cox, C Lima, JAC AF Vavere, Andrea L. Simon, Gregory G. George, Richard T. Rochitte, Carlos E. Arai, Andrew E. Miller, Julie M. Di Carli, Marcello Zadeh, Armin A. Dewey, Marc Niinuma, Hiroyuki Laham, Roger Rybicki, Frank J. Schuijf, Joanne D. Paul, Narinder Hoe, John Kuribyashi, Sachio Sakuma, Hajime Nomura, Cesar Yaw, Tan Swee Kofoed, Klaus F. Yoshioka, Kunihiro Clouse, Melvin E. Brinker, Jeffrey Cox, Christopher Lima, Joao A. C. TI Diagnostic performance of combined noninvasive coronary angiography and myocardial perfusion imaging using 320 row detector computed tomography: design and implementation of the CORE320 multicenter, multinational diagnostic study SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Computed tomography; Coronary angiography; Myocardial perfusion imaging; Study design and implementation; Multicenter study ID MULTIDETECTOR CT ANGIOGRAPHY; ARTERY-DISEASE; ADENOSINE STRESS; LEFT MAIN; ACCURACY; METAANALYSIS; SPECT; CARDIOLOGY; ISCHEMIA; LESIONS AB Multidetector coronary computed tomography angiography (CTA) is a promising modality for widespread clinical application because of its noninvasive nature and high diagnostic accuracy as found in previous studies using 64 to 320 simultaneous detector rows. It is, however, limited in its ability to detect myocardial ischemia. In this article, we describe the design of the CORE320 study ("Combined coronary atherosclerosis and myocardial perfusion evaluation using 320 detector row computed tomography"). This prospective, multicenter, multinational study is unique in that it is designed to assess the diagnostic performance of combined 320-row CTA and myocardial CT perfusion imaging (CTP) in comparison with the combination of invasive coronary angiography and single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The trial is being performed at 16 medical centers located in 8 countries worldwide. CT has the potential to assess both anatomy and physiology in a single imaging session. The co-primary aim of the CORE320 study is to define the per-patient diagnostic accuracy of the combination of coronary CTA and myocardial CTP to detect physiologically significant coronary artery disease compared with (1) the combination of conventional coronary angiography and SPECT-MPI and (2) conventional coronary angiography alone. If successful, the technology could revolutionize the management of patients with symptomatic CAD. (C) 2011 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Vavere, Andrea L.; Simon, Gregory G.; George, Richard T.; Miller, Julie M.; Zadeh, Armin A.; Brinker, Jeffrey; Lima, Joao A. C.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Rochitte, Carlos E.] Univ Sao Paulo, InCor Sao Paulo Heart Inst, Sao Paulo, Brazil. [Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Di Carli, Marcello; Rybicki, Frank J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Dewey, Marc] Humboldt Univ, Charite Med Sch, D-10099 Berlin, Germany. [Dewey, Marc] Free Univ Berlin, Berlin, Germany. [Niinuma, Hiroyuki] St Lukes Int Hosp, Tokyo, Japan. [Laham, Roger; Clouse, Melvin E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Schuijf, Joanne D.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Paul, Narinder] Toronto Gen Hosp, Toronto, ON, Canada. [Hoe, John] Mt Elizabeth Hosp, Singapore, Singapore. [Kuribyashi, Sachio] Keio Univ, Tokyo, Japan. [Sakuma, Hajime] Mie Univ Hosp, Tsu, Mie, Japan. [Nomura, Cesar] Albert Einstein Hosp, Sao Paulo, Brazil. [Yaw, Tan Swee] Natl Heart Ctr, Singapore, Singapore. [Kofoed, Klaus F.] Univ Copenhagen, Rigshosp, DK-2100 Copenhagen, Denmark. [Yoshioka, Kunihiro] Iwate Med Univ, Morioka, Iwate 020, Japan. [Cox, Christopher] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu OI Hoe, John/0000-0003-2591-5648; Dewey, Marc/0000-0002-4402-2733 FU Toshiba Medical Systems; Doris Duke Charitable Foundation; Lantheus Medical Imaging; European Regional Development Fund; German Heart Foundation/German Foundation of Heart Research; German Science Foundation (DFG); German Federal Ministry of Education and Research (BMBF); GE Healthcare (Amersham); Bracco; Guerbet; Cardiac MR Academy Berlin; Bayer-Schering; GE Healthcare, Japan; Bracco Diagnostics; Toshiba Corporation FX R.T.G. received research support from Toshiba Medical Systems and has done consulting for ICON Medical Imaging. J.M.M.'s institution has grants from Toshiba Medical Systems and Doris Duke Charitable Foundation; the institution receives support for travel to study meetings and educational purposes from Toshiba Medical Systems; Individual and institution receive honoraria from Toshiba Medical Systems. M.D.C. received significant research grants from Toshiba Medical Systems and Lantheus Medical Imaging. A.A.Z. is a steering committee member of the CORE320 study. M.D. received significant research grants from European Regional Development Fund, German Heart Foundation/German Foundation of Heart Research, Joint program from the German Science Foundation (DFG) and the German Federal Ministry of Education and Research (BMBF) for meta-analyses, GE Healthcare (Amersham), Bracco, Guerbet, and Toshiba Medical Systems; modest speakers bureau grants from Toshiba Medical Systems, Guerbet, Cardiac MR Academy Berlin, and Bayer-Schering; is a consultant to Guerbet; and has institutional master research agreements with Siemens Medical Solutions, Philips Medical Systems, and Toshiba Medical Systems (the terms of these arrangements are managed by the legal department of Charite-Universitatsmedizin Berlin). H.N. received a significant research grant from Toshiba Medical Systems. F.J.R. has research agreements with Toshiba Medical Systems and Bracco Diagnostics. N.P. has research Support from Toshiba Medical Systems. J.H. has a research grant from Toshiba Medical systems and Speakers Bureau-Toshiba Medical Systems, Bayer Schering Pharma, Infinitt Systems. S.K. has a research grant from GE Healthcare, Japan. H.S. has a departmental research grant from Toshiba Corporation. J.A.C.L. is principal investigator of grants from Toshiba Medical Systems and Bracco Diagnostics that, in part, support the Core320 study. All other authors report no conflicts of interest. NR 35 TC 33 Z9 36 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD NOV-DEC PY 2011 VL 5 IS 6 BP 370 EP 381 DI 10.1016/j.jcct.2011.11.001 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 035HJ UT WOS:000310933700004 PM 22146496 ER PT J AU Mazumdar, M Sung, MH Misteli, T AF Mazumdar, Manjari Sung, Myong-Hee Misteli, Tom TI Chromatin maintenance by a molecular motor protein SO NUCLEUS-AUSTIN LA English DT Article AB The kinesin motor protein KIF4 performs essential functions in mitosis. Like other mitotic kinesins, loss of KIF4 causes spindle defects, aneuploidy, genomic instability and ultimately tumor formation. However, KIF4 is unique among molecular motors in that it resides in the cell nucleus throughout interphase, suggesting a non-mitotic function as well. Here we identify a novel cellular function for a molecular motor protein by demonstrating that KIF4 acts as a modulator of large-scale chromatin architecture during interphase. KIF4 binds globally to chromatin and its absence leads to chromatin decondensation and loss of heterochromatin domains. KIF4-dependent chromatin decondensation has functional consequences by causing replication defects and global mis-regulation of gene expression programs. KIF4 exerts its function in chromatin architecture via regulation of ADP-ribosylation of core and linker histones and by physical interaction and recruitment of chromatin assembly proteins during S-phase. These observations document a novel function for a molecular motor protein in establishment and maintenance of higher order chromatin structure. C1 [Mazumdar, Manjari] Indiana Univ, Sch Med, Med Sci Program, Bloomington, IN 47405 USA. [Sung, Myong-Hee; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Mazumdar, M (reprint author), Indiana Univ, Sch Med, Med Sci Program, Bloomington, IN 47405 USA. EM manjmazu@iupui.edu FU National Institutes of Health (NIH), NCI, Center for Cancer Research; Indiana University FX We thank G. Almouzni, Institute Pasteur, Paris for providing the p150 CAF-1 and Asf1 antibodies, M. Bustin, NCI, NIH, USA for polyclonal histone H1 antibody, and P. Adams, Beatson Institute, Glasgow, UK, for monoclonal antibodies against HIRA. We thank C. Hassel, Indiana University Flow cytometry facility and S. Dasari for help with FACS analysis and K. Meaburn for help with FISH protocols. EM was performed by K. Nageshima at the NCI, EM facility. This research was in part supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research and by start-up funds from Indiana University. M. M. conceived, performed and analyzed most experiments. M-H.S. analyzed the microarray data. M. M. and T. M. consulted on data interpretation, M. M. and T. M wrote the manuscript. NR 48 TC 5 Z9 6 U1 2 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD NOV-DEC PY 2011 VL 2 IS 6 BP 591 EP 600 DI 10.4161/nucl.2.6.18044 PG 10 WC Cell Biology SC Cell Biology GA V28GM UT WOS:000208669300016 PM 22130187 ER PT J AU Siahanidou, T Garatzioti, M Lazaropoulou, C Papassotiriou, I Kino, T Nabeshima, YI Mandyla, H Chrousos, G AF Siahanidou, T. Garatzioti, M. Lazaropoulou, C. Papassotiriou, I. Kino, T. Nabeshima, Y. -I. Mandyla, H. Chrousos, G. TI CIRCULATING LEVELS OF KLOTHO IN PREMATURE AND TERM BABIES: CORRELATIONS WITH GROWTH AND METABOLIC PARAMETERS SO PEDIATRIC RESEARCH LA English DT Meeting Abstract C1 [Siahanidou, T.; Garatzioti, M.; Mandyla, H.; Chrousos, G.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. [Lazaropoulou, C.; Papassotiriou, I.] Aghia Sophia Childrens Hosp, Dept Clin Biochem, Athens, Greece. [Kino, T.] NICHD, NIH, PRAE, Bethesda, MD USA. [Nabeshima, Y. -I.] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, 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 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2011 VL 70 SU 5 MA 397 BP 397 EP 397 DI 10.1038/pr.2011.622 PG 1 WC Pediatrics SC Pediatrics GA V31FS UT WOS:000208870100398 ER PT J AU Greten, TF AF Greten, T. F. TI Improved Survival in Patients with NET of the Pancreas with Molecular Therapies SO ZEITSCHRIFT FUR GASTROENTEROLOGIE LA German DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0044-2771 EI 1439-7803 J9 Z GASTROENTEROL JI Z. Gastroent. PD NOV PY 2011 VL 49 IS 11 BP 1489 EP 1490 DI 10.1055/s-0031-1281595 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857IL UT WOS:000297711600021 PM 22069050 ER PT J AU Li, Y Li, ZH Graubard, BI AF Li, Yan Li, Zhaohai Graubard, Barry I. TI Testing for Hardy Weinberg Equilibrium in National Household Surveys that Collect Family-Based Genetic Data SO ANNALS OF HUMAN GENETICS LA English DT Article DE Complex sampling; condensed coefficients of identity; quasi-score test; survey data; Taylor linearization ID COMPLEX SURVEYS; ASSOCIATION; DISEQUILIBRIUM AB In population-based household surveys, for example, the National Health and Nutrition Examination Survey (NHANES), blood-related individuals are often sampled from the same household. Therefore, genetic data collected from national household surveys are often correlated due to two levels of clustering (correlation) with one induced by the multistage geographical cluster sampling, and the other induced by biological inheritance among multiple participants within the same sampled household. In this paper, we develop efficient statistical methods that consider the weighting effect induced by the differential selection probabilities in complex sample designs, as well as the clustering (correlation) effects described above. We examine and compare the magnitude of each level of clustering effects under different scenarios and identify the scenario under which the clustering effect induced by one level dominates the other. The proposed method is evaluated via Monte Carlo simulation studies and illustrated using the Hispanic Health and Nutrition Survey (HHANES) with simulated genotype data. C1 [Li, Yan] Univ Texas Arlington, Dept Math, Arlington, TX 76019 USA. [Li, Yan; Li, Zhaohai; Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Li, Y (reprint author), Univ Texas Arlington, Dept Math, 411 S Nedderman St, Arlington, TX 76019 USA. EM liyanna@uta.edu FU NIH [5RO1ESO16626] FX The authors are grateful to anonymous referees for their constructive comments. The research was partially supported by NIH grant 5RO1ESO16626. NR 26 TC 2 Z9 2 U1 1 U2 8 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 NOV PY 2011 VL 75 BP 732 EP 741 DI 10.1111/j.1469-1809.2011.00680.x PN 6 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 828PO UT WOS:000295514600010 PM 21972963 ER PT J AU Mackiewicz, M Huppi, K Pitt, JJ Dorsey, TH Ambs, S Caplen, NJ AF Mackiewicz, Mark Huppi, Konrad Pitt, Jason J. Dorsey, Tiffany H. Ambs, Stefan Caplen, Natasha J. TI Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE MicroRNAs; AXL; miR-34a; Triple negative; Breast cancer ID TUMOR-SUPPRESSOR NETWORK; GENE-EXPRESSION; DOWN-REGULATION; THERAPEUTIC TARGET; CELL-PROLIFERATION; C-MET; P53; APOPTOSIS; MIGRATION; METASTASIS AB The identification of molecular features that contribute to the progression of breast cancer can provide valuable insight into the pathogenesis of this disease. Deregulated microRNA expression represents one type of molecular event that has been associated with many different human cancers. In order to identify a miRNA/mRNA regulatory interaction that is biologically relevant to the triple-negative breast cancer genotype/phenotype, we initially conducted a miRNA profiling experiment to detect differentially expressed miRNAs in cell line models representing triple-negative (MDA-MB-231), ER(+) (MCF7), and HER-2 overexpressed (SK-BR-3) histotypes. We identified human miR-34a expression as being > 3-fold down (from its median expression value across all cell lines) in MDA-MB-231 cells, and identified AXL as a putative mRNA target using multiple miRNA/target prediction algorithms. The miR-34a/AXL interaction was functionally characterized through ectopic overexpression experiments with a miR-34a mimic in two independent triple-negative breast cancer cell lines. In reporter assays, miR-34a binds to its putative target site within the AXL 3'UTR to inhibit luciferase expression. We also observed degradation of AXL mRNA and decreased AXL protein levels, as well as cell signaling effects on AKT phosphorylation and phenotypic effects on cell migration. Finally, we present an inverse correlative trend in miR-34a and AXL expression for both cell line and patient tumor samples. C1 [Mackiewicz, Mark; Huppi, Konrad; Pitt, Jason J.; Caplen, Natasha J.] NCI, Genet Branch, Ctr Canc Res,Natl Canc Inst, NIH, Bethesda, MD 20892 USA. [Dorsey, Tiffany H.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Genet Branch, Ctr Canc Res,Natl Canc Inst, NIH, 37 Convent Dr,Bldg 37,Rm 6128, Bethesda, MD 20892 USA. EM mackiewiczm@mail.nih.gov; huppi@helix.nih.gov; pittjj@mail.nih.gov; howet@mail.nih.gov; ambss@mail.nih.gov; ncaplen@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU (Center for Cancer Research, NCI) of the NIH FX This research was supported by the Intramural Research Program (Center for Cancer Research, NCI) of the NIH. The authors thank Drs Stan Lipkowitz, Thomas Reid, Scott Martin, Philip Lorenzi, Amanda Hummon, Michael Difilippantonio, and Paul Meltzer for their useful comments and suggestions. The authors also thank Robert Cornelison, Diane Palmieri, Sarah Anzick, Kristen Gehlhaus, Tamara Jones, Lihui Ou, and Brady Wahlberg for their technical assistance. The authors greatly appreciate the gesture extended by Ashish Lal and Judy Lieberman (Harvard Medical School) in sharing their unpublished data on miR-34a/AXL targeting with us. Finally, the authors gratefully acknowledge the technical assistance that Subu Yerramilli (Qiagen) provided to us in regard to the qRT-PCR analysis of miR-34a primary, precursor, and mature transcripts. NR 58 TC 47 Z9 49 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2011 VL 130 IS 2 BP 663 EP 679 DI 10.1007/s10549-011-1690-0 PG 17 WC Oncology SC Oncology GA 830RY UT WOS:000295675700031 PM 21814748 ER PT J AU Dropulic, LK Cohen, JI AF Dropulic, Lesia K. Cohen, Jeffrey I. TI Severe Viral Infections and Primary Immunodeficiencies SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID LINKED LYMPHOPROLIFERATIVE-DISEASE; COMMON VARIABLE IMMUNODEFICIENCY; HERPES-SIMPLEX ENCEPHALITIS; B ESSENTIAL MODULATOR; NATURAL-KILLER-CELLS; BARR-VIRUS INFECTION; EPIDERMODYSPLASIA-VERRUCIFORMIS; HOST-DEFENSE; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; AUTOSOMAL-DOMINANT AB Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor-interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens. C1 [Dropulic, Lesia K.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Dropulic, LK (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike MSC 1888,Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM dropulicl@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 49 TC 12 Z9 12 U1 2 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD NOV 1 PY 2011 VL 53 IS 9 BP 897 EP 909 DI 10.1093/cid/cir610 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 830UW UT WOS:000295683700019 PM 21960712 ER PT J AU Gottfredsson, M Reynisson, IK Ingvarsson, RF Kristjansdottir, H Nardini, MV Sigurdsson, JF Schneerson, R Robbins, JB Miller, MA AF Gottfredsson, Magnus Reynisson, Ingi K. Ingvarsson, Ragnar F. Kristjansdottir, Hafrun Nardini, Martina V. Sigurdsson, Jon F. Schneerson, Rachel Robbins, John B. Miller, Mark A. TI Comparative Long-term Adverse Effects Elicited by Invasive Group B and C Meningococcal Infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID QUALITY-OF-LIFE; NEISSERIA-MENINGITIDIS; CAPSULAR POLYSACCHARIDE; BACTERIAL-MENINGITIS; PROSPECTIVE COHORT; N-CAM; DISEASE; ANTIBODIES; RISK; CLASSIFICATION AB Background. Given the identity between Neisseria meningitidis serogroup B (MenB) capsular polysaccharide (polysialic acid; PSA) and PSA found on neural cell adhesion molecules, it has been proposed that infection with MenB or vaccination with PSA may be associated with subsequent autoimmune or neurological disease. Methods. We conducted 2 studies. The first was a retrospective nationwide study of invasive meningococcal disease (IMD) in Iceland (with 541 subjects) during the period 1975-2004, and we cross referenced this cohort with databases with respect to subsequent diagnosis of autoimmune disorders. A follow-up study involving 120 survivors of IMD was performed. The study included 70 patients with a history of MenB and 50 patients with N. meningitidis serogroup C (MenC) infection, who served as control subjects. Participants answered standardized questionnaires (Beck's Depression Inventory [BDI] II, Depression Anxiety Stress Scales [DASS], and Patient Health Questionnaire [PHQ]), and serum levels of immunoglobulin (Ig) G against MenB and MenC capsular polysaccharides were measured. Results. The nationwide cohort had 9166 patient-years of follow up. No evidence of increased autoimmunity was found to be associated with MenB, compared with MenC. In the follow-up study, patients were evaluated 16.6 years after the infection, representing 2022 patient-years of observation. Comparable rates of most complications were recorded, but MenC infections were associated with arthritis (P = .008) and migraine headaches (P = .01) more frequently than were MenB infections. No difference was observed with respect to scores on BDI-II, DASS, or PHQ. IgG anti-MenB and anti-MenC capsular polysaccharide levels were not related to patient complaints. Conclusions. This study does not support the hypothesis that MenB infection may predispose to autoimmunity. MenC infections are associated with a higher prevalence of arthritis and migraine headaches. No evidence of antibody-associated pathology was detected at long-term follow-up. C1 [Gottfredsson, Magnus; Kristjansdottir, Hafrun; Nardini, Martina V.; Sigurdsson, Jon F.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Schneerson, Rachel; Robbins, John B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev & Mol Immun Lab, Bethesda, MD USA. [Gottfredsson, Magnus; Miller, Mark A.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Gottfredsson, M (reprint author), Landspitali Univ Hosp, Div Infect Dis, IS-108 Reykjavik, Iceland. EM magnusgo@landspitali.is RI Sigurdsson, Jon Fridrik/M-1844-2015; OI Sigurdsson, Jon Fridrik/0000-0001-6873-8157; Gottfredsson, Magnus/0000-0003-2465-0422 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Fogarty International Center, National Institutes of Health [MD-418614]; Fulbright Scholarship; Hafdis Hlif Bjornsdottir Memorial Fund 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, a Professional Services Contract from the Fogarty International Center, National Institutes of Health (grant MD-418614 to M. G.), a Fulbright Scholarship (to M. G.), and The Hafdis Hlif Bjornsdottir Memorial Fund (to M. G.). NR 34 TC 15 Z9 16 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD NOV 1 PY 2011 VL 53 IS 9 BP E117 EP E124 DI 10.1093/cid/cir500 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 830UW UT WOS:000295683700010 PM 21946191 ER PT J AU Raciti, GA Bera, TK Gavrilova, O Pastan, I AF Raciti, G. A. Bera, T. K. Gavrilova, O. Pastan, I. TI Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice SO DIABETOLOGIA LA English DT Article DE Ankrd26; Diabetes; Energy intake restriction; Insulin sensitivity; Obesity; WAT ID CALORIE RESTRICTION; GLUCOSE-TOLERANCE; TRANSGENIC MICE; WEIGHT-LOSS; OB/OB MICE; OBESITY; FAT; AMPHETAMINE; EXPRESSION; SECRETION AB Aims/hypothesis ANKRD26 is a newly described gene located at 10p12 in humans, a locus that has been identified with some forms of hereditary obesity. Previous studies have shown that partial inactivation of Ankrd26 in mice causes hyperphagia, obesity and gigantism. Hypothesising that Ankrd26 mutant (MT) mice could develop diabetes, we sought to establish whether the observed phenotype could be (1) solely related to the development of obesity or (2) caused by a direct action of ankyrin repeat domain 26 (ANKRD26) in peripheral tissues. Methods To test the hypothesis, we did a full metabolic characterisation of Ankrd26 MT mice that had free access to chow or were placed under two different energy-restricted dietary regimens. Results Highly obese Ankrd26 MT mice developed an unusual form of diabetes in which white adipose tissue is insulin-sensitive, while other tissues are insulin-resistant. When obese MT mice were placed on a food-restricted diet, their weight and glucose homeostasis returned to normal. In addition, when young MT mice were placed on a pair-feeding diet with normal mice, they maintained normal body weight, but showed better glucose tolerance than normal mice, an increased responsiveness of white adipose tissue to insulin and enhanced phosphorylation of the insulin receptor. Conclusions/interpretation These findings show that the ANKRD26 protein has at least two functions in mice. One is to control the response of white adipose tissue to insulin; the other is to control appetite, which when Ankrd26 is mutated, leads to hyperphagia and diabetes in an obesity-dependent manner. C1 [Raciti, G. A.; Bera, T. K.; Pastan, I.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gavrilova, O.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU NIH; NCI; Center for Cancer Research; NIDDK FX We thank W. Jou and T. Chanturiya (Mouse Metabolism Core, NIDDK) for invaluable technical support with the hyperinsulinaemic-euglycaemic clamp procedures. This research was supported in part by the Intramural Research Program of the NIH, the NCI, the Center for Cancer Research and in part by the NIDDK. NR 36 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2011 VL 54 IS 11 BP 2911 EP 2922 DI 10.1007/s00125-011-2263-9 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 830TJ UT WOS:000295679800019 PM 21842266 ER PT J AU Kramer-Marek, G Shenoy, N Seidel, J Griffiths, GL Choyke, P Capala, J AF Kramer-Marek, Gabriela Shenoy, Nalini Seidel, Jurgen Griffiths, Gary L. Choyke, Peter Capala, Jacek TI Ga-68-DOTA-Affibody molecule for in vivo assessment of HER2/neu expression with PET SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Affibody molecules; Molecular imaging; HER2/neu; PET; Ga-68 ID HER2-POSITIVE BREAST-CANCER; AFFIBODY MOLECULES; HER-2 OVEREXPRESSION; THERAPY; GA-68; CETUXIMAB; ANTIBODY; RECEPTOR; PROTEIN; TUMORS AB Purpose Overexpression of HER2/neu in breast cancer is correlated with a poor prognosis. It may vary between primary tumors and metastatic lesions and change during the treatment. Therefore, there is a need for a new means to assess HER2/neu expression in vivo. In this work, we used Ga-68-labeled DOTA-Z(HER2:2891)-Affibody to monitor HER2/neu expression in a panel of breast cancer xenografts. Methods DOTA-Z(HER2:2891)-Affibody molecules were labeled with Ga-68. In vitro binding was characterized by a receptor saturation assay. Biodistribution and PET imaging studies were conducted in athymic nude mice bearing subcutaneous human breast cancer tumors with three different levels of HER2/neu expression. Nonspecific uptake was analyzed using non-HER2-specific Affibody molecules. Signal detected by PET was compared with ex vivo assessment of the tracer uptake and HER2/neu expression. Results The Ga-68-DOTA-Z(HER2:2891)-Affibody probe showed high binding affinity to MDA-MB-361 cells (K (D) = 1.4 +/- 0.19 nM). In vivo biodistribution and PET imaging studies demonstrated high radioactivity uptake in HER2/neu-positive tumors. Tracer was eliminated quickly from the blood and normal tissues, resulting in high tumor-to-blood ratios. The highest concentration of radioactivity in normal tissue was seen in the kidneys (227 +/- 14%ID/g). High-contrast PET images of HER2/neu-overexpressing tumors were recorded as soon as 1 h after tracer injection. A good correlation was observed between PET imaging, biodistribution estimates of tumor tracer concentration, and the receptor expression. Conclusion These results suggest that PET imaging using Ga-68-DOTA-Z(HER2:2891)-Affibody is sensitive enough to detect different levels of HER2/neu expression in vivo. C1 [Seidel, Jurgen; Choyke, Peter; Capala, Jacek] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shenoy, Nalini; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. RP Capala, J (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov RI Shenoy, Nalini/O-2132-2013 FU Affibody AB; Center for Cancer Research of the National Cancer Institute; Imaging Probe Development Center; National Heart, Lung, and Blood Institute; Breast Cancer Research Stamp Fund; National Cancer Institute, National Institutes of Health [N01-CO-12400, N01-CO-12401] FX The authors appreciate the support of Affibody AB. We owe special thanks to Michael Green for constructive discussions. We also appreciate the technical assistance of Ilya Lyakhov, Monika Kuban, and Alesia Holly.; This research was supported in part by the Center for Cancer Research, an Intramural Research Program of the National Cancer Institute, the Imaging Probe Development Center, the National Heart, Lung, and Blood Institute, and the Breast Cancer Research Stamp Fund (awarded through competitive peer review), and was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contracts N01-CO-12400 and N01-CO-12401. NR 37 TC 25 Z9 27 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD NOV PY 2011 VL 38 IS 11 BP 1967 EP 1976 DI 10.1007/s00259-011-1810-4 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 830TN UT WOS:000295680200003 PM 21748382 ER PT J AU Gulley, JL Madan, RA Tsang, KY Arlen, PM Camphausen, K Mohebtash, M Kamrava, M Schlom, J Citrin, D AF Gulley, James L. Madan, Ravi A. Tsang, Kwong-Yok Arlen, Philip M. Camphausen, Kevin Mohebtash, Mahsa Kamrava, Mitchell Schlom, Jeffrey Citrin, Deborah TI A pilot safety trial investigating a vector-based vaccine targeting carcinoembryonic antigen in combination with radiotherapy in patients with gastrointestinal malignancies metastatic to the liver SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Article DE CEA/TRICOM; fowlpox; immunotherapy; poxviral vector; therapeutic vaccine; vaccinia ID REGULATORY T-CELLS; RESISTANT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; HUMAN-TUMOR-MARKER; IMMUNE-RESPONSES; RADIATION-THERAPY; IMMUNOLOGICAL RESPONSE; COLORECTAL-CARCINOMA; ANTITUMOR-ACTIVITY; DIVERSIFIED PRIME AB Objective: Previous studies have demonstrated the ability of non-lethal doses of radiation to alter the phenotype of tumor cells to facilitate immune mediated killing. This pilot study evaluated the tolerability of a vector-based vaccine targeting carcinoembryonic antigen (CEA) in combination with radiation therapy in patients with gastrointestinal malignancies metastatic to the liver. Methods: Patients enrolled had progressive CEA(+) tumors with metastatic liver lesions. Patients had received a median of three previous chemotherapy regimens, with a median of 2 months since their last chemotherapy regimen. Only 58% had metastatic disease limited to the liver. Vaccination commenced day 1 with biweekly boosters and split-course radiation (total 32 Gy) starting on day 21. Blood was collected at baseline and day 91 for immunological analysis. Results/conclusion: A total of 12 patients were enrolled. There were no grade 3 or greater toxicities or grade 2 or greater hepatic toxicities. Median time on-study was 3 months, with the longest time on treatment being 5 months (n = 2). Immunological analysis was limited to two patients; neither showed an increase above baseline in CEA-specific T cells post-therapy. CEA/TRICOM vaccination in combination with low-dose radiation therapy is safe. There was limited evidence of activity in this patient population. C1 [Gulley, James L.; Madan, Ravi A.; Tsang, Kwong-Yok; Arlen, Philip M.; Schlom, Jeffrey] NCI, NIH, Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Gulley, James L.; Madan, Ravi A.; Arlen, Philip M.; Mohebtash, Mahsa] NCI, NIH, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Camphausen, Kevin; Kamrava, Mitchell; Citrin, Deborah] NCI, NIH, Ctr Canc Res, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, NIH, Ctr Canc Res, Lab Tumor Immunol & Biol, 10 Ctr Dr,8B09 MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland FX This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The authors gratefully acknowledge the participation of patients and their families in this study, the assistance of the research fellows of the Medical Oncology Branch, NCI, and BL Casey for editorial assistance in the preparation of this manuscript. NR 55 TC 11 Z9 11 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD NOV PY 2011 VL 11 IS 11 BP 1409 EP 1418 DI 10.1517/14712598.2011.615741 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 829WM UT WOS:000295616200001 PM 21871012 ER PT J AU Khatami, M AF Khatami, Mahin TI Unresolved inflammation: 'immune tsunami' or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE acute and chronic inflammation; angiogenesis; autoimmune; cancer; BBB; CNS; cornea; dendritic cells; hyperplasia; immune-privilege; immune surveillance; immune tolerance; innate and adaptive immune cells; macrophages; mast cells; natural killer cells; neovascularization; neurodegenerative; neuroretina; tissue integrity ID ALLERGIC CONJUNCTIVITIS; FLUORESCEINYL OVALBUMIN; LANGERHANS CELLS; DENDRITIC CELLS; THERAPY; TOLERANCE; SYSTEM; BRAIN; ACTIVATION; RESOLUTION AB Introduction: Unresolved inflammation is loss of balance between two biologically opposing arms of acute inflammation, 'Yin' (tumoricidal) and 'Yang' (tumorigenic) processes that cause disruption of protective mechanisms of immune system. Areas covered: Hypothesis: Unresolved inflammation-induced exaggerated expression of apoptotic and/or wound healing mediators lead to fundamental erosion ('immune tsunami' or 'immune meltdown') of integrity in tissues that are naturally immune-responsive (immune surveillance); or immune-privileged (immune tolerance). 'Immune tsunami' refers to end results of acute or chronic immune dysfunction leading to inflammatory diseases or cancer. Acute inflammatory diseases including drug-induced cancer cachexia, would fit features of 'immune meltdown' that are otherwise described for end results of age-associated diseases. Pathogens induce rapid destruction of vascular integrity, gain access to tissues and cause excessive expression of apoptotic factors leading to multiple organ failure (MOF). Significant disruptions of immunological barriers and response shifts lead to chronic neurodegenerative and autoimmune diseases, tumor growth, malignancies and angiogenesis and loss of natural immune response balances. Expert opinion: Strategies to promote (stabilize) inherent properties of innate immune cells ('tumoricidal' versus 'tumorigenesis') that would influence polarization of adaptive immune (T or B) cells are key in reducing or preventing incidence of inflammatory and vascular diseases or cancer during aging process. C1 NCI, NIH, Bethesda, MD 20817 USA. RP Khatami, M (reprint author), NCI, NIH, Bethesda, MD 20817 USA. EM mkgoodness@aol.com NR 76 TC 12 Z9 12 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD NOV PY 2011 VL 11 IS 11 BP 1419 EP 1432 DI 10.1517/14712598.2011.592826 PG 14 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 829WM UT WOS:000295616200002 PM 21663532 ER PT J AU Shetty, RS Gallagher, CS Chen, YT Hims, MM Mull, J Leyne, M Pickel, J Kwok, D Slaugenhaupt, SA AF Shetty, Ranjit S. Gallagher, Cary S. Chen, Yei-Tsung Hims, Matthew M. Mull, James Leyne, Maire Pickel, James Kwok, David Slaugenhaupt, Susan A. TI Specific correction of a splice defect in brain by nutritional supplementation SO HUMAN MOLECULAR GENETICS LA English DT Article ID B KINASE COMPLEX; FAMILIAL DYSAUTONOMIA; MESSENGER-RNA; ELONGATOR COMPLEX; TRANSCRIPTIONAL ELONGATION; DISEASE; IKBKAP; PROTEIN; GENE; EXPRESSION AB Recent studies emphasize the importance of mRNA splicing in human genetic disease, as 20-30% of all disease-causing mutations are predicted to result in mRNA splicing defects. The plasticity of the mRNA splicing reaction has made these mutations attractive candidates for the development of therapeutics. Familial dysautonomia (FD) is a severe neurodegenerative disorder, and all patients have an intronic IVS2016T>C splice site mutation in the IKBKAP gene, which results in tissue-specific skipping of exon 20 and a corresponding reduction in ikappaB kinase complex associated protein (IKAP) levels. We created transgenic mouse lines using a human IKBKAP bacterial artificial chromosome (BAC) into which we inserted the IKBKAP splice mutation (FD BAC) and have shown that the transgenic mice exhibit the same tissue-specific aberrant splicing patterns as seen in FD patients. We have previously demonstrated that the plant cytokinin kinetin can significantly improve the production of wild-type IKBKAP transcripts in FD lymphoblast cell lines by improving exon inclusion. In this study, we tested the ability of kinetin to alter IKBKAP splicing in the transgenic mice carrying the FD BAC and show that it corrects IKBKAP splicing in all major tissues assayed, including the brain. The amount of wild-type IKBKAP mRNA and IKAP protein was significantly higher in the kinetin-treated mice. These exciting results prove that treatment of FD, as well as other mechanistically related splicing disorders, with kinetin holds great promise as a potential therapeutic aimed at increasing normal protein levels, which may, in turn, slow disease progression. C1 [Shetty, Ranjit S.; Gallagher, Cary S.; Chen, Yei-Tsung; Hims, Matthew M.; Mull, James; Leyne, Maire; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Shetty, Ranjit S.; Gallagher, Cary S.; Chen, Yei-Tsung; Hims, Matthew M.; Mull, James; Leyne, Maire; Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Pickel, James] NIMH, NIH, Bethesda, MD 20892 USA. [Kwok, David] BRI Biopharmaceut Res Inc, Vancouver, BC V6P 3S8, Canada. RP Slaugenhaupt, SA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5254, Boston, MA 02114 USA. EM slaugenhaupt@chgr.mgh.harvard.edu FU Dysautonomia Foundation, Inc; NIH [R01 NS36326, R21 NS R21NS058318]; Massachusetts General Hospital FX This work was supported by a grant from the Dysautonomia Foundation, Inc, and NIH (R01 NS36326 and R21 NS R21NS058318) to S. A. S. R. S. S. was supported by a Massachusetts General Hospital ECOR Fund for Medical Discovery Award. NR 46 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2011 VL 20 IS 21 BP 4093 EP 4101 DI 10.1093/hmg/ddr333 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000001 PM 21821670 ER PT J AU Cheng, H Khan, NW Roger, JE Swaroop, A AF Cheng, Hong Khan, Naheed W. Roger, Jerome E. Swaroop, Anand TI Excess cones in the retinal degeneration rd7 mouse, caused by the loss of function of orphan nuclear receptor Nr2e3, originate from early-born photoreceptor precursors SO HUMAN MOLECULAR GENETICS LA English DT Article ID CELL-FATE DETERMINATION; TEMPORAL EXPRESSION; ROD PHOTORECEPTORS; FACTOR NRL; MUTATIONS; GENE; DIFFERENTIATION; CRX; TRANSCRIPTION; OPSINS AB The orphan nuclear receptor NR2E3 is a direct transcriptional target of NRL, the key basic motif leucine zipper transcription factor that dictates rod versus cone photoreceptor cell fate in the mammalian retina. The lack of NR2E3 function in humans and in retinal degeneration rd7 mutant mouse leads to increased S-cones accompanied by rod degeneration, whereas ectopic expression of Nr2e3 in the cone-only Nrl(-/-) retina generates rod-like cells that do not exhibit any visual function. Using GFP to tag the newborn rods and by 5-bromo-2'-deoxyuridine birthdating, we demonstrate that early-born post-mitotic photoreceptor precursors in the rd7 retina express cone-specific genes. Transgenic mouse studies in the rd7 background show that Nr2e3 when expressed under the control of Crx promoter can restore rod photoreceptor function and suppress cone gene expression. Furthermore, Nr2e3 expression in photoreceptor precursors committed to be rods (driven by the Nrl promoter) could completely rescue the retinal phenotype of the rd7 mice. We conclude that excess of S-cones in the rd7 retina originate from photoreceptor precursors with a 'default' fate and not from proliferation of cones and that Nr2e3 is required to suppress the expression of S-cone genes during normal rod differentiation. These studies further support the 'transcriptional dominance' model of photoreceptor cell fate determination and provide insights into the pathogenesis of retinal disease phenotypes caused by NR2E3 mutations. C1 [Roger, Jerome E.; Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. [Cheng, Hong; Khan, Naheed W.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. RP Swaroop, A (reprint author), NEI, N NRL, NIH, Bldg 6-338,MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Roger, Jerome/0000-0002-5061-230X; Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute; National Institutes of Health [EY011115]; Foundation Fighting Blindness; Organogenesis Training Program [T-32-HD007505]; Michigan Diabetes Research and Training Center; Research to Prevent Blindness FX This research was supported by the intramural program of the National Eye Institute and by grants from the National Institutes of Health (EY011115), The Foundation Fighting Blindness, Research to Prevent Blindness, Organogenesis Training Program (T-32-HD007505) and Michigan Diabetes Research and Training Center. NR 61 TC 18 Z9 19 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2011 VL 20 IS 21 BP 4102 EP 4115 DI 10.1093/hmg/ddr334 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000002 PM 21813656 ER PT J AU Li, B Rauhauser, AA Dai, J Sakthivel, R Igarashi, P Jetten, AM Attanasio, M AF Li, Binghua Rauhauser, Alysha A. Dai, Julie Sakthivel, Ramanavelan Igarashi, Peter Jetten, Anton M. Attanasio, Massimo TI Increased hedgehog signaling in postnatal kidney results in aberrant activation of nephron developmental programs SO HUMAN MOLECULAR GENETICS LA English DT Article ID ZINC-FINGER PROTEIN; TRANSCRIPTION FACTOR; EPITHELIAL TRANSFORMATION; INCREASED APOPTOSIS; PAX-2 EXPRESSION; SONIC HEDGEHOG; MUTANT MICE; FLOOR PLATE; GLI2; SUPPRESSOR AB Hedgehog (Hh) is a core signaling pathway implicated in fundamental processes during embryonic kidney development. We previously found that loss-of-function mutations in the transcription factor GLIS2, a putative vertebrate ortholog of Drosophila Ci, cause nephronophthisis type 7 in humans and mice. Kidney tubular cells in Glis2-knockout mice acquire mesenchymal phenotype, but the cellular mechanisms of this transition are unknown. Here, we demonstrate that Glis2 is a functional component of Hh signaling and is necessary to suppress this pathway in the postnatal kidney. In the epithelial compartment, Glis2 opposes Gli1 activity by binding cis-acting regulatory sequences in the 5' flanking regions of Snai1 and Wnt4, thereby inhibiting de-differentiation of tubular cells. We conclude that Glis2 is necessary to inhibit Hh signaling and to maintain the mature tubular epithelial phenotype in the adult kidney. This is the first description of a molecular mechanism that links the Hh signaling pathway to cystic kidney diseases and can open new avenues for the treatment of diverse ciliopathies. C1 [Li, Binghua; Rauhauser, Alysha A.; Dai, Julie; Sakthivel, Ramanavelan; Igarashi, Peter; Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Growth & Dev, Dallas, TX 75390 USA. [Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Attanasio, M (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM massimo.attanasio@utsouthwestern.edu OI Jetten, Anton/0000-0003-0954-4445; Igarashi, Peter/0000-0001-8698-1185 FU ASN Carl W. Gottschalk Research Scholar Grant; NIH UT Southwestern O'Brien Kidney Research Core Center [P30DK079328-04] FX M.A. is supported by 2010 ASN Carl W. Gottschalk Research Scholar Grant and by NIH UT Southwestern O'Brien Kidney Research Core Center Grant (P30DK079328-04). NR 49 TC 13 Z9 14 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2011 VL 20 IS 21 BP 4155 EP 4166 DI 10.1093/hmg/ddr339 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000006 PM 21816948 ER PT J AU Garcia-Closas, M Ye, YQ Rothman, N Figueroa, JD Malats, N Dinney, CP Chatterjee, N Prokunina-Olsson, L Wang, ZM Lin, J Real, FX Jacobs, KB Baris, D Thun, M De Vivo, I Albanes, D Purdue, MP Kogevinas, M Kamat, AM Lerner, SP Grossman, HB Gu, J Pu, X Hutchinson, A Fu, YP Burdett, L Yeager, M Tang, W Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Johnson, A Schwenn, M Karagas, MR Schned, A Andriole, G Grubb, R Black, A Jacobs, EJ Diver, WR Gapstur, SM Weinstein, SJ Virtamo, J Hunter, DJ Caporaso, N Landi, MT Fraumeni, JF Silverman, DT Chanock, SJ Wu, XF AF Garcia-Closas, Montserrat Ye, Yuanqing Rothman, Nathaniel Figueroa, Jonine D. Malats, Nuria Dinney, Colin P. Chatterjee, Nilanjan Prokunina-Olsson, Ludmila Wang, Zhaoming Lin, Jie Real, Francisco X. Jacobs, Kevin B. Baris, Dalsu Thun, Michael De Vivo, Immaculata Albanes, Demetrius Purdue, Mark P. Kogevinas, Manolis Kamat, Ashish M. Lerner, Seth P. Grossman, H. Barton Gu, Jian Pu, Xia Hutchinson, Amy Fu, Yi-Ping Burdett, Laurie Yeager, Meredith Tang, Wei Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison Schwenn, Molly Karagas, Margaret R. Schned, Alan Andriole, Gerald, Jr. Grubb, Robert, III Black, Amanda Jacobs, Eric J. Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie J. Virtamo, Jarmo Hunter, David J. Caporaso, Neil Landi, Maria Teresa Fraumeni, Joseph F., Jr. Silverman, Debra T. Chanock, Stephen J. Wu, Xifeng TI A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3 SO HUMAN MOLECULAR GENETICS LA English DT Article ID CONFERS SUSCEPTIBILITY; RECOMBINATION HOTSPOTS; SEQUENCE VARIANT; RISK; PHENOTYPE; METAANALYSIS; GENOTYPE; FAMILY; DEFECT; GSTM1 AB Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2) = 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis. C1 [Garcia-Closas, Montserrat; Rothman, Nathaniel; Figueroa, Jonine D.; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fu, Yi-Ping; Tang, Wei; Black, Amanda; Weinstein, Stephanie J.; Caporaso, Neil; Landi, Maria Teresa; Fraumeni, Joseph F., Jr.; Silverman, Debra T.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Ye, Yuanqing; Lin, Jie; Gu, Jian; Pu, Xia; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Malats, Nuria; Real, Francisco X.] Spanish Natl Canc Res Ctr, Madrid, Spain. [Dinney, Colin P.; Kamat, Ashish M.; Grossman, H. Barton] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Wang, Zhaoming; Jacobs, Kevin B.; Hutchinson, Amy; Burdett, Laurie; Yeager, Meredith] SAIC Frederick Inc, Core Genotype Facil, Natl Canc Inst Frederick, Frederick, MD USA. [Real, Francisco X.; Serra, Consol; Lloreta, Josep] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Thun, Michael; Jacobs, Eric J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Kogevinas, Manolis] Ctr Recerca Epidemiol Ambiental CREAL, Barcelona, Spain. [Kogevinas, Manolis; Lloreta, Josep] Parc Salut Mar Inst Municipal Invest Med IMIM, Barcelona, Spain. [Kogevinas, Manolis; Tardon, Adonina] CIBER Epidemio & Salud Publ CIBERESP, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Lerner, Seth P.] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Carrato, Alfredo] Ramon & Cajal Univ Hosp, Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Karagas, Margaret R.] Dartmouth Coll, Hanover, NH 03755 USA. [Andriole, Gerald, Jr.; Grubb, Robert, III] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Schned, Alan; Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. RP Garcia-Closas, M (reprint author), Inst Canc Res, Epidemiol Sect, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM montse.garciaclosas@icr.ac.uk RI Pu, Xia/H-2670-2012; Tang, Wei/H-7103-2013; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Albanes, Demetrius/B-9749-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Purdue, Mark/C-9228-2016; Kogevinas, Manolis/C-3918-2017 OI Tang, Wei/0000-0002-7089-4391; Serra, C/0000-0001-8337-8356; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Lloreta, J/0000-0003-1644-9470; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Purdue, Mark/0000-0003-1177-3108; FU National Institutes of Health [HHSN261200800001E, HHSN26820 0782096C]; National Cancer Institute; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [NCI N02-CP-11015, NCI N02-CP-01037]; FIS/Spain [98/1274, 00/0745, PI061614, G03/174]; Fundacio Marato TV3; Red Tematica Investigacion Cooperativa en Cancer (RTICC); Consolider ONCOBIO; EU [201663, RO1-CA089715, CA34627]; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01]; Johns Hopkins University Center for Inherited Disease Research [U01HG004438]; Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health FX The NCI bladder cancer GWAS was supported by the intramural research program of the National Institutes of Health, National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.; SBCS (D. T. S., N.R., S.J.C., M. G. C.)-Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614 and G03/174, Fundacio Marato TV3, Red Tematica Investigacion Cooperativa en Cancer (RTICC), Consolider ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627.; NEBCS (D. T. S.)-Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-01037.; PLCO (M. P. P)-the NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN26820 0782096C) and study coordination at the GENEVA (N.C.)-The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health.; ATBC (D. A.)-this research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U. S. Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services.; TXBCS1 & TXBCS2-U01 CA 127615 (X. W.), R01 CA 74880 (X. W.) and P50 CA 91846 (X. W., C. P. D.), UT MD Anderson Cancer Centre Research Trust (X. W.), Centre for Translational and Public Health Genomics at MD Anderson Cancer Centre.; NHS & HPFS (I. D. V.)-CA055075 and CA087969. NR 28 TC 43 Z9 44 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2011 VL 20 IS 21 BP 4282 EP 4289 DI 10.1093/hmg/ddr342 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000017 PM 21824976 ER PT J AU Kuningas, M Estrada, K Hsu, YH Nandakumar, K Uitterlinden, AG Lunetta, KL van Duijn, CM Karasik, D Hofman, A Murabito, J Rivadeneira, F Kiel, DP Tiemeier, H AF Kuningas, Maris Estrada, Karol Hsu, Yi-Hsiang Nandakumar, Kannabiran Uitterlinden, Andre G. Lunetta, Kathryn L. van Duijn, Cornelia M. Karasik, David Hofman, Albert Murabito, Joanne Rivadeneira, Fernando Kiel, Douglas P. Tiemeier, Henning TI Large common deletions associate with mortality at old age SO HUMAN MOLECULAR GENETICS LA English DT Article ID COPY NUMBER VARIATION; RARE CHROMOSOMAL DELETIONS; GENOME-WIDE ASSOCIATION; HUMAN LONGEVITY; BIPOLAR DISORDER; GENE-EXPRESSION; CELL CARCINOMA; INCREASE RISK; LIFE-SPAN; SCHIZOPHRENIA AB Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (>= 500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02-1.07, P = 5.82 x 10(-5)] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31-1.93, P = 2.87 x 10(-6)) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19-2.07, P = 1.53 x 10(-3)) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality. C1 [Kuningas, Maris; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Hofman, Albert; Tiemeier, Henning] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Estrada, Karol; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Psychiat, NL-3000 CA Rotterdam, Netherlands. [Hsu, Yi-Hsiang; Nandakumar, Kannabiran; Karasik, David; Kiel, Douglas P.] Hebrew Senior Life Inst Aging Res, Boston, MA 02131 USA. [Hsu, Yi-Hsiang; Nandakumar, Kannabiran; Karasik, David; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA 02131 USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA 02115 USA. [Uitterlinden, Andre G.; van Duijn, Cornelia M.; Hofman, Albert; Rivadeneira, Fernando; Tiemeier, Henning] Netherlands Genom Initiat NGI Sponsored Netherlan, NL-2300 RC Leiden, Netherlands. [Lunetta, Kathryn L.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Murabito, Joanne] Boston Univ, Gen Internal Med Sect, Dept Med, Sch Med, Boston, MA 02118 USA. [Murabito, Joanne] Boston Univ, Sect Prevent Med, Dept Med, Sch Med, Boston, MA 02118 USA. [Murabito, Joanne] Boston Univ, Sect Cardiol & Neurol, Dept Med, Sch Med, Boston, MA 02118 USA. [Murabito, Joanne] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA 01702 USA. RP Kuningas, M (reprint author), Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. EM m.kuningas@erasmusmc.nl RI Rivadeneira, Fernando/O-5385-2015; OI Murabito, Joanne/0000-0002-0192-7516; Lunetta, Kathryn/0000-0002-9268-810X; Tiemeier, Henning/0000-0002-4395-1397; Kiel, Douglas/0000-0001-8474-0310; Rivadeneira, Fernando/0000-0001-9435-9441; Karasik, David/0000-0002-8826-0530 FU Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810;]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization of Scientific Research NWO [175.010.2005.011, 911-03-012, 017-106-370 VIDI]; US National Institute for Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [R01 AR/AG 41398, R01 AR 050066, R01 AG 29451]; Hebrew SeniorLife Men's Associate; National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This work was supported by the Research Institute for Diseases in the Elderly (grant number 014-93-015; RIDE2); and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project (grant number 050-060-810; NCHA), Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organization of Scientific Research NWO Investments (grant numbers 175.010.2005.011, 911-03-012 and 017-106-370 VIDI to H. T.). The FHS was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398 D. P. K.; R01 AR 050066 D. K.; R01 AG 29451 J.M. and K. L. L.) and Hebrew SeniorLife Men's Associate. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 40 TC 16 Z9 17 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2011 VL 20 IS 21 BP 4290 EP 4296 DI 10.1093/hmg/ddr340 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000018 PM 21835882 ER PT J AU Bar-Yehuda, S Luger, D Ochaion, A Cohen, S Patokaa, R Zozulya, G Silver, PB De Morales, JMGR Caspi, RR Fishman, P AF Bar-Yehuda, Sara Luger, Dror Ochaion, Avivit Cohen, Shira Patokaa, Renana Zozulya, Galina Silver, Phyllis B. De Morales, Jose Maria Garcia Ruiz Caspi, Rachel R. Fishman, Pnina TI Inhibition of experimental auto-immune uveitis by the A3 adenosine receptor agonist CF101 SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE CF101; A3 adenosine receptor; uveitis; inflammation ID RETINAL GANGLION-CELLS; PSEUDOEXFOLIATION SYNDROME; IN-VIVO; EXPRESSION; STIMULATION; INDUCTION; THERAPY; IL-10; GAMMA; RATS AB Uveitis is an inflammation of the middle layer of the eye with a high risk of blindness. The Gi protein associated A(3) adenosine receptor (A(3)AR) is highly expressed in inflammatory cells whereas low expression is found in normal cells. CF101 is a highly specific agonist at the A(3)AR known to induce a robust anti-inflammatory effect in different experimental animal models. The CF101 mechanism of action entails down-regulation of the NF-kappa B-TNF-alpha signaling pathway, resulting in inhibition of pro-inflammatory cytokine production and apoptosis of inflammatory cells. In this study the effect of CF101 on the development of retinal antigen interphotoreceptor retinoid-binding protein (IRBP)-induced experimental autoimmune uveitis (EAU) was assessed. Oral treatment with CF101 (10 mu g/kg, twice daily), initiated upon disease onset, improved uveitis clinical score measured by fundoscopy and ameliorated the pathological manifestations of the disease. Shortly after treatment with CF101 A(3)AR expression levels were down-regulated in the lymph node and spleen cells pointing towards receptor activation. Downstream events included a decrease in PI3K and STAT-1 and proliferation inhibition of IRPB auto-reactive T cells ex vivo. Inhibition of interleukin-2, tumor necrosis factor-alpha (TINF-alpha) and interferon-gamma (IFN-gamma) production and up-regulation of interleukin-10 was found in cultured splenocytes derived from CF101-treated animals. Overall, the present study data point towards a marked anti-inflammatory effect of CF101 in EAU and support further exploration of this small molecule drug for the treatment of uveitis. C1 [Luger, Dror; Silver, Phyllis B.; De Morales, Jose Maria Garcia Ruiz; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bar-Yehuda, Sara; Ochaion, Avivit; Cohen, Shira; Patokaa, Renana; Zozulya, Galina; Fishman, Pnina] Can Fite BioPharma, Petah Tiqwa, Israel. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS [ZIA EY000184-28, Z99 EY999999] NR 27 TC 29 Z9 29 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD NOV PY 2011 VL 28 IS 5 BP 727 EP 731 DI 10.3892/ijmm.2011.753 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 827IQ UT WOS:000295422600007 PM 21887476 ER PT J AU Percy, DB Ribot, EJ Chen, Y McFadden, C Simedrea, C Steeg, PS Chambers, AF Foster, PJ AF Percy, Dean B. Ribot, Emeline J. Chen, Yuhua McFadden, Catherine Simedrea, Carmen Steeg, Patricia S. Chambers, Ann F. Foster, Paula J. TI In Vivo Characterization of Changing Blood-Tumor Barrier Permeability in a Mouse Model of Breast Cancer Metastasis A Complementary Magnetic Resonance Imaging Approach SO INVESTIGATIVE RADIOLOGY LA English DT Article DE MRI; brain metastasis; blood-brain barrier; breast cancer; permeability; gadolinium ID EXPERIMENTAL BRAIN METASTASES; GADOPENTETATE DIMEGLUMINE; NUDE-MICE; RAT MODEL; 3 TESLA; GLIOMA; MRI; GADOBUTROL; CELLS; MDA-MB-231 AB Objectives: The current lack of efficacy for any chemo- or molecular therapeutic in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the blood-brain-barrier (BBB). Little is known about how heterogeneous permeability develops, or how it varies among individual metastases. Understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies. In this article, we developed the first magnetic resonance imaging-based strategy to detect and measure the volumes of BBB permeable and nonpermeable metastases and studied the development of altered BBB permeability in metastases in vivo, over time in a mouse model of breast cancer metastasis to the brain. Materials and Methods: Animals bearing human experimental brain metastases of breast cancer (231-BR cells) were imaged, using 3-dimensional balanced steady-state free precession to visualize total metastases, and contrast-enhanced T1-weighted spin echo with gadopentetic acid (GdDTPA) to visualize which of these displayed contrast enhancement, as Gd-DTPA leakage is indicative of altered BBB permeability. Results: Metastases detected 20 days after injection showed no Gd-DTPA enhancement. At day 25, 6.1% +/- 6.3% (mean +/- standard deviation) of metastases enhanced, and by day 30, 28.1% +/- 14.2% enhanced (P < 0.05). Enhancing metastases (mid: 0.14 +/- 0.18 mm(3), late: 0.24 +/- 0.32 mm(3)) had larger volumes than nonenhancing (mid: 0.04 +/- 0.04 mm(3), late: 0.09 +/- 0.09 mm(3), P < 0.05); however, there was no significant difference between the growth rates of the 2. Conclusions: A significant number of brain metastases were uniformly nonpermeable, which highlights the need for developing treatment strategies that can overcome the permeability of the BBB. The model developed herein can provide the basis for in vivo evaluation of both BBB permeable and nonpermeable metastases response to therapy. C1 [Percy, Dean B.; Ribot, Emeline J.; Chen, Yuhua; McFadden, Catherine; Foster, Paula J.] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada. [Simedrea, Carmen; Chambers, Ann F.] London Reg Canc Program, London, ON, Canada. [Steeg, Patricia S.] NCI, Womens Cancers Sect, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Foster, PJ (reprint author), Univ Western Ontario, Robarts Res Inst, 100 Perth St, London, ON N6A 5K8, Canada. EM pfoster@imaging.robarts.ca RI Foster, Paula/M-2201-2013; Chambers, Ann/L-6285-2015 OI Foster, Paula/0000-0002-4868-3395; Chambers, Ann/0000-0002-9509-5123 FU US Department of Defense [W81XWH-06-2-0033]; Canadian Institute of Health Research; University of Western Ontario; Canada Research Chairs Program; NCI FX Supported by the US Department of Defense Breast Cancer Research Program (grant W81XWH-06-2-0033 to PSS, AFC, and PJF). Funded by the Canadian Institute of Health Research and the University of Western Ontario (to D.B.P.). Ann F. Chambers is Canada Research Chair in Oncology and receives salary support from the Canada Research Chairs Program. Funded by the Intramural research program of the NCI (to P.S.S.). NR 45 TC 34 Z9 35 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD NOV PY 2011 VL 46 IS 11 BP 718 EP 725 DI 10.1097/RLI.0b013e318226c427 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832TK UT WOS:000295830600008 PM 21788908 ER PT J AU Hrobjartsson, A Kaptchuk, TJ Miller, FG AF Hrobjartsson, Asbjorn Kaptchuk, Ted J. Miller, Franklin G. TI Placebo effect studies are susceptible to response bias and to other types of biases SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Placebo; Placebo effect; Response bias; Bias; Randomized trial; Experiment ID RANDOMIZED CONTROLLED-TRIAL; IRRITABLE-BOWEL-SYNDROME; POWERFUL PLACEBO; COMPARING PLACEBO; INFORMED-CONSENT; CLINICAL-TRIALS; NO TREATMENT; PAIN; ANALGESIA; ACUPUNCTURE AB Objective: Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo. Study Design and Setting: A methodological analysis and discussion. Results: The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients' reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments. Conclusions: Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hrobjartsson, Asbjorn] Rigshosp, Nord Cochrane Ctr, DK-2100 Copenhagen, Denmark. [Kaptchuk, Ted J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Hrobjartsson, A (reprint author), Rigshosp, Nord Cochrane Ctr, DK-2100 Copenhagen, Denmark. EM ah@cochrane.dk FU NCCAM-NIH [K24 AT004095] FX This study was supported by NCCAM-NIH grant # K24 AT004095 funded T.J.K. for work on this analysis. Kong Jian provided valuable feedback. NR 40 TC 42 Z9 43 U1 1 U2 23 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 NOV PY 2011 VL 64 IS 11 BP 1223 EP 1229 DI 10.1016/j.jclinepi.2011.01.008 PG 7 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 829SQ UT WOS:000295605000009 PM 21524568 ER PT J AU Embree, M Ono, M Kilts, T Walker, D Langguth, J Mao, J Bi, Y Barth, JL Young, M AF Embree, M. Ono, M. Kilts, T. Walker, D. Langguth, J. Mao, J. Bi, Y. Barth, J. L. Young, M. TI Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE temporomandibular disorders; osteoclasts; matrix biology; bone biology osteoarthritis; cartilage ID TEMPOROMANDIBULAR-JOINT OSTEOARTHRITIS; GENE-EXPRESSION; MICE DEFICIENT; IX COLLAGEN; CARTILAGE; BIOLOGY; PROTEIN; CHONDROGENESIS; FIBROMODULIN; BIGLYCAN AB Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease that affects both cartilage and subchondral bone. We used microarray to identify changes in gene expression levels in the TMJ during early stages of the disease, using an established TMJ OA genetic mouse model deficient in 2 extracellular matrix proteins, biglycan and fibromodulin (bgn(-/0)fmod(-/-)). Differential gene expression analysis was performed with RNA extracted from 3-week-old WT and bgn(-/0)fmod(-/) TMJs with an intact cartilage/subchondral bone interface. In total, 22 genes were differentially expressed in bgn(-/0)fmod(-/-) TMJs, including 5 genes involved in osteoclast activity/differentiation. The number of TRAP-positive cells were three-fold higher in bgn(-/0)fmod(-/-) TMJs than in WT. Quantitative RT-PCR showed up-regulation of RANKL and OPG, with a 128% increase in RANKL/OPG ratio in bgn(-/0)fmod(-/-) TMJs. Histology and immunohistochemistry revealed tissue disorganization and reduced type I collagen in bgn(-/0)fmod(-/-) TMJ subchondral bone. Early changes in gene expression and tissue defects in young bgn(-/0)fmod(-/-) TMJ subchondral bone are likely attributed to increased osteoclast activity. Analysis of these data shows that biglycan and fibromodulin are critical for TMJ subchondral bone integrity and reveal a potential role for TMJ subchondral bone turnover during the initial early stages of TMJ OA disease in this model. C1 [Embree, M.; Ono, M.; Kilts, T.; Walker, D.; Langguth, J.; Bi, Y.; Young, M.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Embree, M.; Mao, J.] Columbia Univ, Med Ctr, Ctr Craniofacial Regenerat, New York, NY 10032 USA. [Barth, J. L.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. RP Young, M (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. EM myoung@dir.nidcr.nih.gov FU NIDCR [5F30 DE018072-04]; Division of Intramural Research, NIDCR; NIH; NIH/NIDCR [RC2DE020767]; NCRR [RR16434, RR16461] FX This investigation was supported by NIDCR grant 5F30 DE018072-04, the Division of Intramural Research, NIDCR, the Intramural Research Program, NIH, and NIH/NIDCR grant RC2DE020767. Microarray and bioinformatic resources of the MUSC Proteogenomics Facility were supported by NCRR grants RR16434 and RR16461. We thank Victor Fresco at MUSC for technical assistance with microarray experimentation and Ms. Qiongfen Guo at Columbia University for laboratory assistance. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 34 TC 18 Z9 18 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1331 EP 1338 DI 10.1177/0022034511421930 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600012 PM 21917603 ER PT J AU Pugach, MK Ozer, F Li, Y Sheth, K Beasley, R Resnick, A Daneshmehr, L Kulkarni, AB Bartlett, JD Gibson, CW Lindemeyer, RG AF Pugach, M. K. Ozer, F. Li, Y. Sheth, K. Beasley, R. Resnick, A. Daneshmehr, L. Kulkarni, A. B. Bartlett, J. D. Gibson, C. W. Lindemeyer, R. G. TI The Use of Mouse Models to Investigate Shear Bond Strength in Amelogenesis Imperfecta SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE enamel; acid-etching; amelogenesis imperfecta; shear bond strength; amelogenin; matrix metalloproteinase-20 ID CONSERVATIVE TREATMENT; MICE DISPLAY; PHENOTYPE; MUTATION; ENAMEL; RESTORATIONS AB Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knockout (AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI. C1 [Lindemeyer, R. G.] Univ Penn, Sch Dent Med, Div Pediat Dent, Philadelphia, PA 19104 USA. [Pugach, M. K.; Li, Y.; Sheth, K.; Beasley, R.; Resnick, A.; Gibson, C. W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Ozer, F.; Daneshmehr, L.] Univ Penn, Sch Dent Med, Dept Prevent & Restorat Sci, Philadelphia, PA 19104 USA. [Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Bartlett, J. D.] Harvard Univ, Sch Dent Med, Dept Cytokine Biol, Forsyth Inst, Cambridge, MA 02142 USA. [Bartlett, J. D.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Cambridge, MA 02142 USA. RP Lindemeyer, RG (reprint author), Univ Penn, Sch Dent Med, Div Pediat Dent, 240 S 40th St, Philadelphia, PA 19104 USA. EM lindemey@dental.upenn.edu FU National Institute of Dental and Craniofacial Research (National Institutes of Health) [DE011089, DE019968, DE016276] FX The authors acknowledge Z. Nelson and A. Clark for assistance with sample preparation, B. Winkelstein and Y. Shimada for technical discussions, M. Blatz for clinical insights, and the National Institute of Dental and Craniofacial Research (National Institutes of Health) grants DE011089, DE019968, and DE016276 for supporting this study. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 29 TC 1 Z9 1 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1352 EP 1357 DI 10.1177/0022034511421929 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600015 PM 21917602 ER PT J AU Amodio, E Valentini, M Gori-Savellini, G Valenti, RM Romano, N Goedert, JJ Cusi, MG AF Amodio, Emanuele Valentini, Melissa Gori-Savellini, Gianni Valenti, Rosalia Maria Romano, Nino Goedert, James J. Cusi, Maria Grazia TI Prevalence of Toscana and Sicilian Phlebovirus Antibodies in Classic Kaposi Sarcoma Case Patients and Control Subjects in Sicily SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-HERPESVIRUS-8; SEROPREVALENCE; TRANSMISSION; HERPESVIRUS; VIRUS; BITES AB To assess whether arthropod bites promote Kaposi sarcoma (KS), we determined the seroprevalence of Sicilian (SFSV) and Toscana (TOSV) phlebovirus antibodies in 30 patients with classic KS and 100 controls in Sicily. Nine (6.9%) subjects, all controls, were positive for SFSV, whereas 41 (31.5%) were positive for TOSV. Seroprevalence with immunoglobulin (Ig) M or IgG against either virus was significantly higher in controls (43% vs 13.3% in case patients; P < .01). Adjusted for age, IgG seroprevalence was significantly lower in KS patients compared to controls (adjusted odds ratio, 0.22; 95% confidence interval, .07-.72). Low phlebovirus seroprevalence in patients with KS may reflect incapacity to produce robust, persistent antibody responses, and suggests that arthropod bites do not promote KS. C1 [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Valentini, Melissa; Gori-Savellini, Gianni; Cusi, Maria Grazia] Univ Siena, Microbiol Sect, Dept Mol Biol, I-53100 Siena, Italy. [Amodio, Emanuele; Valenti, Rosalia Maria; Romano, Nino] Univ Palermo, Dept Sci Hlth Promot G DAlessandro, I-90133 Palermo, Italy. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Rm 7068,MSC 7248, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov OI Gori Savellini, Gianni/0000-0003-2287-9258 FU National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 19 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2011 VL 204 IS 9 BP 1423 EP 1426 DI 10.1093/infdis/jir546 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 828NS UT WOS:000295509300016 PM 21900487 ER PT J AU Christodoulou-Smith, J Gold, JI Romero, R Goodwin, TM MacGibbon, KW Mullin, PM Fejzo, MS AF Christodoulou-Smith, Joan Gold, Jeffrey I. Romero, Roberto Goodwin, Thomas M. MacGibbon, Kimber W. Mullin, Patrick M. Fejzo, Marlena S. TI Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Nausea; pregnancy; posttraumatic stress disorder ID WERNICKES ENCEPHALOPATHY; PSYCHOLOGICAL-FACTORS; LARGE COHORT; WOMEN; OUTCOMES AB Objective. Hyperemesis gravidarum (HG) can be accompanied by severe physical and emotional distress. Most studies have focused on the physical and psychological stress associated with this condition during the affected pregnancy. This study explores posttraumatic stress symptoms (PTSS) and negative life outcomes following HG pregnancies. Methods. A total of 610 women (HG - 377 and control - 233) were recruited and completed an online survey. chi-square analyses were used to compare the HG and control groups on various life outcome variables. Results. Eighteen percent of women with HG reported full criteria PTSS (n = 68). Negative life outcomes regarding financial and marital status, career, as well as psychological and physical well-being differed significantly for the HG groups compared to the control group (0.001 < p < 0.05). Conclusions. PTSS is common following HG pregnancies and is associated with negative life outcomes including inability to breastfeed, marital problems, financial problems, and inability of self care. C1 [Goodwin, Thomas M.; Mullin, Patrick M.; Fejzo, Marlena S.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Fejzo, Marlena S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [MacGibbon, Kimber W.] Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Christodoulou-Smith, Joan; Gold, Jeffrey I.] Childrens Hosp Los Angeles, Dept Anesthesiol, Los Angeles, CA 90027 USA. [Gold, Jeffrey I.] Univ So Calif, Keck Sch Med, Dept Anesthesiol, Los Angeles, CA 90033 USA. [Gold, Jeffrey I.] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90033 USA. [Romero, Roberto] NIHD, NIH, DHHS, Perinatol Res Branch, Bethesda, MD USA. [Romero, Roberto] NIHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, NIH, Detroit, MI USA. RP Fejzo, MS (reprint author), Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. EM nvpstudy@usc.edu OI MacGibbon, Kimber/0000-0002-6534-3114 FU Intramural NIH HHS [ZIA HD002401-17] NR 22 TC 11 Z9 11 U1 1 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD NOV PY 2011 VL 24 IS 11 BP 1307 EP 1311 DI 10.3109/14767058.2011.582904 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 829XL UT WOS:000295619500001 PM 21635201 ER PT J AU Foreman, JE Chang, WCL Palkar, PS Zhu, BK Borland, MG Williams, JL Kramer, LR Clapper, ML Gonzalez, FJ Peters, JM AF Foreman, Jennifer E. Chang, Wen-Chi L. Palkar, Prajakta S. Zhu, Bokai Borland, Michael G. Williams, Jennie L. Kramer, Lance R. Clapper, Margie L. Gonzalez, Frank J. Peters, Jeffrey M. TI Functional Characterization of Peroxisome Proliferator-Activated Receptor-beta/delta Expression in Colon Cancer SO MOLECULAR CARCINOGENESIS LA English DT Article DE apoptosis; clonogenicity; tumorigenicity ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PPAR-DELTA; DIFFERENTIAL EXPRESSION; ACROMEGALIC PATIENTS; REVERSE CHOLESTEROL; GENETIC DISRUPTION; LIGAND ACTIVATION; LIPID-METABOLISM; POLYP FORMATION; CELL APOPTOSIS AB This study critically examined the role of PPAR beta/delta in colon cancer models. Expression of PPAR beta/delta mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc(+/Min-FCCC) mice compared to control tissue. Dietary administration of sulindac to Apc(+/Min-FCCC) mice had no influence on expression of PPAR beta/delta in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3 epsilon was not influenced in human colon cancer cell lines cultured with the PPAR beta/delta ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPAR beta/delta following treatment with hydrogen peroxide, this change was associated with an increase in late apoptotic/necrotic cells, but not an increase in viable cells. Stable over-expression of PPAR beta/delta in human colon cancer cell lines enhanced ligand activation of PPAR beta/delta and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPAR beta/delta is lower in human and Apc(+/Min-FCCC) mouse colon tumors than in corresponding normal tissue, consistent with the finding that increasing expression and activation of PPAR beta/delta in human colon cancer cell lines inhibits clonogenicity. Because ligand-induced attenuation of early apoptosis can be associated with more late, apoptotic/necrotic cells, but not more viable cells, these studies illustrate why more comprehensive analysis of PPAR beta/delta-dependent modulation of apoptosis is required in the future. (C) 2011 Wiley Periodicals, Inc. C1 [Foreman, Jennifer E.; Palkar, Prajakta S.; Zhu, Bokai; Borland, Michael G.; Kramer, Lance R.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Foreman, Jennifer E.; Palkar, Prajakta S.; Zhu, Bokai; Borland, Michael G.; Kramer, Lance R.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Chang, Wen-Chi L.; Clapper, Margie L.] Fox Chase Canc Ctr, Canc Prevent & Control Program, Philadelphia, PA 19111 USA. [Williams, Jennie L.] SUNY Stony Brook, Canc Prevent Lab, Stony Brook, NY 11794 USA. [Gonzalez, Frank J.] Natl Canc Inst, Lab Metab, Bethesda, MD USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. FU [CA97999]; [CA124533]; [CA126826]; [CA141029]; [CA 140369]; [CA006927]; [CA129467]; [CA140487] FX We gratefully acknowledge Dr. Andrew Billin and Dr. Timothy Willson for providing the GW0742, Elaine Kunze, Susan Magargee, and Nicole Bem from the Center for Quantitative Cell Analysis at the Huck Institutes of Life Sciences of The Pennsylvania State University for their technical support with flow cytometry and data analysis, and Daniel Beard from the Penn State Hershey Cancer Institute Tissue Bank for providing the human tissue samples, and the Laboratory Animal Facility and the Genomics Facility at Fox Chase Cancer Center. This work was supported in part by CA97999, CA124533, CA126826, CA141029, CA 140369 (to J.M.P.), CA006927 and CA129467 (to M.L.C.) and CA140487 (to J.L.W.). NR 51 TC 18 Z9 19 U1 0 U2 3 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 NOV PY 2011 VL 50 IS 11 BP 884 EP 900 DI 10.1002/mc.20757 PG 17 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 833AJ UT WOS:000295853700008 PM 21400612 ER PT J AU Kovar, H Niedan, S Bilke, S Schwentner, R Ban, J Kauer, M Mestdagh, P Vandesompele, J Meltzer, P AF Kovar, Heinrich Niedan, Stephan Bilke, Sven Schwentner, Raphaela Ban, Jozef Kauer, Maximilian Mestdagh, Pieter Vandesompele, Joke Meltzer, Paul TI EWINGS SARCOMA AND PROSTATE CANCER: DIFFERENT YET SIMILAR SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Kovar, Heinrich; Niedan, Stephan; Schwentner, Raphaela; Ban, Jozef; Kauer, Maximilian] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Bilke, Sven; Meltzer, Paul] NCI, NIH, Bethesda, MD 20892 USA. [Mestdagh, Pieter] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Vandesompele, Joke] Univ Ghent, Med Ctr, B-9000 Ghent, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2011 VL 57 IS 5 BP 711 EP 711 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600016 ER PT J AU Steven, D Shusterman, S Reid, J Ingle, A Ahern, C Baruchel, S Glade-Bender, J Ivy, P Grier, H Adamson, P Blaney, S AF Steven, DuBois Shusterman, Suzanne Reid, Joel Ingle, Ashish Ahern, Charlotte Baruchel, Sylvain Glade-Bender, Julie Ivy, Percy Grier, Holcombe Adamson, Peter Blaney, Susan TI TOLERABILITY AND PHARMACOKINETIC PROFILE OF SUNITINIB GIVEN AS A POWDER FORMULATION TO CHILDREN WITH REFRACTORY SOLID TUMORS: A CHILDREN'S ONCOLOGY GROUP STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Steven, DuBois] UCSF Sch Med, Dept Pediat, San Francisco, CA USA. [Shusterman, Suzanne; Grier, Holcombe] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shusterman, Suzanne; Grier, Holcombe] Harvard Univ, Sch Med, Boston, MA USA. [Reid, Joel] Mayo Coll Med, Rochester, NY USA. [Ingle, Ashish] Childrens Oncol Grp, Arcadia, CA USA. [Ahern, Charlotte; Blaney, Susan] Baylor Coll Med, Houston, TX 77030 USA. [Baruchel, Sylvain] Univ Toronto, Toronto, ON, Canada. [Baruchel, Sylvain] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Glade-Bender, Julie] Columbia Univ, New York, NY USA. [Glade-Bender, Julie] Morgan Stanley Childrens Hosp, New York, NY USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Adamson, Peter] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Blaney, Susan] Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 717 EP 718 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600043 ER PT J AU Wood, A Bosse, K Wang, K Diskin, S Schnepp, R Diamond, M Attiyeh, E Morozova, O Pugh, T Mosse, Y Cole, K Devoto, M Hakonarson, H Maris, J AF Wood, Andrew Bosse, Kristopher Wang, Kai Diskin, Sharon Schnepp, Robert Diamond, Maura Attiyeh, Edward Morozova, Olena Pugh, Trevor Mosse, Yael Cole, Kristina Devoto, Marcella Hakonarson, Hakon Maris, John CA NBL TARGET Consortium TI GERMLINE VARIATIONS ARE ASSOCIATED WITH SUSCEPTIBILITY TO HIGH-RISK NEUROBLASTOMA AND IDENTIFY PATHWAYS WITH GAIN OF FUNCTION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Wood, Andrew] Childrens Hosp Philadelphia, Bala Cynwyd, PA USA. [Wang, Kai] CHOP, CAG, Philadelphia, PA USA. [Morozova, Olena] BC Canc Agency, Genome Sci Ctr, Vancouver, BC, Canada. [Pugh, Trevor] Broad Inst, Canc Program, Cambridge, MA USA. [NBL TARGET Consortium] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2011 VL 57 IS 5 BP 724 EP 724 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600069 ER PT J AU Blink, M van den Heuvel-Eibrink, M Aalbers, A Balgobind, B Hollink, I Meijerink, J de Haas, V Hasle, H Reinhardt, D Klusmann, JH Pieters, R Calado, R Young, N Zwaan, M AF Blink, Marjolein van den Heuvel-Eibrink, Marry Aalbers, Anna Balgobind, Brian Hollink, Iris Meijerink, Jules de Haas, Valerie Hasle, Henrik Reinhardt, Dirk Klusmann, Jan-Henning Pieters, Rob Calado, Rodrigo Young, Neal Zwaan, Michel TI HIGH FREQUENCY OF COPY NUMBER VARIATIONS IN MYELOID LEUKEMIA OF DOWN SYNDROME SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Blink, Marjolein; van den Heuvel-Eibrink, Marry; Aalbers, Anna; Balgobind, Brian; Hollink, Iris; Meijerink, Jules; Pieters, Rob; Zwaan, Michel] Erasmus MC Sophia Childrens Hosp, Rotterdam, Netherlands. [de Haas, Valerie] Dutch Childhood Oncol Grp, The Hague, Netherlands. [Hasle, Henrik] Aarhus Univ Hosp Skejby, Dept Pediat, Aarhus, Denmark. [Reinhardt, Dirk; Klusmann, Jan-Henning] Med High Sch, Dept Pediat Oncol Hematol, Hannover, Germany. [Calado, Rodrigo; Young, Neal] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RI Calado, Rodrigo/G-2619-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 771 EP 771 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600258 ER PT J AU Pomerantsev, AP Pomerantseva, OM Moayeri, M Fattah, R Tallant, C Leppla, SH AF Pomerantsev, Andrei P. Pomerantseva, Olga M. Moayeri, Mahtab Fattah, Rasem Tallant, Cynthia Leppla, Stephen H. TI A Bacillus anthracis strain deleted for six proteases serves as an effective host for production of recombinant proteins SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Bacillus anthracis; Protease deficient; Protein overproduction; Edema factor; Gene knockout ID PROTECTIVE ANTIGEN; RECEPTOR-BINDING; GENOME SEQUENCE; LETHAL FACTOR; TOXIN; BACTERIA; DEFICIENT; SUBTILIS; METALLOPROTEASES; PURIFICATION AB Bacillus anthracis produces a number of extracellular proteases that impact the integrity and yield of other proteins in the B. anthracis secretome. In this study we show that anthrolysin O (ALO) and the three anthrax toxin proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF), produced from the B. anthracis Ames 35 strain (pXO1(+), pXO2(-)), are completely degraded at the onset of stationary phase due to the action of proteases. An improved Cre-loxP gene knockout system was used to sequentially delete the genes encoding six proteases (InhA1, InhA2, camelysin, TasA, NprB, and MmpZ). The role of each protease in degradation of the B. anthracis toxin components and ALO was demonstrated. Levels of the anthrax toxin components and ALO in the supernatant of the sporulation defective, pXO1(+) A35HMS mutant strain deleted for the six proteases were significantly increased and remained stable over 24 h. A pXO1-free variant of this six-protease mutant strain, designated BH460, provides an improved host strain for the preparation of recombinant proteins. As an example, BH460 was used to produce recombinant EF, which previously has been difficult to obtain from B. anthracis. The EF protein produced from BH460 had the highest in vivo potency of any EF previously purified from B. anthracis or Escherichia coli hosts. BH460 is recommended as an effective host strain for recombinant protein production, typically yielding greater than 10 mg pure protein per liter of culture. Published by Elsevier Inc. C1 [Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Pomerantseva, Olga M.] USN, Biol Def Res Directorate, Med Res Ctr, Rockville, MD 20852 USA. [Tallant, Cynthia] CSIC, Proteolysis Lab, Dept Biol Struct, Mol Biol Inst Barcelona, E-08028 Barcelona, Spain. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, 33 N DR,BG 33 RM 1W20B MSC 3202, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA FX We thank Richard Rest (Drexel University College of Medicine, Philadelphia, PA) for supplying rabbit antibody against recombinant ALO, Wei-Jen Tang (University of Chicago) for providing plasmid pPro-EX-H6-EF, and Aaron Firoved and Pradeep K. Gupta for constructing pSJ136EFOS. We thank Lisa Yeh for assistance with some experiments, D. Eric Anderson (NIDDK) for assistance with ESI-MS, Devorah Crown for help with animal studies, and Xavier Gomis Ruth for his support and encouragement. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA. NR 39 TC 26 Z9 26 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD NOV PY 2011 VL 80 IS 1 BP 80 EP 90 DI 10.1016/j.pep.2011.05.016 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 829UC UT WOS:000295608800013 PM 21827967 ER PT J AU Maringwa, JT Quinten, C King, M Ringash, J Osoba, D Coens, C Martinelli, F Vercauteren, J Cleeland, CS Flechtner, H Gotay, C Greimel, E Taphoorn, MJ Reeve, BB Schmucker-Von Koch, J Weis, J Smit, EF van Meerbeeck, JP Bottomley, A AF Maringwa, John T. Quinten, Chantal King, Madeleine Ringash, Jolie Osoba, David Coens, Corneel Martinelli, Francesca Vercauteren, Jurgen Cleeland, Charles S. Flechtner, Henning Gotay, Carolyn Greimel, Eva Taphoorn, Martin J. Reeve, Bryce B. Schmucker-Von Koch, Joseph Weis, Joachim Smit, Egbert F. van Meerbeeck, Jan P. Bottomley, Andrew CA EORTC PROBE Project Lung Canc Grp TI Minimal important differences for interpreting health-related quality of life scores from the EORTC QLQ-C30 in lung cancer patients participating in randomized controlled trials SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Anchoring; EORTC QLQ-C30; Health-related quality of life; Minimal important difference ID CLINICALLY IMPORTANT DIFFERENCES; EUROPEAN-ORGANIZATION; MEANINGFUL CHANGE; FUNCTIONAL ASSESSMENT; STANDARD-DEVIATION; REPORTED OUTCOMES; QUESTIONNAIRE; UNIVERSALITY; CISPLATIN; HALF AB The aim of this study was to determine the smallest changes in health-related quality of life (HRQOL) scores in a subset of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) scales, which could be considered as clinically meaningful in patients with non-small-cell lung cancer (NSCLC). WHO performance status (PS) and weight change were used as clinical anchors to determine minimal important differences (MIDs) in HRQOL change scores (range, 0-100) in the EORTC QLQ-C30 scales. Selected distribution-based methods were used for comparison. In a pooled dataset of 812 NSCLC patients undergoing treatment, the values determined to represent the MID depended on whether patients were improving or deteriorating. MID estimates for improvement (based on a one-category change in PS, 5 -aEuro parts per thousand < 20% weight gain) were physical functioning (9, 5); role functioning (14, 7); social functioning (5, 7); global health status (9, 4); fatigue (14, 5); and pain (16, 2). The respective MID estimates for deterioration (based on PS, weight loss) were physical (4, 6); role (5, 5); social (7, 9); global health status (4, 4); fatigue (6, 11); and pain (3, 7). Based on the selected QLQ-C30 scales, the MID may depend upon whether the patients' PS is improving or worsening, but our results are not definitive. The MID estimates for the specified scales can help clinicians and researchers evaluate the significance of changes in HRQOL and assess the value of a health care intervention or compare treatments. The estimates also can be useful in determining sample sizes in the design of future clinical trials. C1 [Maringwa, John T.; Quinten, Chantal; Coens, Corneel; Martinelli, Francesca; Vercauteren, Jurgen; Bottomley, Andrew] EORTC, Qual Life Dept, Brussels, Belgium. [King, Madeleine] Univ Sydney, Psychooncol Cooperat Res Grp, Sydney, NSW 2006, Australia. [Ringash, Jolie] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Osoba, David] Qual Life Consulting, Vancouver, BC, Canada. [Cleeland, Charles S.] Univ Texas Houston, Dept Symptom Res, Houston, TX USA. [Flechtner, Henning] Univ Magdeburg, D-39106 Magdeburg, Germany. [Gotay, Carolyn] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Greimel, Eva] Med Univ Graz, Graz, Austria. [Taphoorn, Martin J.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Reeve, Bryce B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schmucker-Von Koch, Joseph] Univ Regensburg, Regensburg, Germany. [Weis, Joachim] Univ Freiburg, Tumor Biol Ctr, Freiburg, Germany. [Smit, Egbert F.] Vrije Univ VUMC, Dept Pulm Dis, Amsterdam, Netherlands. [van Meerbeeck, Jan P.] Ghent Univ Hosp, Dept Resp Med, B-9000 Ghent, Belgium. [Taphoorn, Martin J.] Med Ctr Haaglanden, The Hague, Netherlands. RP Maringwa, JT (reprint author), EORTC, Qual Life Dept, Brussels, Belgium. EM john.maringwa@eortc.be FU Pfizer Foundation FX This study was funded by an unrestricted academic grant from the Pfizer Foundation. We thank the EORTC clinical Lung Group and their clinical investigators and all the patients who participated in these trials. NR 27 TC 36 Z9 37 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2011 VL 19 IS 11 BP 1753 EP 1760 DI 10.1007/s00520-010-1016-5 PG 8 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 828UL UT WOS:000295528600010 PM 20886240 ER PT J AU Fennell, T Watson, S Snyder, R Jeffcoat, R Waidyanatha, S AF Fennell, Timothy Watson, Scott Snyder, Rodney Jeffcoat, Robert Waidyanatha, Suramya TI Disposition and metabolism of N,N-dimethylacetoacetamide in male F344 and Wistar-Han rats and female B6C3F1 mice SO XENOBIOTICA LA English DT Article DE Dimethylacetoacetamide; metabolism; disposition AB 1. N,N-dimethylacetoacetamide (DMAAm) is a beta-dicarbonyl compound used as an industrial intermediate. This study investigated the disposition and metabolism of [(14)C]DMAAm in male rats and female mice. 2. A single oral dose of [(14)C]DMAAm (target dose of 10 or 130 mg/kg) was administered to male F344 and Wistar-Han rats. [(14)C]DMAAm was almost completely absorbed and excreted in urine, with ca. 80-90% of the dose recovered within 24 h for both rat strains. Fecal excretion and CO(2) exhalation were minimal (1 and 2%, respectively). Less than 3% of the dose remained in tissues at 24 h. There was no apparent dose- or strain-related difference in the disposition of [(14)C]DMAAm in rats. 3. In female B6C3F1 mice administered 8 mg/kg [(14)C]DMAAm, 80% of the administered radioactivity was recovered in urine and cage rinse in 24 h. 4. Urinary metabolites were isolated and characterized by liquid chromatography /mass spectrometry following oral administration of 435 mg/kg [(14)C]DMAAm in male F344 rats. Metabolism occurred via reduction of the 3-keto group and oxidation of the N-methyl groups, to give N,N-dimethyl-3-hydroxybutanamide, N-methyl-N-hydroxymethyl-3-hydroxybutanamide, and N-hydroxymethyl-3-hydroxybutanamide, and N-demethylation to give N-monomethylacetoacetamide (MMAAm). C1 [Fennell, Timothy; Watson, Scott; Snyder, Rodney; Jeffcoat, Robert] RTI Int, Res Triangle Pk, NC 27709 USA. [Waidyanatha, Suramya] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. RP Fennell, T (reprint author), RTI Int, POB 12194 3040,Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM Fennell@rti.org FU U.S. Department of Health and Human Services [N01-ES-75563 (HHSN29120077563)] FX The authors are grateful to Drs. J. Michael Sanders and Helen Cunny for their review of this manuscript. This work was performed for the National Toxicology program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, under Contract No. N01-ES-75563 (HHSN29120077563). NR 13 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD NOV PY 2011 VL 41 IS 11 BP 1013 EP 1020 DI 10.3109/00498254.2011.599444 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 829XD UT WOS:000295618400010 PM 21819270 ER PT J AU Alfano, CM Lichstein, KL Vander Wal, GS Smith, AW Reeve, BB McTiernan, A Bernstein, L Baumgartner, KB Ballard-Barbash, R AF Alfano, Catherine M. Lichstein, Kenneth L. Vander Wal, Gregory S. Smith, Ashley Wilder Reeve, Bryce B. McTiernan, Anne Bernstein, Leslie Baumgartner, Kathy B. Ballard-Barbash, Rachel TI Sleep duration change across breast cancer survivorship: associations with symptoms and health-related quality of life SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Survivors; Long-term effects; Sleep; Quality of life ID DEPRESSIVE SYMPTOMS; INSOMNIA SECONDARY; RISK-FACTORS; HOT FLASHES; WOMEN; FATIGUE; MORTALITY; THERAPY; PREVALENCE; OBESITY AB Sleep duration among breast cancer survivors correlates with fatigue, depression, and health-related quality of life (HRQOL); however, this has not been studied longitudinally. This study investigated patterns of sleep duration change across the early breast cancer survivorship period, their demographic and clinical predictors, and their relationships with subsequent cancer-related symptoms and HRQOL. Breast cancer survivors (n = 572), were assessed 6 months post-diagnosis (current sleep & retrospective reports of pre-diagnosis sleep), 30 months post-diagnosis (sleep), and 39 months post-diagnosis (symptoms, HRQOL). Sleep duration change was determined by examining sleep at each time point in relation to published norms. Analysis of variance and logistic regression models tested demographic and clinical differences between the sleep change groups; linear regression models tested differences in symptoms and HRQOL. Half of the survivors reported no sleep duration change over time; however, 25% reported sleep changes indicating a temporary (5.6%), late-occurring (14%), or sustained (5.9%) change. Survivors reporting sustained or temporary sleep changes were more likely to have been treated with chemotherapy (OR = 2.62, P < 0.001) or gained weight after diagnosis (OR = 1.82, P = 0.04) than those with no sleep change. Sustained sleep changes were related to greater subsequent severity, affective, and sensory aspects of fatigue (beta s = 2.0, 2.3, 1.8; all P < 0.0001) and lower vitality (beta = -10.8, P = 0.005). Survivors treated with chemotherapy and those who gain weight after diagnosis may have increased risk for sustained sleep duration changes, which may increase their fatigue. These results point to the need for routine assessment of sleep as part of survivorship care. C1 [Alfano, Catherine M.] NCI, Off Canc Survivorship, DCCPS, NIH,DHHS, Bethesda, MD 20892 USA. [Lichstein, Kenneth L.; Vander Wal, Gregory S.] Univ Alabama, Dept Psychol, Tuscaloosa, AL 35487 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, ARP, DCCPS,NIH,DHHS, Bethesda, MD 20892 USA. [Reeve, Bryce B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [McTiernan, Anne] Univ Washington, Seattle, WA 98195 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Canc Etiol, Duarte, CA 91010 USA. [Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Clin Informat Sci, Louisville, KY 40292 USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, DCCPS, NIH,DHHS, Bethesda, MD 20892 USA. RP Alfano, CM (reprint author), NCI, Off Canc Survivorship, DCCPS, NIH,DHHS, 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM Alfanoc@mail.nih.gov FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010] FX Supported by contracts from the National Cancer Institute: N01-CN-75036-20, N01-CN-05228, N01-PC-67010. NR 53 TC 16 Z9 17 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2011 VL 130 IS 1 BP 243 EP 254 DI 10.1007/s10549-011-1530-2 PG 12 WC Oncology SC Oncology GA 826OJ UT WOS:000295363200025 PM 21567239 ER PT J AU Veeranna Yang, DS Lee, JH Vinod, KY Stavrides, P Amin, ND Pant, HC Nixon, RA AF Veeranna Yang, Dun-Sheng Lee, Ju-Hyun Vinod, K. Yaragudri Stavrides, Philip Amin, Niranjana D. Pant, Harish C. Nixon, Ralph A. TI Declining phosphatases underlie aging-related hyperphosphorylation of neurofilaments SO NEUROBIOLOGY OF AGING LA English DT Article DE Neurofilament; Phosphorylation; Dephosphorylation; Kinases; Phosphatases; Maturation; Aging; RT-97 epitope; Immunoreactivity ID ALZHEIMER-DISEASE BRAIN; DEPENDENT PROTEIN-KINASE; CELL-SURFACE EXPRESSION; ACID-TREATED NEURONS; OKADAIC ACID; INTERMEDIATE-FILAMENTS; SPINAL-CORD; IN-VIVO; NEUROFIBRILLARY DEGENERATION; CDC2-LIKE KINASE AB Cytoskeletal protein phosphorylation is frequently altered in neuropathologic states but little is known about changes during normal aging. Here we report that declining protein phosphatase activity, rather than activation of kinases, underlies aging-related neurofilament hyperphosphorylation. Purified PP2A or PP2B dephosphorylated the heavy neurofilament (NFH) subunit or its extensively phorphorylated carboxyl-terminal domain in vitro. In cultured primary hippocampal neurons, inhibiting either phosphatase induced NFH phosphorylation without activating known neurofilament kinases. Neurofilament phosphorylation in the mouse CNS, as reflected by levels of the RT-97 phosphoepitope associated with late axon maturation, more than doubled during the 12-month period after NFH expression plateaued at p21. This was accompanied by declines in levels and activity of PP2A but not PP2B, and no rise in activities of neurofilament kinases (Erk1,2, cdk5 and JNK1,2). Inhibiting PP2A in mice in vivo restored brain RT-97 to levels seen in young mice. Declining PP2A activity, therefore, can account for rising neurofilament phosphorylation in maturing brain, potentially compounding similar changes associated with adult-onset neurodegenerative diseases. (C) 2009 Elsevier Inc. All rights reserved. C1 [Nixon, Ralph A.] NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY 10962 USA. [Vinod, K. Yaragudri] Nathan S Kline Inst Psychiat Res, Div Analyt Psychopharmacol, Orangeburg, NY 10962 USA. [Veeranna; Yang, Dun-Sheng; Lee, Ju-Hyun; Nixon, Ralph A.] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. [Nixon, Ralph A.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Amin, Niranjana D.; Pant, Harish C.] NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Nixon, RA (reprint author), NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM nixon@nki.rfmh.org OI Lee, Ju-hyun/0000-0002-0280-8375 FU NIA [AG05604]; NIH FX The authors thank Corrinne Peterhoff for assistance with figures, and Nicole Piorkowski for assistance with manuscript preparation. This work was supported by NIA AG05604 (R.A.N.) and the NIH intramural program (H.C.P.). NR 73 TC 13 Z9 13 U1 0 U2 4 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 NOV PY 2011 VL 32 IS 11 BP 2016 EP 2029 DI 10.1016/j.neurobiolaging.2009.12.001 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 824RV UT WOS:000295220700010 PM 20031277 ER PT J AU Yaffe, K Lindquist, K Kluse, M Cawthon, R Harris, T Hsueh, WC Simonsick, EM Kuller, L Li, RL Ayonayon, HN Rubin, SM Cummings, SR AF Yaffe, Kristine Lindquist, Karla Kluse, Molly Cawthon, Richard Harris, Tamara Hsueh, Wen-Chi Simonsick, Eleanor M. Kuller, Lewis Li, Rongling Ayonayon, Hilsa N. Rubin, Susan M. Cummings, Steven R. CA Health ABC Study TI Telomere length and cognitive function in community-dwelling elders: Findings from the Health ABC Study SO NEUROBIOLOGY OF AGING LA English DT Article DE Cognitive decline; Biomarker; Genetics; Telomeres; Epidemiology ID CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; MORTALITY; DEMENTIA; RISK; ASSOCIATION; LEUKOCYTES; SHORTER; PEOPLE AB Telomere shortening is a marker of cellular aging and has been associated with risk of Alzheimer's disease. Few studies have determined if telomere length is associated with cognitive decline in non-demented elders. We prospectively studied 2734 non-demented elders (mean age: 74 years). We measured cognition with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST) repeatedly over 7 years. Baseline telomere length was measured in blood leukocytes and classified by tertile as "short", "medium", or "long". At baseline, longer telomere length was associated with better DSST score (36.4, 34.9 and 34.4 points for long, medium and short, p < 0.01) but not for change in score. However, 7-year 3MS change scores were less among those with longer telomere length (-1.7 points vs. -2.5 and -2.9, p = 0.01). Findings were similar after multivariable adjustment for age, gender, race, education, assay batch, and baseline score. There was a borderline statistically significant interaction for telomere length and APOE e4 on 3MS change score (p = 0.06). Thus, telomere length may serve as a biomarker for cognitive aging. Published by Elsevier Inc. C1 [Yaffe, Kristine; Kluse, Molly] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine; Ayonayon, Hilsa N.; Rubin, Susan M.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Lindquist, Karla; Hsueh, Wen-Chi] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94121 USA. [Yaffe, Kristine] San Francisco VA Med Ctr KY, San Francisco, CA 94121 USA. [Cawthon, Richard] Univ Utah, Dept Human Genet, Salt Lake City, UT 84132 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometty, Intramural Res Program, Bethesda, MD 20892 USA. [Kuller, Lewis] Univ Pittsburgh, Sch Med, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Li, Rongling] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38163 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco, CA 94115 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Sch Med, Dept Psychiat, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU NIH; National Institute on Aging; [AG-6-2101]; [AG-6-2103]; [AG-6-2106]; [AG021918]; [AG031155] FX This study was conducted on behalf of the Health, Aging and Body Composition (Health ABC) Study. This work was funded by: AG-6-2101, AG-6-2103, AG-6-2106, and AG021918. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Dr. Yaffe was supported in part by AG031155 and an anonymous foundation. NR 30 TC 43 Z9 45 U1 5 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2011 VL 32 IS 11 BP 2055 EP 2060 DI 10.1016/j.neurobiolaging.2009.12.006 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 824RV UT WOS:000295220700013 PM 20031273 ER PT J AU Gao, JJ Huang, XM Park, YK Liu, R Hollenbeck, A Schatzkin, A Mailman, RB Chen, HL AF Gao, Jianjun Huang, Xuemei Park, Yikyung Liu, Rui Hollenbeck, Albert Schatzkin, Arthur Mailman, Richard B. Chen, Honglei TI Apolipoprotein E genotypes and the risk of Parkinson disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson disease (PD); Apolipoprotein E (ApoE); Dementia; Association ID ALZHEIMERS-DISEASE; METAANALYSIS; ASSOCIATION; CHOLESTEROL; DEMENTIA; APOE; SUSCEPTIBILITY; ALLELE; ONSET; AGE AB We examined apolipoprotein E (ApoE) genotypes in relation to Parkinson's disease (PD) among 786 cases and 1537 controls, all non-Hispanic Caucasians. Odds ratios (ORO and 95% confidence intervals (CIs) were derived from multivariate logistic regression models, adjusting for year of birth, sex, smoking status, daily caffeine intake, and family history of PD. Compared with participants with ApoE epsilon 33, epsilon 4 carriers (epsilon 34/epsilon 44) had significantly lower odds for having PD (OR, 0.75; 95% Cl, 0.59-0.94; p = 0.01), whereas epsilon 2 carriers (epsilon 23/epsilon 22) did not (OR, 0.95; 95% CI, 0.73-1.24; p = 0.71). Subgroup analyses showed similar results. in addition, we conducted a meta-analysis which confirmed our primary findings (epsilon 34/epsilon 44 vs. epsilon 33: OR, 0.90; 95% CI, 0.81-0.99; p = 0.024 and epsilon 23/epsilon 22 vs. epsilon 33: OR, 1.10; 95% CI, 0.97-1.23; p = 0.13). in PD patients, the prevalence of dementia appeared to be higher among epsilon 4 carriers (compared with epsilon 33: OR, 1.59; 95% CI, 0.98-2.58; p = 0.06), but lower among epsilon 2 carriers (OR, 0.75; 95% CI, 0.40-1.42; p = 0.38), although neither test was statistically significant. Our study suggested that the ApoE epsilon 4 allele may be associated with a lower PD risk among non-Hispanic Caucasians. Published by Elsevier Inc. C1 [Gao, Jianjun; Liu, Rui; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Huang, Xuemei; Mailman, Richard B.] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei; Mailman, Richard B.] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Park, Yikyung; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Rockville, MD USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Mailman, Richard/0000-0003-1353-2738; Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU National Institute of Environmental Health Sciences [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02, R01 N5060722]; Pennsylvania Commonwealth Universal Research Enhancemehnt FX This study was supported by the intramural research program of the National Institute of Environmental Health Sciences (Z01-ES-101986) and the National Cancer Institute (Z01 CP010196-02), R01 N5060722 (Dr. Huang), and a grant from the Pennsylvania Commonwealth Universal Research Enhancemehnt Program (Drs. Mailman and Huang). NR 29 TC 0 Z9 1 U1 0 U2 4 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 NOV PY 2011 VL 32 IS 11 AR 2106.e1 DI 10.1016/j.neurobiolaging.2011.05.016 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 824RV UT WOS:000295220700020 PM 21741729 ER PT J AU Walter, S Atzmon, G Demerath, EW Garcia, ME Kaplan, RC Kumari, M Lunetta, KL Milaneschi, Y Tanaka, T Tranah, GJ Volker, U Yu, L Arnold, A Benjamin, EJ Biffar, R Buchman, AS Boerwinkle, E Couper, D De Jager, PL Evans, DA Harris, TB Hoffmann, W Hofman, A Karasik, D Kiel, DP Kocher, T Kuningas, M Launer, LJ Lohman, KK Lutsey, PL Mackenbach, J Marciante, K Psaty, BM Reiman, EM Rotter, JI Seshadri, S Shardell, MD Smith, AV van Duijn, C Walston, J Zillikens, MC Bandinelli, S Baumeister, SE Bennett, DA Ferrucci, L Gudnason, V Kivimaki, M Liu, YM Murabito, JM Newman, AB Tiemeier, H Franceschini, N AF Walter, Stefan Atzmon, Gil Demerath, Ellen W. Garcia, Melissa E. Kaplan, Robert C. Kumari, Meena Lunetta, Kathryn L. Milaneschi, Yuri Tanaka, Toshiko Tranah, Gregory J. Voelker, Uwe Yu, Lei Arnold, Alice Benjamin, Emelia J. Biffar, Reiner Buchman, Aron S. Boerwinkle, Eric Couper, David De Jager, Philip L. Evans, Denis A. Harris, Tamara B. Hoffmann, Wolfgang Hofman, Albert Karasik, David Kiel, Douglas P. Kocher, Thomas Kuningas, Maris Launer, Lenore J. Lohman, Kurt K. Lutsey, Pamela L. Mackenbach, Johan Marciante, Kristin Psaty, Bruce M. Reiman, Eric M. Rotter, Jerome I. Seshadri, Sudha Shardell, Michelle D. Smith, Albert V. van Duijn, Cornelia Walston, Jeremy Zillikens, M. Carola Bandinelli, Stefania Baumeister, Sebastian E. Bennett, David A. Ferrucci, Luigi Gudnason, Vilmundur Kivimaki, Mika Liu, Yongmei Murabito, Joanne M. Newman, Anne B. Tiemeier, Henning Franceschini, Nora TI A genome-wide association study of aging SO NEUROBIOLOGY OF AGING LA English DT Article DE Genome-wide association analysis; Mortality; Disease-free survival; Longevity; Aging; Brain aging ID APOLIPOPROTEIN-E GENOTYPE; FUNCTION EVOLUTION DATA; GROWTH-FACTOR RECEPTOR; HUMAN LONGEVITY; BLOOD-PRESSURE; GENETIC ASSOCIATION; PROTEIN-SEQUENCE; RARE VARIANTS; PLASMA-LEVELS; FOXO3A AB Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 x 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity. (C) 2011 Elsevier Inc. All rights reserved. C1 [Walter, Stefan; Mackenbach, Johan] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Walter, Stefan; Hofman, Albert; Kuningas, Maris; van Duijn, Cornelia; Tiemeier, Henning] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Atzmon, Gil] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA. [Atzmon, Gil] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10467 USA. [Atzmon, Gil] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Atzmon, Gil] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Demerath, Ellen W.; Lutsey, Pamela L.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Garcia, Melissa E.; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Kumari, Meena; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London, England. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Milaneschi, Yuri; Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Tranah, Gregory J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Yu, Lei; Buchman, Aron S.; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Arnold, Alice] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Benjamin, Emelia J.; Seshadri, Sudha; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Seshadri, Sudha; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Seshadri, Sudha; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Seshadri, Sudha; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Neurol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Seshadri, Sudha; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Biffar, Reiner; Kocher, Thomas] Ernst Moritz Arndt Univ Greifswald, Sch Dent, Greifswald, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Couper, David] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [De Jager, Philip L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Program Translat NeuroPsychiat Genom,Dept Neurol, Boston, MA 02115 USA. [Evans, Denis A.] Rush Univ, Med Ctr, Rush Inst Hlth Aging, Chicago, IL 60612 USA. [Hoffmann, Wolfgang; Baumeister, Sebastian E.] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Hoffmann, Wolfgang] Ctr Integrated Dementia Care Res CIDC, Bonn, Germany. [Hoffmann, Wolfgang] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Karasik, David; Kiel, Douglas P.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Lohman, Kurt K.; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Ctr Human Genom, Winston Salem, NC USA. [Marciante, Kristin; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Marciante, Kristin; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Marciante, Kristin; Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Unit, Seattle, WA USA. [Reiman, Eric M.] Banner Alzheimers Inst, Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Shardell, Michelle D.] Univ Maryland, College Pk, MD 20742 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Walston, Jeremy] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Zillikens, M. Carola] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Tiemeier, Henning] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Franceschini, Nora] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Tiemeier, H (reprint author), Erasmus MC, Dept Epidemiol & Biostat, POB 1738, NL-3000 DR Rotterdam, Netherlands. EM h.tiemeier@erasmusmc.nl RI Kivimaki, Mika/B-3607-2012; Newman, Anne/C-6408-2013; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; OI Tiemeier, Henning/0000-0002-4395-1397; Benjamin, Emelia/0000-0003-4076-2336; Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530; Newman, Anne/0000-0002-0106-1150; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Murabito, Joanne/0000-0002-0192-7516; Seshadri, Sudha/0000-0001-6135-2622; Lunetta, Kathryn/0000-0002-9268-810X; Kivimaki, Mika/0000-0002-4699-5627 FU Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [050-060-810]; Netherlands Organisation for Scientific Research (NWO) [904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010. 2005.011, 911-03-012, 017.106.370]; Netspar-Living longer for a good health; Erasmus Medical Center; Erasmus University in Rotterdam; Netherlands Organization for Health Research and Development; Netherlands Research Institute for Diseases in the Elderly; Dutch Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam, the Netherlands; National Heart, Lung, and Blood Institute [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; National Institute of Aging [R01 AG031890, R01AG029451, R01 AR/AG 41398, N01AG62101, N01AG62103, N01AG62106, 1R03AG032498-01, 1R01AG032098-01A1]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Affymetrix, Inc., [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Arthritis, Musculoskeletal and Skin Diseases; NIH [N01-AG-12100, HHSN268200782096C]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; NIH, National Institute on Aging; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg, West Pomerania; [AG033193]; [AG081220]; [NS17950]; [P30AG013846]; [1R01-AG028321] FX Rotterdam Study: The Rotterdam Study is supported by Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research ( NWO) (904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010. 2005.011, 911-03-012 and 017.106.370); Netspar-Living longer for a good health; the Erasmus Medical Center, and Erasmus University in Rotterdam; the Netherlands Organization for Health Research and Development, the Netherlands Research Institute for Diseases in the Elderly; the Dutch Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam, the Netherlands.; Cardiovascular Health Study: The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, the National Institute of Aging R01 AG031890 with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; Framingham Heart Study: Phenotype-genotype analyses were supported by the National Institute of Aging grant number R01AG029451 (PI: JMM). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr. Kiel's effort as well as all hip fracture data from the Framingham Osteoporosis Study was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging; R01 AR/AG 41398. This research was additionally supported by the following grants: AG033193, AG081220, NS17950, P30AG013846, 1R01-AG028321.; Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions.; Age, Gene/Environment Susceptibility - Reykjavik Study: The Age, Gene/Environment Susceptibility-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA IRP Laboratory of Neurogenetics.; Invecchiare nel Chianti: The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336).; Baltimore Longitudinal Study of Aging: The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through an R&D contract with MedStar Research Institute.; Health, Aging and Body Composition: This research is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106 and NIA grant 1R03AG032498-01. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.; Study of Health in Pomerania: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the "Center of Knowledge Interchange" program of the Siemens AG. NR 73 TC 15 Z9 17 U1 1 U2 13 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 NOV PY 2011 VL 32 IS 11 AR 2109.e15 DI 10.1016/j.neurobiolaging.2011.05.026 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 824RV UT WOS:000295220700027 PM 21782286 ER PT J AU Gong, EJ Park, HR Kim, ME Piao, S Lee, E Jo, DG Chung, HY Ha, NC Mattson, MP Lee, J AF Gong, Eun Ji Park, Hee Ra Kim, Mi Eun Piao, Shunfu Lee, Eunjin Jo, Dong-Gyu Chung, Hae Young Ha, Nam-Chul Mattson, Mark P. Lee, Jaewon TI Morin attenuates tau hyperphosphorylation by inhibiting GSK3 beta SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Alzheimer's disease; GSK3 beta; Tau hyperphosphorylation; Morin ID GLYCOGEN-SYNTHASE KINASE-3; AMYLOID-INDUCED NEURODEGENERATION; ALZHEIMERS-DISEASE MICE; TRIPLE-TRANSGENIC MODEL; OXIDATIVE STRESS; IN-VIVO; HIPPOCAMPAL-NEURONS; PRECURSOR PROTEIN; INDUCED TOXICITY; BETA-SECRETASE AB Alzheimer's disease (AD) is the major form of age-related dementia and is characterized by progressive cognitive impairment, the accumulation of extracellular amyloid beta-peptide (A beta), and intracellular hyperphosphorylated tau aggregates in affected brain regions. Tau hyperphosphorylation and accumulation in neurofibrillary tangles is strongly correlated with cognitive deficits, and is apparently a critical event in the dementia process because mutations in tau can cause a tangle-only form of dementia called frontotemporal lobe dementia. Among kinases that phosphorylate tau, glycogen synthase kinase 3 beta (GSK3 beta) is strongly implicated in AD pathogenesis. In the present study, we established an ELISA to screen for agents that inhibit GSK3 beta activity and found that the flavonoid morin effectively inhibited GSK3 beta activity and blocked GSK3 beta-induced tau phosphorylation in vitro. In addition, morin attenuated A beta-induced tau phosphorylation and protected human neuroblastoma cells against A beta cytotoxicity. Furthermore, treatment of 3xTg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons. Morin is a novel inhibitor of GSK3 beta that can reduce tau pathology in vivo and may have potential as a therapeutic agent in tauopathies. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gong, Eun Ji; Park, Hee Ra; Kim, Mi Eun; Piao, Shunfu; Lee, Eunjin; Chung, Hae Young; Ha, Nam-Chul; Lee, Jaewon] Pusan Natl Univ, Coll Pharm, Dept Pharm, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. [Gong, Eun Ji; Park, Hee Ra; Kim, Mi Eun; Piao, Shunfu; Lee, Eunjin; Chung, Hae Young; Ha, Nam-Chul; Lee, Jaewon] Pusan Natl Univ, Res Inst Drug Dev, Pusan 609735, South Korea. [Jo, Dong-Gyu] Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea. [Mattson, Mark P.] Natl Inst Aging Intramural, Res Program, Lab Neurosci, Baltimore, MD USA. RP Lee, J (reprint author), Pusan Natl Univ, Coll Pharm, Dept Pharm, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. EM neuron@pusan.ac.kr RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 FU Ministry for Health, Welfare & Family Affairs, Republic of Korea [A084225]; National Research Foundation of Korea (NRF); Korea government (MEST) [20090083538] FX This research was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A084225). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 20090083538). NR 70 TC 23 Z9 25 U1 2 U2 9 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 NOV PY 2011 VL 44 IS 2 BP 223 EP 230 DI 10.1016/j.nbd.2011.07.005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 820WX UT WOS:000294937900007 PM 21782947 ER PT J AU Habermann, JK Bundgen, NK Gemoll, T Hautaniemi, S Lundgren, C Wangsa, D Doering, J Bruch, HP Nordstroem, B Roblick, UJ Jornvall, H Auer, G Ried, T AF Habermann, Jens K. Buendgen, Nana K. Gemoll, Timo Hautaniemi, Sampsa Lundgren, Caroline Wangsa, Danny Doering, Jana Bruch, Hans-Peter Nordstroem, Britta Roblick, Uwe J. Jornvall, Hans Auer, Gert Ried, Thomas TI Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes SO MOLECULAR CANCER LA English DT Article DE aneuploidy; endometrial carcinoma; genomic instability; comparative genomic hybridization; expression arrays; pathway analysis; UPSC ID FEMALE REPRODUCTIVE-TRACT; ANNEXIN-II OVEREXPRESSION; NUCLEAR-DNA CONTENT; GENE-EXPRESSION; PROSTATE-CANCER; BREAST-CANCER; CELL-LINES; CARCINOMA; ADENOCARCINOMAS; HYBRIDIZATION AB Background: In addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular. We mapped ploidy-associated chromosomal aberrations and identified corresponding gene and protein expression changes in endometrial cancers of different prognostic subgroups. Methods: DNA image cytometry classified 25 endometrioid cancers to be either diploid (n = 16) or aneuploid (n = 9), and all uterine papillary serous cancers (UPSC) to be aneuploid (n = 8). All samples were subjected to comparative genomic hybridization and gene expression profiling. Identified genes were subjected to Ingenuity pathway analysis (IPA) and were correlated to protein expression changes. Results: Comparative genomic hybridization revealed ploidy-associated specific, recurrent genomic imbalances. Gene expression analysis identified 54 genes between diploid and aneuploid endometrioid carcinomas, 39 genes between aneuploid endometrioid cancer and UPSC, and 76 genes between diploid endometrioid and aneuploid UPSC to be differentially expressed. Protein profiling identified AKR7A2 and ANXA2 to show translational alterations consistent with the transcriptional changes. The majority of differentially expressed genes and proteins belonged to identical molecular functions, foremost Cancer, Cell Death, and Cellular Assembly and Organization. Conclusions: We conclude that the grade of genomic instability rather than the histopathological subtype correlates with specific gene and protein expression changes. The identified genes and proteins might be useful as molecular targets for improved diagnostic and therapeutic intervention and merit prospective validation. C1 [Habermann, Jens K.; Buendgen, Nana K.; Gemoll, Timo; Doering, Jana; Bruch, Hans-Peter; Roblick, Uwe J.] Univ Lubeck, Surg Res Lab, Dept Surg, Lubeck, Germany. [Hautaniemi, Sampsa] Univ Helsinki, Computat Syst Biol Lab, Biomedicum Helsinki, FIN-00014 Helsinki, Finland. [Hautaniemi, Sampsa] Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland. [Lundgren, Caroline; Nordstroem, Britta] Karolinska Univ Hosp Solna, Dept Gynaecol Oncol, CCK, Solna, Sweden. [Habermann, Jens K.; Gemoll, Timo; Jornvall, Hans] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden. [Gemoll, Timo; Auer, Gert] Karolinska Inst, Unit Canc Prote, Biom Ctr Karolinska, Stockholm, Sweden. [Habermann, Jens K.; Wangsa, Danny; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Habermann, JK (reprint author), Univ Lubeck, Surg Res Lab, Dept Surg, Lubeck, Germany. EM Jens.Habermann@gmail.com; riedt@mail.nih.gov RI Hautaniemi, Sampsa/A-3122-2009; Habermann, Jens/E-2968-2010 OI Hautaniemi, Sampsa/0000-0002-7749-2694; FU Boehringer Ingelheim Fonds; Werner and Clara Kreitz Foundation; North German Tumorbank of Colorectal Cancer [108446]; Ad Infinitum Foundation; National Institutes of Health, National Cancer Institute FX We thank Inga Maurin and Ulla Aspenblad for assistance with immunohistochemical analysis and Buddy Chen, Tom Ellerman and Joseph Cheng for IT support. Grants from the Boehringer Ingelheim Fonds, the Werner and Clara Kreitz Foundation, the North German Tumorbank of Colorectal Cancer (DKH #108446), and the Ad Infinitum Foundation are gratefully acknowledged. This study was performed in connection with the Surgical Center for Translational Oncology-Lubeck (SCTO-L). This study was supported in part by the intramural research program of the National Institutes of Health, National Cancer Institute. NR 48 TC 9 Z9 9 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD OCT 31 PY 2011 VL 10 AR 132 DI 10.1186/1476-4598-10-132 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 878UB UT WOS:000299281400001 PM 22040021 ER PT J AU Graciotti, L Becker, J Granata, AL Procopio, AD Tessarollo, L Fulgenzi, G AF Graciotti, Laura Becker, Jodi Granata, Anna Luisa Procopio, Antonio Domenico Tessarollo, Lino Fulgenzi, Gianluca TI Dystrophin Is Required for the Normal Function of the Cardio-Protective K-ATP Channel in Cardiomyocytes SO PLOS ONE LA English DT Article ID SENSITIVE POTASSIUM CHANNELS; DUCHENNE MUSCULAR-DYSTROPHY; MDX MICE; CARDIAC MYOCYTES; CREATINE-KINASE; MOUSE MODEL; CARDIOMYOPATHY; CELL; MUSCLE; STRESS AB Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (K-ATP) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including K-ATP ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of K-ATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the K-ATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective K-ATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients. C1 [Graciotti, Laura; Granata, Anna Luisa; Procopio, Antonio Domenico; Fulgenzi, Gianluca] Univ Politecn Marche, Dept Clin & Mol Sci, Ancona, Italy. [Becker, Jodi; Tessarollo, Lino; Fulgenzi, Gianluca] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Procopio, Antonio Domenico] INRCA Ancona, Ctr Clin Pathol & Innovat Therapy, Ancona, Italy. RP Graciotti, L (reprint author), Univ Politecn Marche, Dept Clin & Mol Sci, Ancona, Italy. EM tessarol@mail.nih.gov; fulgenzig@mail.nih.gov OI Fulgenzi, Gianluca/0000-0003-2646-7728 FU National Institutes of Health (NIH), National Cancer Institute; Polytechnic University of Marche FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute for JB, LT and GF. LG, ADP, and ALG were supported by Polytechnic University of Marche "finanziamento di Ateneo 2005,06,07,08,09''. There are no current external funding sources for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 6 Z9 6 U1 0 U2 1 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 OCT 31 PY 2011 VL 6 IS 10 AR e27034 DI 10.1371/journal.pone.0027034 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 846PP UT WOS:000296916000047 PM 22066028 ER PT J AU Husain, FT Pajor, NM Smith, JF Kim, HJ Rudy, S Zalewski, C Brewer, C Horwitz, B AF Husain, Fatima T. Pajor, Nathan M. Smith, Jason F. Kim, H. Jeff Rudy, Susan Zalewski, Christopher Brewer, Carmen Horwitz, Barry TI Discrimination Task Reveals Differences in Neural Bases of Tinnitus and Hearing Impairment SO PLOS ONE LA English DT Article ID OLDER-ADULTS; SELECTIVE ATTENTION; AUDITORY ATTENTION; SPEECH; PERCEPTION; MEMORY; DEPRESSION; INVENTORY; NETWORKS; SYSTEM AB We investigated auditory perception and cognitive processing in individuals with chronic tinnitus or hearing loss using functional magnetic resonance imaging (fMRI). Our participants belonged to one of three groups: bilateral hearing loss and tinnitus (TIN), bilateral hearing loss without tinnitus (HL), and normal hearing without tinnitus (NH). We employed pure tones and frequency-modulated sweeps as stimuli in two tasks: passive listening and active discrimination. All subjects had normal hearing through 2 kHz and all stimuli were low-pass filtered at 2 kHz so that all participants could hear them equally well. Performance was similar among all three groups for the discrimination task. In all participants, a distributed set of brain regions including the primary and non-primary auditory cortices showed greater response for both tasks compared to rest. Comparing the groups directly, we found decreased activation in the parietal and frontal lobes in the participants with tinnitus compared to the HL group and decreased response in the frontal lobes relative to the NH group. Additionally, the HL subjects exhibited increased response in the anterior cingulate relative to the NH group. Our results suggest that a differential engagement of a putative auditory attention and short-term memory network, comprising regions in the frontal, parietal and temporal cortices and the anterior cingulate, may represent a key difference in the neural bases of chronic tinnitus accompanied by hearing loss relative to hearing loss alone. C1 [Husain, Fatima T.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. [Husain, Fatima T.; Pajor, Nathan M.; Smith, Jason F.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. [Kim, H. Jeff; Rudy, Susan; Zalewski, Christopher; Brewer, Carmen] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Bethesda, MD USA. RP Husain, FT (reprint author), Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. EM husainf@illinois.edu FU National Institutes of Health-National Institute on Deafness and Other Communication Disorders; Tinnitus Research Consortium FX The research was supported by the National Institutes of Health-National Institute on Deafness and Other Communication Disorders Intramural Research Program and a grant from the Tinnitus Research Consortium to FTH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 25 Z9 26 U1 4 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 OCT 31 PY 2011 VL 6 IS 10 AR e26639 DI 10.1371/journal.pone.0026639 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 846PP UT WOS:000296916000019 PM 22066003 ER PT J AU Nasrollahzadeh, D Aghcheli, K Sotoudeh, M Shakeri, R Persson, EC Islami, F Kamangar, F Abnet, CC Boffetta, P Engstrand, L Dawsey, SM Malekzadeh, R Ye, WM AF Nasrollahzadeh, Dariush Aghcheli, Karim Sotoudeh, Masoud Shakeri, Ramin Persson, E. Christina Islami, Farhad Kamangar, Farin Abnet, Christian C. Boffetta, Paolo Engstrand, Lars Dawsey, Sanford M. Malekzadeh, Reza Ye, Weimin TI Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis SO PLOS ONE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; SERUM PEPSINOGEN; GENERAL-POPULATION; ESOPHAGEAL CANCER; ACID-SECRETION; RISK; MARKERS; IRAN; ERADICATION; SEVERITY AB Background: To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study. Methods: We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology. Results: 309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 mu g/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 mu g/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6-97.9) and its specificity decreased to 88.8% (95%CI 80.8-94.3). Conclusions: Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis. C1 [Nasrollahzadeh, Dariush; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Nasrollahzadeh, Dariush; Aghcheli, Karim; Sotoudeh, Masoud; Shakeri, Ramin; Islami, Farhad; Kamangar, Farin; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Persson, E. Christina; Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Islami, Farhad] Int Agcy Res Canc, F-69372 Lyon, France. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst & Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Engstrand, Lars] Swedish Inst Infect Dis Control, Stockholm, Sweden. RP Nasrollahzadeh, D (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM malek@ams.ac.ir; weimin.ye@ki.se RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Swedish Research Council; Digestive Disease Research Centre, Tehran University of Medical Sciences; Karolinska Institute FX This study was supported by the research grants from Swedish Research Council and Digestive Disease Research Centre, Tehran University of Medical Sciences. DN was partly supported by a scholarship from Karolinska Institute (KID-December 2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 19 Z9 22 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2011 VL 6 IS 10 AR e26957 DI 10.1371/journal.pone.0026957 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 846PP UT WOS:000296916000036 PM 22066020 ER PT J AU Meyers, N Fromm, S Luckenbaugh, DA Drevets, WC Hasler, G AF Meyers, Noah Fromm, Stephen Luckenbaugh, David A. Drevets, Wayne C. Hasler, Gregor TI Neural correlates of sleepiness induced by catecholamine depletion SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Dopamine; Norepinephrine; Mesencephalon; Sleep; Hypothalamus; Prolactin ID MAJOR DEPRESSIVE DISORDER; METHYL-PARA-TYROSINE; BASE-LINE OCCUPANCY; LOCUS-COERULEUS; DOPAMINERGIC-NEURONS; RECEPTOR OCCUPANCY; SUBSTANTIA NIGRA; WAKING CYCLE; BRAIN; HUMANS AB Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep. Published by Elsevier Ireland Ltd. C1 [Hasler, Gregor] Univ Bern, Univ Hosp Psychiat, CH-3000 Bern, Switzerland. [Meyers, Noah; Fromm, Stephen; Luckenbaugh, David A.] NIMH, Mood & Anxiety Disorders Program, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Dept Psychiat, Sch Med, Laureate Inst Brain Res, Tulsa, OK 74136 USA. RP Hasler, G (reprint author), Univ Bern, Univ Hosp Psychiat, Bolligenstr 111, CH-3000 Bern, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 FU NIMH NIH HHS [Z99 MH999999-02] NR 53 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 31 PY 2011 VL 194 IS 1 BP 73 EP 78 DI 10.1016/j.pscychresns.2011.06.015 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 841VW UT WOS:000296544300010 PM 21872452 ER PT J AU Golozar, A Khademi, H Kamangar, F Poutschi, H Islami, F Abnet, CC Freedman, ND Taylor, PR Pharoah, P Boffetta, P Brennan, PJ Dawsey, SM Malekzadeh, R Etemadi, A AF Golozar, Asieh Khademi, Hooman Kamangar, Farin Poutschi, Hossein Islami, Farhad Abnet, Christian C. Freedman, Neal D. Taylor, Philip R. Pharoah, Paul Boffetta, Paolo Brennan, Paul J. Dawsey, Sanford M. Malekzadeh, Reza Etemadi, Arash TI Diabetes Mellitus and Its Correlates in an Iranian Adult Population SO PLOS ONE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; IMPAIRED GLUCOSE-TOLERANCE; SOCIOECONOMIC-STATUS; ESOPHAGEAL CANCER; BIRTH-WEIGHT; GREEN TEA; NONCOMMUNICABLE DISEASES; DEVELOPING-COUNTRIES; WAIST CIRCUMFERENCE; INSULIN-RESISTANCE AB The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention. C1 [Golozar, Asieh; Khademi, Hooman; Kamangar, Farin; Poutschi, Hossein; Islami, Farhad; Malekzadeh, Reza; Etemadi, Arash] Univ Tehran Med Sci, Digest Dis Res Inst, Shariati Hosp, Tehran, Iran. [Golozar, Asieh; Kamangar, Farin; Abnet, Christian C.; Freedman, Neal D.; Taylor, Philip R.; Dawsey, Sanford M.; Etemadi, Arash] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Islami, Farhad; Brennan, Paul J.] Int Agcy Res Canc, F-69372 Lyon, France. [Pharoah, Paul] Univ Cambridge, Canc Res UK, Dept Oncol, Cambridge, England. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Golozar, A (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Shariati Hosp, Tehran, Iran. EM etemadia@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Etemadi, Arash/C-1386-2016 OI Malekzadeh, Reza/0000-0003-1043-3814; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Etemadi, Arash/0000-0002-3458-1072 FU Division of Cancer Epidemiology and Genetics; National Cancer Institute at the National Institutes of Health; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health, by the Digestive Disease Research Center of Tehran University of Medical Sciences (grant No 82-603), and by the International Agency for Research on Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 18 Z9 18 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2011 VL 6 IS 10 AR e26725 DI 10.1371/journal.pone.0026725 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 876BL UT WOS:000299081800032 PM 22053206 ER PT J AU Soman, G Yang, XY Jiang, HG Giardina, S Mitra, G AF Soman, Gopalan Yang, Xiaoyi Jiang, Hengguang Giardina, Steve Mitra, Gautam TI Comparison of GD2 binding capture ELISA assays for anti-GD2-antibodies using GD2-coated plates and a GD2-expressing cell-based ELISA SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Disialoganglioside; Antibody; Enzyme-linked immunono sorbent assay; Cell-based enzyme-linked immunosorbent assay; Potency assay ID COLONY-STIMULATING FACTOR; CHILDRENS ONCOLOGY GROUP; HIGH-RISK NEUROBLASTOMA; I CLINICAL-TRIAL; PHASE-I; ANTI-GD2 ANTIBODY; HU14.18-IL2 EMD-273063; DEPENDENT CYTOTOXICITY; CH14.18; INTERLEUKIN-2 AB Two assay methods for quantification of the disialoganglioside (GD2)-specific binding activities of anti-GD2 monoclonal antibodies and antibody immunofusion proteins, such as ch14.18 and hu14.18-1L2, were developed. The methods differed in the use of either microtiter plates coated with purified GD2 or plates seeded with GD2-expressing cell lines to bind the anti-GD2 molecules. The bound antibodies were subsequently detected using the reactivity of the antibodies to an HRP-labeled anti-IgG Fc or antibodies recognizing the conjugate IL-2 part of the Hu 14.18IL-2 fusion protein. The bound HRP was detected using reagents such as orthophenylene diamine, 2, 2'-azinobis [3-ethylbenzothiazoline-6-sulfonic acid] or tetramethylbenzidine. The capture ELISA using GD2-coated plates was developed earlier in assay development and used to demonstrate assay specificity and to compare lot-to-lot consistency and stability of ch14.18, and Hu14.18 IL-2 in clinical development. During this study, we found a number of issues related to plate-to-plate variability, GD2 lot variability, and variations due to GD2 storage stability, etc., that frequently lead to assay failure in plates coated with purified GD2. The cell-based ELISA (CbELISA) using the GD2 expressing melanoma cell line, M21/P6, was developed as an alternative to the GD2-coated plate ELISA. The results on the comparability of the capture ELISA on GD2-coated plates and the cell-based assay show that both assays give comparable results. However, the cell-based assay is more consistent and reproducible. Subsequently, the anti-GD2 capture ELISA using the GD2-coated plate was replaced with the CbELISA for product lot release testing and stability assessment. (C) 2011 Elsevier B.V. All rights reserved. C1 [Soman, Gopalan; Yang, Xiaoyi; Jiang, Hengguang; Giardina, Steve; Mitra, Gautam] NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Soman, G (reprint author), NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM somang@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 31 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 28 PY 2011 VL 373 IS 1-2 BP 181 EP 191 DI 10.1016/j.jim.2011.08.016 PG 11 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 852ZG UT WOS:000297395400020 PM 21893062 ER PT J AU Liu, YN Tian, XL Leitner, WW Aldridge, ME Zheng, JY Yu, ZY Restifo, NP Weiss, R Scheiblhofer, S Xie, C Sun, R Cheng, GH Zeng, G AF Liu, Yanan Tian, Xiaoli Leitner, Wolfgang W. Aldridge, Michael E. Zheng, Junying Yu, Zhiya Restifo, Nicholas P. Weiss, Richard Scheiblhofer, Sandra Xie, Chong Sun, Ren Cheng, Genhong Zeng, Gang TI Polymeric Structure and Host Toll-like Receptor 4 Dictate Immunogenicity of NY-ESO-1 Antigen in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNE-SYSTEM; SURFACE CALRETICULIN; TUMOR-ANTIGEN; GENE; IDENTIFICATION; IMMUNOTHERAPY; PROGRESSION; EXPRESSION; TOLERANCE; DANGER AB In search of intrinsic factors that contribute to the distinctively strong immunogenicity of a non-mutated cancer/testis antigen, we found that NY-ESO-1 forms polymeric structures through disulfide bonds. NY-ESO-1 binding to immature dendritic cells was dependent on its polymeric structure and involved Toll-like receptor-4 (TLR4) on the surface of immature dendritic cells in mouse and human. Gene gun-delivered plasmid encoding the wild-type NY-ESO-1 readily induced T cell-dependent antibody (Ab) responses in wild-type C57BL/10 mice but not TLR4-knock-out C57BL/10ScNJ mice. Disrupting polymeric structures of NY-ESO-1 by cysteine-to-serine (Cys-to-Ser) substitutions lead to diminished immunogenicity and altered TLR4-dependence in the induced Ab response. To demonstrate its adjuvant effect, NY-ESO-1 was fused with a major mugwort pollen allergen Art v 1 and a tumor-associated antigen, carbonic anhydrase 9. Plasmid DNA vaccines encoding the fusion genes generated robust immune responses against otherwise non-immunogenic targets in mice. Polymeric structure and TLR4 may play important roles in rendering NY-ESO-1 immunogenic and thus serve as a potent molecular adjuvant. NY-ESO-1 thus represents the first example of a cancer/testis antigen that is a also damage-associated molecular pattern. C1 [Liu, Yanan; Tian, Xiaoli; Aldridge, Michael E.; Zheng, Junying; Xie, Chong; Zeng, Gang] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Leitner, Wolfgang W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Yu, Zhiya; Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Weiss, Richard; Scheiblhofer, Sandra] Salzburg Univ, Dept Mol Biol, Christian Doppler Lab Allergy Diag & Therapy, A-5020 Salzburg, Austria. RP Zeng, G (reprint author), 66 128 Ctr Hlth Sci, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM gzeng@mednet.ucla.edu RI Leitner, Wolfgang/F-5741-2011; Restifo, Nicholas/A-5713-2008; Weiss, Richard/N-7279-2013; OI Leitner, Wolfgang/0000-0003-3125-5922; Weiss, Richard/0000-0003-3185-7253; Restifo, Nicholas P./0000-0003-4229-4580 FU UCLA; American Cancer Society [RSG-08-070-01-LIB] FX This work was supported in part by the UCLA Gene Medicine Program (to G. Z.) and Research Scholar Award RSG-08-070-01-LIB from the American Cancer Society (to G. Z.). NR 22 TC 4 Z9 6 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 28 PY 2011 VL 286 IS 43 BP 37077 EP 37084 DI 10.1074/jbc.M111.280123 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841VD UT WOS:000296542400008 PM 21900253 ER PT J AU Ogura, K Yahiro, K Tsutsuki, H Nagasawa, S Yamasaki, S Moss, J Noda, M AF Ogura, Kohei Yahiro, Kinnosuke Tsutsuki, Hiroyasu Nagasawa, Sayaka Yamasaki, Shinji Moss, Joel Noda, Masatoshi TI Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATING FACTOR; VIBRIO-CHOLERAE; CYTOCHROME-C; UNITED-STATES; DEATH; ACTIVATION; PROTEINS; MECHANISMS; CASPASES; CLEAVAGE AB Cholix toxin (Cholix) is a novel ADP-ribosylating cytotoxin produced by Vibrio cholerae, which utilizes eukaryotic elongation factor 2 as a substrate and acts by a mechanism similar to that of diphtheria toxin and Pseudomonas exotoxin A. First it was found that Cholix-treated HeLa cells exhibited caspase-dependent apoptosis, whereas intestinal cells such as Caco-2, HCT116, and RKO did not. Here we investigated Cholix-induced cell death signaling pathways in HeLa cells. Cholix-induced cytochrome c release into cytosol was initiated by specific conformational changes of pro-apoptotic Bak associated with Bax. Silencing of bak/bax genes or bak gene alone using siRNA significantly suppressed cytochrome c release and caspase-7 activation, but not activation of caspases-3 and -9. Although pretreatment with a caspase-8 inhibitor (Z-IETD-FMK) reduced Cholix-induced cytochrome c release and activation of caspases-3, -7, and -9, cytotoxicity was not decreased. Pretreatment with Z-YVAD-FMK, which inhibits caspase-1, -4, and -5, suppressed not only cytochrome c release, activation of caspase-3, -7, -8, or -9, and PARP cleavage, but also cytotoxicity, indicating that caspase-1, -4, and -5 activation is initiated at an early stage of Cholix-induced apoptosis and promotes caspase-8 activation. These results show that the inflammatory caspases (caspase-1, -4, and -5) and caspase-8 are responsible for both mitochondrial signals and other caspase activation. In conclusion, we showed that Cholix-induced caspase activation plays an essential role in generation of apoptotic signals, which are mediated by both mitochondria-dependent and -independent pathways. C1 [Ogura, Kohei; Yahiro, Kinnosuke; Tsutsuki, Hiroyasu; Nagasawa, Sayaka; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chuo Ku, Chiba, Japan. [Nagasawa, Sayaka] Chiba Univ, Grad Sch Med, Dept Legal Med, Chuo Ku, Chiba, Japan. [Yamasaki, Shinji] Osaka Prefecture Univ, Grad Sch Life & Environm Sci, Osaka 5988531, 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, Chuo Ku, 1-8-1 Inohana, Chiba, Japan. EM yahirok@faculty.chiba-u.jp FU 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 for Young Scientists (B) of Japan and Improvement of Research Environment for Young Researchers from Japan Science and Technology Agency.; Supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 41 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 28 PY 2011 VL 286 IS 43 BP 37207 EP 37215 DI 10.1074/jbc.M111.246504 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841VD UT WOS:000296542400021 PM 21903588 ER PT J AU Pfeiffer, M Kayzer, EB Yang, XM Abramson, E Kenaston, MA Lago, CU Lo, HH Sedensky, MM Lunceford, A Clarke, CF Wu, SJ McLeod, C Finkel, T Morgan, PG Mills, EM AF Pfeiffer, Matthew Kayzer, Ernst-Bernhard Yang, Xianmei Abramson, Ellen Kenaston, M. Alexander Lago, Cory U. Lo, Herng-Hsiang Sedensky, Margaret M. Lunceford, Adam Clarke, Catherine F. Wu, Sarah J. McLeod, Chris Finkel, Toren Morgan, Philip G. Mills, Edward M. TI Caenorhabditis elegans UCP4 Protein Controls Complex II-mediated Oxidative Phosphorylation through Succinate Transport SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL UNCOUPLING-PROTEIN; BROWN-ADIPOSE-TISSUE; RECEPTOR GPR91; PROTON CONDUCTANCE; CLK-1 MUTANTS; FAT STORAGE; C-ELEGANS; RECONSTITUTION; SUPEROXIDE; METABOLISM AB The novel uncoupling proteins (UCP2-5) are implicated in the mitochondrial control of oxidant production, insulin signaling, and aging. Attempts to understand their functions have been complicated by overlapping expression patterns in most organisms. Caenorhabditis elegans nematodes are unique because they express only one UCP ortholog, ceUCP4 (ucp4). Here, we performed detailed metabolic analyzes in genetically modified nematodes to define the function of the ceUCP4. The knock-out mutant ucp4 (ok195) exhibited sharply decreased mitochondrial succinate-driven (complex II) respiration. However, respiratory coupling and electron transport chain function were normal in ucp4 mitochondria. Surprisingly, isolated ucp4 mitochondria showed markedly decreased succinate uptake. Similarly, ceUCP4 inhibition blocked succinate respiration and import in wild type mitochondria. Genetic and pharmacologic inhibition of complex I function was selectively lethal to ucp4 worms, arguing that ceUCP4-regulated succinate transport is required for optimal complex II function in vivo. Additionally, ceUCP4 deficiency prolonged lifespan in the short-lived mev1 mutant that exhibits complex II-generated oxidant production. These results identify a novel function for ceUCP4 in the regulation of complex II-based metabolism through an unexpected mechanism involving succinate transport. C1 [Kayzer, Ernst-Bernhard; Sedensky, Margaret M.; Morgan, Philip G.] Seattle Childrens Res Inst, Ctr Dev Therapeut, Seattle, WA USA. [Pfeiffer, Matthew; Abramson, Ellen; Kenaston, M. Alexander; Lago, Cory U.; Lo, Herng-Hsiang; Wu, Sarah J.; Mills, Edward M.] Univ Texas Austin, Dept Pharmacol & Toxicol, Coll Pharm, Austin, TX 78712 USA. [Abramson, Ellen; Lago, Cory U.; Lo, Herng-Hsiang; Mills, Edward M.] Univ Texas Austin, Inst Cell & Mol Biol, Austin, TX 78712 USA. [Yang, Xianmei] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [Lunceford, Adam; Clarke, Catherine F.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90024 USA. [Lago, Cory U.; Finkel, Toren] NHLBI, NIH, Bethesda, MD 20892 USA. [McLeod, Chris] Mayo Clin, Rochester, MN 55905 USA. RP Morgan, PG (reprint author), Seattle Childrens Res Inst, Ctr Dev Therapeut, Seattle, WA USA. EM philip.morgan@seattlechildrens.org; ted_mills@mail.utexas.edu FU National Institutes of Health [DK089224, GM58881, AG026073, GMS 45952, ES007247] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK089224 (to E. M. M.), GM58881 and AG026073 (to P. G. M., M. M. S., and E.-B. K.), and GMS 45952 (to C. F. C.), and Training Grant ES007247 (to M. E. P). NR 52 TC 16 Z9 19 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 28 PY 2011 VL 286 IS 43 BP 37712 EP 37720 DI 10.1074/jbc.M111.271452 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841VD UT WOS:000296542400067 PM 21862587 ER PT J AU Wu, J Petralia, RS Kurushima, H Patel, H Jung, MY Volk, L Chowdhury, S Shepherd, JD Dehoff, M Li, Y Kuhl, D Huganir, RL Price, DL Scannevin, R Troncoso, JC Wong, PC Worley, PF AF Wu, Jing Petralia, Ronald S. Kurushima, Hideaki Patel, Hiral Jung, Mi-Young Volk, Lenora Chowdhury, Shoaib Shepherd, Jason D. Dehoff, Marlin Li, Yueming Kuhl, Dietmar Huganir, Richard L. Price, Donald L. Scannevin, Robert Troncoso, Juan C. Wong, Philip C. Worley, Paul F. TI Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent beta-Amyloid Generation SO CELL LA English DT Article ID GAMMA-SECRETASE ACTIVITY; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; PRECURSOR PROTEIN; CELL BIOLOGY; IN-VIVO; DEPOSITION; TRAFFICKING; PRESENILINS; FRAGMENTS AB Assemblies of beta-amyloid (A beta) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. The generation of A beta is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene Arc is required for activity-dependent generation of A beta. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both Hebbian and non-Hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate gamma-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces A beta load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypothesize that Arc participates in the pathogenesis of AD. C1 [Wu, Jing; Kurushima, Hideaki; Volk, Lenora; Chowdhury, Shoaib; Shepherd, Jason D.; Dehoff, Marlin; Huganir, Richard L.; Price, Donald L.; Wong, Philip C.; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Price, Donald L.; Troncoso, Juan C.; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Price, Donald L.; Troncoso, Juan C.; Wong, Philip C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Volk, Lenora; Huganir, Richard L.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Petralia, Ronald S.] NIDCD, Lab Neurochem, NIH, Bethesda, MD 20892 USA. [Patel, Hiral; Jung, Mi-Young; Scannevin, Robert] Biogen Idec Inc, Cambridge, MA 02142 USA. [Li, Yueming] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10021 USA. [Kuhl, Dietmar] Univ Med Ctr Hamburg Eppendorf UKE, Ctr Mol Neurobiol ZMNH, Inst Mol & Cellular Cognit, D-20251 Hamburg, Germany. RP Worley, PF (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. EM pworley@jhmi.edu OI Kuhl, Dietmar/0000-0002-4772-6701; Scannevin, Robert/0000-0002-5749-2785 FU NIMH [RO1 MH053608]; Johns Hopkins Alzheimer's Disease Research Center (NIH) [P50AG005146]; NIDCD; NIH [MH084020] FX We would like to thank Gopal Thinakaran, Sangram Sisodia (University of Chicago), and Tong Li for critical reagents and helpful discussions. Thanks to Gay Rudow for helping with unbiased stereology. Thanks to Desheng Xu and Shi Yang for help with lentivirus packaging. Many thanks to Robert Ardiuni, Melissa Levesque, Darren Baker, and Stephan Miller from Biogen Idec for their excellent technical support on in vitro binding assay. We thank Ya-Xian Wang for help with the EM studies. We also thank Robert Malinow (University of California at San Diego) and Mike Ehlers (Duke University) for APP Sindbis virus constructs and GFP-Rab constructs. This work was supported by NIMH grant RO1 MH053608 (P.F.W.), the Johns Hopkins Alzheimer's Disease Research Center (NIH grant P50AG005146) and in part by the NIDCD Intramural Program (R.S.P.) and NIH grant MH084020. NR 30 TC 62 Z9 62 U1 0 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 28 PY 2011 VL 147 IS 3 BP 615 EP 628 DI 10.1016/j.cell.2011.09.036 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842EH UT WOS:000296573700016 PM 22036569 ER PT J AU Inglese, J Hasson, SA AF Inglese, James Hasson, Samuel A. TI Biology-Driven Library Design for Probe Discovery SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID TOOLS AB Libraries of diverse small molecules are important to probe and drug discovery. The current trend toward building massive screening collections to support drug development, a special application of chemical biology, can limit their broader potential. Biology-driven construction methods (Wallace et al., 2011) are rapidly emerging to bring chemical libraries back on a viable path. C1 [Inglese, James; Hasson, Samuel A.] NHGRI, NIH Ctr Translat Therapeut, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), NHGRI, NIH Ctr Translat Therapeut, NIH, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD OCT 28 PY 2011 VL 18 IS 10 BP 1204 EP 1205 DI 10.1016/j.chembiol.2011.10.004 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842KC UT WOS:000296597200004 PM 22035786 ER PT J AU Morris, SE Holroyd, CB Mann-Wrobel, MC Gold, JM AF Morris, Sarah E. Holroyd, Clay B. Mann-Wrobel, Monica C. Gold, James M. TI Dissociation of response and feedback negativity in schizophrenia: electrophysiological and computational evidence for a deficit in the representation of value SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE schizophrenia; error-related negativity; feedback; reward; dopamine ID ERROR-RELATED NEGATIVITY; ANTERIOR CINGULATE CORTEX; MEDIAL FRONTAL-CORTEX; TIME-ESTIMATION TASK; PREDICTION ERROR; REWARD PREDICTION; ANTIPSYCHOTIC TREATMENT; CORRECTING BEHAVIOR; DOPAMINE NEURONS; EFFERENCE COPY AB Contrasting theories of schizophrenia propose that the disorder is characterized by a deficient in phasic changes in dopamine activity in response to ongoing events or, alternatively, by a weakness in the representation of the value of responses. Schizophrenia patients have reliable reduced brain activity following incorrect responses but other research suggests that may have intact feedback-related potentials, indicating that the impairment may be specifically response-related. We used event-related brain potentials and computational modeling to examine this issue by comparing the neural response to outcomes with the neural response to behaviors that predict outcomes in patients with schizophrenia and psychiatrically healthy comparison subjects. We recorded feedback-related activity in a passive gambling task and a time estimation task and error-related activity in a flanker task. Patients' brain activity following an erroneous response was reduced compared to comparison subjects but feedback-related activity did not differ between groups. To test hypotheses about the possible causes of this pattern of results, we used computational modeling of the electrophysiological data to simulate the effects of an overall reduction in patients' sensitivity to feedback, selective insensitivity to positive or negative feedback, reduced learning rate, and a decreased representation of the value of the response given the stimulus on each trial. The results of the computational modeling suggest that schizophrenia patients exhibit weakened representation of response values, possible due to failure of the basal ganglia to strongly associate stimuli with appropriate response alternatives. C1 [Morris, Sarah E.; Mann-Wrobel, Monica C.] VISN 5 Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. [Morris, Sarah E.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Holroyd, Clay B.] Univ Victoria, Dept Psychol, Victoria, BC, Canada. [Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. RP Morris, SE (reprint author), NIMH, Div Adult Translat Res, Room 7107,6001 Execut Blvd, Bethesda, MD 20892 USA. EM sarah.morris@nih.gov FU Department of Veterans Affairs Rehabilitation Research and Development Service [D6064W]; National Institute of Mental Health [1R01 MH080066, 1R24 MH72647] FX This work was supported by the Department of Veterans Affairs Rehabilitation Research and Development Service (grant number D6064W to Sarah E. Morris); and the National Institute of Mental Health (grant numbers 1R01 MH080066, 1R24 MH72647 to James M. Gold). NR 99 TC 27 Z9 27 U1 6 U2 16 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 28 PY 2011 VL 5 AR 123 DI 10.3389/fnhum.2011.00123 PG 16 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 844VO UT WOS:000296778000001 PM 22065618 ER PT J AU Hershko, AY Suzuki, R Charles, N Alvarez-Errico, D Sargent, JL Laurence, A Rivera, J AF Hershko, Alon Y. Suzuki, Ryo Charles, Nicolas Alvarez-Errico, Damiana Sargent, Jennifer L. Laurence, Arian Rivera, Juan TI Mast Cell Interleukin-2 Production Contributes to Suppression of Chronic Allergic Dermatitis SO IMMUNITY LA English DT Article ID REGULATORY T-CELLS; ATOPIC-DERMATITIS; CONTACT HYPERSENSITIVITY; MURINE MODEL; IN-VIVO; IMMUNE-RESPONSES; ULTRAVIOLET-B; MICE; DISEASE; MOUSE AB The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (Kit(W-sh/W-sh)), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not ll2(-/-), mast cells into Kit(W-sh/W-sh) mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation. C1 [Hershko, Alon Y.; Suzuki, Ryo; Charles, Nicolas; Alvarez-Errico, Damiana; Sargent, Jennifer L.; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Laurence, Arian/A-8770-2009; Charles, Nicolas/P-5430-2014 OI Laurence, Arian/0000-0003-0942-8292; Charles, Nicolas/0000-0002-5416-5834 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health; American Physician Fellowship; Legacy Heritage Fund - Israel Science Foundation; Laboratory Animal Care and Use Section, the Flow Cytometry Unit, and the Light Imaging Section of NIAMS FX This work was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health. A.Y.H. was also supported by the American Physician Fellowship and by the Legacy Heritage Fund - Israel Science Foundation. We also thank the Laboratory Animal Care and Use Section, the Flow Cytometry Unit, and the Light Imaging Section of NIAMS for support of this work. NR 51 TC 40 Z9 42 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 28 PY 2011 VL 35 IS 4 BP 562 EP 571 DI 10.1016/j.immuni.2011.07.013 PG 10 WC Immunology SC Immunology GA 843FM UT WOS:000296657700015 PM 21982597 ER PT J AU Lu, KT Kanno, Y Cannons, JL Handon, R Bible, P Elkahloun, AG Anderson, SM Wei, L Sun, HW O'Shea, JJ Schwartzberg, PL AF Lu, Kristina T. Kanno, Yuka Cannons, Jennifer L. Handon, Robin Bible, Paul Elkahloun, Abdel G. Anderson, Stacie M. Wei, Lai Sun, Hongwei O'Shea, John J. Schwartzberg, Pamela L. TI Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells SO IMMUNITY LA English DT Article ID CENTER B-CELL; MECHANISM DISTINCT; HUMORAL IMMUNITY; PROVIDE HELP; IN-VIVO; EXPRESSION; RECEPTOR; IL-21; RESPONSES; LINEAGE AB Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex vivo Tfh cells and on Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations. C1 [Lu, Kristina T.; Cannons, Jennifer L.; Handon, Robin; Elkahloun, Abdel G.; Anderson, Stacie M.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kanno, Yuka; Bible, Paul; Wei, Lai; Sun, Hongwei; O'Shea, John J.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Wei, Lai/D-1088-2014; OI Kanno, Yuka/0000-0001-5668-9319 FU NHGRI; NIAMS (NIH); NIGMS (NIH) FX We thank J. Gomez-Rodriguez, J. Zhu, and K. Zhao for helpful advice and J. Reilley and A. Venegas for technical assistance. This work was funded in part by the intramural research programs of the NHGRI and NIAMS (NIH). K.T.L. was supported by a PRAT Fellowship from the NIGMS (NIH). NR 56 TC 101 Z9 108 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 28 PY 2011 VL 35 IS 4 BP 622 EP 632 DI 10.1016/j.immuni.2011.07.015 PG 11 WC Immunology SC Immunology GA 843FM UT WOS:000296657700020 PM 22018472 ER PT J AU Epstein, JE Tewari, K Lyke, KE Sim, BKL Billingsley, PF Laurens, MB Gunasekera, A Chakravarty, S James, ER Sedegah, M Richman, A Velmurugan, S Reyes, S Li, M Tucker, K Ahumada, A Ruben, AJ Li, T Stafford, R Eappen, AG Tamminga, C Bennett, JW Ockenhouse, CF Murphy, JR Komisar, J Thomas, N Loyevsky, M Birkett, A Plowe, CV Loucq, C Edelman, R Richie, TL Seder, RA Hoffman, SL AF Epstein, J. E. Tewari, K. Lyke, K. E. Sim, B. K. L. Billingsley, P. F. Laurens, M. B. Gunasekera, A. Chakravarty, S. James, E. R. Sedegah, M. Richman, A. Velmurugan, S. Reyes, S. Li, M. Tucker, K. Ahumada, A. Ruben, A. J. Li, T. Stafford, R. Eappen, A. G. Tamminga, C. Bennett, J. W. Ockenhouse, C. F. Murphy, J. R. Komisar, J. Thomas, N. Loyevsky, M. Birkett, A. Plowe, C. V. Loucq, C. Edelman, R. Richie, T. L. Seder, R. A. Hoffman, S. L. TI Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8(+) T Cell Immunity SO SCIENCE LA English DT Article ID SPOROZOITE SURFACE PROTEIN-2; PLASMODIUM-FALCIPARUM SPOROZOITES; CIRCUMSPOROZOITE PROTEIN; INFECTED HEPATOCYTES; PREERYTHROCYTIC STAGES; GAMMA-INTERFERON; IMMUNIZATION; RESPONSES; HUMANS; MICE AB Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in >= 80% of recipients. Pf sporozoites (Pf SPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans. Such protection is thought to be mediated by CD8(+) T cells in the liver that secrete interferon-gamma (IFN-gamma). We report that purified irradiated Pf SPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of Pf SPZ-specific CD8(+), IFN-gamma-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria. C1 [Tewari, K.; Seder, R. A.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Epstein, J. E.; Sedegah, M.; Reyes, S.; Tamminga, C.; Thomas, N.; Richie, T. L.] USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD 20910 USA. [Lyke, K. E.; Laurens, M. B.; Plowe, C. V.; Edelman, R.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Sim, B. K. L.; Billingsley, P. F.; Gunasekera, A.; Chakravarty, S.; James, E. R.; Richman, A.; Velmurugan, S.; Ahumada, A.; Ruben, A. J.; Li, T.; Stafford, R.; Eappen, A. G.; Loyevsky, M.; Hoffman, S. L.] Sanaria Inc, Rockville, MD 20850 USA. [Sim, B. K. L.; Li, M.; Ahumada, A.; Stafford, R.; Hoffman, S. L.] Prot Potential LLC, Rockville, MD 20850 USA. [Laurens, M. B.; Plowe, C. V.] Howard Hughes Med Inst, Baltimore, MD 21201 USA. [Tucker, K.] Stat Collaborat Inc, Washington, DC 20036 USA. [Bennett, J. W.; Ockenhouse, C. F.; Murphy, J. R.; Komisar, J.] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Silver Spring, MD 20910 USA. [Birkett, A.; Loucq, C.] PATH Malaria Vaccine Initiat, Bethesda, MD 20814 USA. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov; slhoffman@sanaria.com RI Bennett, Jason/B-3547-2011; Laurens, Matthew/E-7293-2013 OI Laurens, Matthew/0000-0003-3874-581X FU Bill and Melinda Gates Foundation (BMGF); National Institute of Allergy and Infectious Diseases-NIH [5R44AI055229-07, 5R44AI058499-05, 5R44AI058375-05]; Institute for OneWorld Health (BMGF); U.S. Military Infectious Disease; Work Unit [6000.RAD1.F.A0309]; Howard Hughes Medical Institute; Doris Duke Charitable Foundation FX We thank the volunteers and the PfSPZ Vaccine Development Teams and NHP team (see SOM) for their participation and efforts. The PATH Malaria Vaccine Initiative (MVI) supported the clinical trial with funds from the Bill and Melinda Gates Foundation (BMGF). Sanaria acknowledges support from National Institute of Allergy and Infectious Diseases-NIH Small Business Innovation Research grants, especially 5R44AI055229-07, 5R44AI058499-05, and 5R44AI058375-05; Institute for OneWorld Health (funds from BMGF); and U.S. Military Infectious Disease Research Program, which enabled development and manufacture of the vaccine. At Naval Medical Research Center, work was funded by Work Unit Number 6000.RAD1.F.A0309. At UMD, PCR work was funded by the Howard Hughes Medical Institute and Doris Duke Charitable Foundation. All of the data reported in the manuscript are tabulated in the main text and in the SOM. A materials transfer agreement will be required for the use of recombinant PfMSP-1 and PfEBA-175 and for HC-04 cells. A number of patents on PfSPZ have been issued, allowed, or filed in the United States and internationally. The U.S. patents include S. L. Hoffman et al., U.S. Patent 7,229,627 (2007) (there is a divisional of this patent with claims directed to aseptic adult Anopheles-species mosquitoes and aseptic Plasmodium-species sporozoites, USSN 11/726,622); S. L. Hoffman et al., U.S. Patent Pub. US2005/0208078 (2005); and B. K. L. Sim, S. L. Hoffman, M. Li, R. E. Stafford, U.S. Patent Pub U. S. 2010/0183680 (2010). There is also a patent on HC-04 cells [J. Prachumsri et al., U.S. Patent 7015036 (2006)]. NR 51 TC 181 Z9 183 U1 2 U2 42 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 28 PY 2011 VL 334 IS 6055 BP 475 EP 480 DI 10.1126/science.1211548 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837UR UT WOS:000296230500037 PM 21903775 ER PT J AU Hayashi, Y Ito, Y Yamagishi, N Yanagiba, Y Tamada, H Wang, D Ramdhan, DH Naito, H Harada, Y Kamijima, M Gonzales, FJ Nakajima, T AF Hayashi, Yumi Ito, Yuki Yamagishi, Nozomi Yanagiba, Yukie Tamada, Hazuki Wang, Dong Ramdhan, Doni Hikmat Naito, Hisao Harada, Yukiko Kamijima, Michihiro Gonzales, Frank J. Nakajima, Tamie TI Hepatic peroxisome proliferator-activated receptor a may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice SO TOXICOLOGY LA English DT Article DE DEHP; PPAR alpha; Offspring; TG; MTP; beta-Oxidation ID TRIGLYCERIDE TRANSFER PROTEIN; CLINICAL-CHEMISTRY VALUES; ALPHA PPAR-ALPHA; DEVELOPMENTAL TOXICITY; PHTHALATE DEHP; EXPRESSION; RATS; PREGNANCY; LIVER; ENZYMES AB Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) alpha, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPAR alpha. Male and female Sv/129 wild-type (mPPAR alpha), Ppar alpha-null and humanized PPAR alpha (hPPAR alpha) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPAR alpha mice. In hPPAR alpha mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPAR alpha and at the high dose in hPPAR alpha mice. No such findings were observed in Ppar alpha-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPAR alpha mice, but not in Ppar alpha-null and hPPAR alpha ones. Above the medium dose in mPPAR alpha mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium-and/or high-dose DEHP increased the levels of maternal PPAR alpha target genes in mPPAR alpha and hPPAR alpha mice. Taken together, PPAR alpha expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPAR alpha mice and not in hPPAR alpha mice. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Hayashi, Yumi; Ito, Yuki; Yamagishi, Nozomi; Yanagiba, Yukie; Tamada, Hazuki; Wang, Dong; Ramdhan, Doni Hikmat; Naito, Hisao; Kamijima, Michihiro; Nakajima, Tamie] Nagoya Univ, Dept Occupat & Environm Hlth, Grad Sch Med, Showa Ku, Nagoya, Aichi 4668550, Japan. [Ito, Yuki; Kamijima, Michihiro] Nagoya City Univ, Dept Occupat & Environm Hlth, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Yanagiba, Yukie] Natl Inst Occupat Safety & Hlth, Tama Ku, Kawasaki, Kanagawa 2148585, Japan. [Harada, Yukiko] Shinshu Univ, Dept Pediat, Grad Sch Med, Matsumoto, Nagano 3908621, Japan. [Gonzales, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Dept Occupat & Environm Hlth, Grad Sch Med, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp RI Ito, Yuki/C-3698-2008 FU Japan Society for the Promotion of Science [B20390171]; Food Safety Commission, Japan [1002]; Research on Food Safety of the Ministry of Health, Labour and Welfare [200939055A] FX This work was supported by Grants-in-Aid for Scientific Research (B20390171) from the Japan Society for the Promotion of Science from Food Safety Commission, Japan (1002) and Health and Labour Sciences Research Grants from Research on Food Safety of the Ministry of Health, Labour and Welfare (200939055A). NR 45 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 0300-483X J9 TOXICOLOGY JI Toxicology PD OCT 28 PY 2011 VL 289 IS 1 BP 1 EP 10 DI 10.1016/j.tox.2011.02.007 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 820BD UT WOS:000294879600001 PM 21354252 ER PT J AU Zhu, YM Luo, TM Jobin, C Young, HA AF Zhu, Yuanmin Luo, T. Michelle Jobin, Christian Young, Howard A. TI Gut microbiota and probiotics in colon tumorigenesis SO CANCER LETTERS LA English DT Review DE Microbiota; Inflammation; Probiotics; Colorectal cancer ID LACTOBACILLUS-RHAMNOSUS; COLORECTAL-CANCER; BIFIDOBACTERIUM-LACTIS; INTESTINAL MICROBIOTA; ULCERATIVE-COLITIS; ANTITUMOR-ACTIVITY; ESCHERICHIA-COLI; RESISTANT STARCH; FED INFANTS; IN-VIVO AB The human gastrointestinal tract harbors a complex and abundant microbial community reaching as high as 10(13)-10(14) microorganisms in the colon. This endogenous microbiota forms a symbiotic relationship with their eukaryotic host and this close partnership helps maintain homeostasis by performing essential and non-redundant tasks (e.g. nutrition/energy and, immune system balance, pathogen exclusion). Although this relationship is essential and beneficial to the host, various events (e.g. infection, diet, stress, inflammation) may impact microbial composition, leading to the formation of a dysbiotic microbiota, further impacting on health and disease states. For example, Crohn's disease and ulcerative colitis, collectively termed inflammatory bowel diseases (IBD), have been associated with the establishment of a dysbiotic microbiota. In addition, extra-intestinal disorders such as obesity and metabolic syndrome are also associated with the development of a dysbiotic microbiota. Consequently, there is an increasing interest in harnessing the power of the microbiome and modulating its composition as a means to alleviate intestinal pathologies/disorders and maintain health status. In this review, we will discuss the emerging relationship between the microbiota and development of colorectal cancer as well as present evidence that microbial manipulation (probiotic, prebiotic) impacts disease development. Published by Elsevier Ireland Ltd. C1 [Young, Howard A.] Natl Canc Inst, Ctr Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21702 USA. [Zhu, Yuanmin] Beijing Univ, Peoples Hosp, Dept Digest Dis, Beijing 100871, Peoples R China. [Jobin, Christian] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Luo, T. Michelle] US FDA, CDRH, OIVD, Silver Spring, MD USA. RP Young, HA (reprint author), Natl Canc Inst, Ctr Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Bldg 560-31-23,Chandler St, Frederick, MD 21702 USA. EM YoungHow@mail.nih.gov FU NIH [HHSN261200800001E]; 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. This project has been funded with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. NR 76 TC 62 Z9 72 U1 3 U2 65 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 28 PY 2011 VL 309 IS 2 BP 119 EP 127 DI 10.1016/j.canlet.2011.06.004 PG 9 WC Oncology SC Oncology GA 816CN UT WOS:000294576400001 PM 21741763 ER PT J AU Bevans, MF AF Bevans, Margaret F. TI Complacency is not an option SO BLOOD LA English DT Editorial Material ID HEMATOPOIETIC-CELL TRANSPLANTATION; LONG-TERM SURVIVORS; OF-THE-LITERATURE; OUTCOMES C1 NIH Clin Ctr, Bethesda, MD USA. RP Bevans, MF (reprint author), NIH Clin Ctr, Bethesda, MD USA. NR 11 TC 1 Z9 1 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 27 PY 2011 VL 118 IS 17 BP 4506 EP 4507 DI 10.1182/blood-2011-08-373332 PG 4 WC Hematology SC Hematology GA 839LY UT WOS:000296368700007 PM 22033945 ER PT J AU Aue, G Du, Y Cleveland, SM Smith, SB Dave, UP Liu, DL Weniger, MA Metais, JY Jenkins, NA Copeland, NG Dunbar, CE AF Aue, Georg Du, Yang Cleveland, Susan M. Smith, Stephen B. Dave, Utpal P. Liu, Delong Weniger, Marc A. Metais, Jean Yves Jenkins, Nancy A. Copeland, Neal G. Dunbar, Cynthia E. TI Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia SO BLOOD LA English DT Article ID GENE-EXPRESSION SIGNATURE; TRANSCRIPTION FACTOR; NADPH OXIDASE; MICE; CANCER; CELLS; DIFFERENTIATION; IDENTIFICATION; PROGENITORS; COMMITMENT AB Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)-expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1(ko/+) bone mar-row progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia. (Blood. 2011; 118(17): 4674-4681) C1 [Aue, Georg; Liu, Delong; Weniger, Marc A.; Metais, Jean Yves; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Du, Yang] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Cleveland, Susan M.; Smith, Stephen B.; Dave, Utpal P.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Jenkins, Nancy A.; Copeland, Neal G.] Inst Mol & Cell Biol, Canc Genet Lab, Proteos, Singapore. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC Rm 4-5132,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM dunbarc@mail.nih.gov RI ASTAR, IMCB/E-2320-2012 FU National Institutes of Health; Department of Pediatrics of the Uniformed Services University of Health Sciences; T. J. Martell Foundation; Hope Street Kids; National Heart, Lung, and Blood Institute [1K08HL089403]; National Cancer Institute [T32 CA009592]; Biomedical Research Council; Agency for Science and Technology and Research (A*STAR), Singapore FX This work was supported by the National Institutes of Health Intramural Research program, the Department of Pediatrics of the Uniformed Services University of Health Sciences, the T. J. Martell Foundation (U. P. D.), Hope Street Kids (U. P. D.), and the National Heart, Lung, and Blood Institute (grant 1K08HL089403, U. P. D.). S. B. S. was supported by the National Cancer Institute (training grant T32 CA009592). N.A.J. and N.G.C. were supported by the Biomedical Research Council, Agency for Science and Technology and Research (A*STAR), Singapore. NR 41 TC 14 Z9 14 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 27 PY 2011 VL 118 IS 17 BP 4674 EP 4681 DI 10.1182/blood-2011-04-351528 PG 8 WC Hematology SC Hematology GA 839LY UT WOS:000296368700030 PM 21878674 ER PT J AU Pilon, AM Ajay, SS Kumar, SA Steiner, LA Cherukuri, PF Wincovitch, S Anderson, SM Mullikin, JC Gallagher, PG Hardison, RC Margulies, EH Bodine, DM AF Pilon, Andre M. Ajay, Subramanian S. Kumar, Swathi Ashok Steiner, Laurie A. Cherukuri, Praveen F. Wincovitch, Stephen Anderson, Stacie M. Mullikin, James C. Gallagher, Patrick G. Hardison, Ross C. Margulies, Elliott H. Bodine, David M. CA NISC Comparative Sequencing Ctr TI Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation SO BLOOD LA English DT Article ID EKLF-DEFICIENT MICE; FACTOR KLF1 CAUSES; CHROMATIN OCCUPANCY; FACTOR GATA-1; GLOBAL ROLE; IN-VITRO; GENE; EXPRESSION; ERYTHROPOIESIS; CELLS AB Erythropoiesis is dependent on the activity of transcription factors, including the erythroid-specific erythroid Kruppel-like factor (EKLF). ChIP followed by massively parallel sequencing (ChIP-Seq) is a powerful, unbiased method to map transfactor occupancy. We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts. We correlated these results with the nuclear distribution of EKLF, RNA-Seq analysis of the transcriptome, and the occupancy of other erythroid transcription factors. In progenitor cells, EKLF is found predominantly at the periphery of the nucleus, where EKLF primarily occupies the promoter regions of genes and acts as a transcriptional activator. In erythroblasts, EKLF is distributed throughout the nucleus, and erythroblast-specific EKLF occupancy is predominantly in intragenic regions. In progenitor cells, EKLF modulates general cell growth and cell cycle regulatory pathways, whereas in erythroblasts EKLF is associated with repression of these pathways. The EKLF interactome shows very little overlap with the interactomes of GATA1, GATA2, or TAL1, leading to a model in which EKLF directs programs that are independent of those regulated by the GATA factors or TAL1. (Blood. 2011; 118(17):e139-e148) C1 [Pilon, Andre M.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Ajay, Subramanian S.; Cherukuri, Praveen F.; Margulies, Elliott H.] NHGRI, Genome Technol Branch, NIH, Rockville, MD USA. [Kumar, Swathi Ashok; Hardison, Ross C.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Steiner, Laurie A.; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Steiner, Laurie A.; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Mullikin, James C.; NISC Comparative Sequencing Ctr] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD USA. RP Bodine, DM (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49,Rm 4A04, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov RI cheng, yong/I-4270-2012; Kumar, Swathi/I-7941-2015 OI Kumar, Swathi/0000-0002-2770-5145 FU NHGRI; NIH Intramural Sequencing Center; NIH [R01HL65448, R01DK62039, R01DK065806, RC2HG005573]; National Science Foundation (Penn State CyberSTAR computer) [OCI-0821527] FX This work was supported by NHGRI intramural funds (D. M. B., and E. H. M.), NIH Intramural Sequencing Center funds (J.C.M.), and the NIH (grants R01HL65448 and R01DK62039, P. G. G.; and grants R01DK065806 and RC2HG005573, R. C. H). This work was supported in part through instrumentation funded by the National Science Foundation (grant OCI-0821527, Penn State CyberSTAR computer). NR 47 TC 54 Z9 55 U1 0 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 27 PY 2011 VL 118 IS 17 BP E139 EP E148 DI 10.1182/blood-2011-05-355107 PG 10 WC Hematology SC Hematology GA 839LY UT WOS:000296368700001 PM 21900194 ER PT J AU Robinson, OJ AF Robinson, Oliver J. TI Boost resilience to tackle mental illness SO NATURE LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), NIMH, Bethesda, MD 20892 USA. EM robinsonoj@mail.nih.gov OI Robinson, Oliver/0000-0002-3100-1132 NR 2 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 459 EP 459 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200025 PM 22031429 ER PT J AU Holmes, EC AF Holmes, Edward C. TI GENOMICS Plague's progress SO NATURE LA English DT Editorial Material ID YERSINIA-PESTIS; ATHENS; VIRUS; DNA C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] Fogarty Int Ctr, Bethesda, MD USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM echolmes@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 10 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 465 EP 466 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200030 PM 22031436 ER PT J AU Lindblad-Toh, K Garber, M Zuk, O Lin, MF Parker, BJ Washietl, S Kheradpour, P Ernst, J Jordan, G Mauceli, E Ward, LD Lowe, CB Holloway, AK Clamp, M Gnerre, S Alfoldi, J Beal, K Chang, J Clawson, H Cuff, J Di Palma, F Fitzgerald, S Flicek, P Guttman, M Hubisz, MJ Jaffe, DB Jungreis, I Kent, WJ Kostka, D Lara, M Martins, AL Massingham, T Moltke, I Raney, BJ Rasmussen, MD Robinson, J Stark, A Vilella, AJ Wen, JY Xie, XH Zody, MC Worley, KC Kovar, CL Muzny, DM Gibbs, RA Warren, WC Mardis, ER Weinstock, GM Wilson, RK Birney, E Margulies, EH Herrero, J Green, ED Haussler, D Siepel, A Goldman, N Pollard, KS Pedersen, JS Lander, ES Kellis, M AF Lindblad-Toh, Kerstin Garber, Manuel Zuk, Or Lin, Michael F. Parker, Brian J. Washietl, Stefan Kheradpour, Pouya Ernst, Jason Jordan, Gregory Mauceli, Evan Ward, Lucas D. Lowe, Craig B. Holloway, Alisha K. Clamp, Michele Gnerre, Sante Alfoeldi, Jessica Beal, Kathryn Chang, Jean Clawson, Hiram Cuff, James Di Palma, Federica Fitzgerald, Stephen Flicek, Paul Guttman, Mitchell Hubisz, Melissa J. Jaffe, David B. Jungreis, Irwin Kent, W. James Kostka, Dennis Lara, Marcia Martins, Andre L. Massingham, Tim Moltke, Ida Raney, Brian J. Rasmussen, Matthew D. Robinson, Jim Stark, Alexander Vilella, Albert J. Wen, Jiayu Xie, Xiaohui Zody, Michael C. Worley, Kim C. Kovar, Christie L. Muzny, Donna M. Gibbs, Richard A. Warren, Wesley C. Mardis, Elaine R. Weinstock, George M. Wilson, Richard K. Birney, Ewan Margulies, Elliott H. Herrero, Javier Green, Eric D. Haussler, David Siepel, Adam Goldman, Nick Pollard, Katherine S. Pedersen, Jakob S. Lander, Eric S. Kellis, Manolis CA Broad Inst Baylor Coll Med Washington Univ TI A high-resolution map of human evolutionary constraint using 29 mammals SO NATURE LA English DT Article ID 12 DROSOPHILA GENOMES; RELIABLE PREDICTION; NONCODING SEQUENCES; CODING SEQUENCE; DISCOVERY; ELEMENTS; REVEALS; GENES; EXPRESSION; VERTEBRATE AB The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate-and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease. C1 [Lindblad-Toh, Kerstin; Garber, Manuel; Zuk, Or; Lin, Michael F.; Kheradpour, Pouya; Ernst, Jason; Mauceli, Evan; Ward, Lucas D.; Clamp, Michele; Gnerre, Sante; Alfoeldi, Jessica; Chang, Jean; Di Palma, Federica; Guttman, Mitchell; Jaffe, David B.; Lara, Marcia; Robinson, Jim; Xie, Xiaohui; Zody, Michael C.; Lander, Eric S.; Kellis, Manolis] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Lindblad-Toh, Kerstin] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, SE-75123 Uppsala, Sweden. [Lin, Michael F.; Washietl, Stefan; Kheradpour, Pouya; Ernst, Jason; Ward, Lucas D.; Jungreis, Irwin; Rasmussen, Matthew D.; Kellis, Manolis] MIT Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Parker, Brian J.; Moltke, Ida; Wen, Jiayu; Pedersen, Jakob S.] Univ Copenhagen, Dept Biol, Bioinformat Ctr, DK-2200 Copenhagen, Denmark. [Jordan, Gregory; Beal, Kathryn; Fitzgerald, Stephen; Flicek, Paul; Massingham, Tim; Vilella, Albert J.; Birney, Ewan; Herrero, Javier; Goldman, Nick] EMBL EBI, Hinxton CB10 1SD, England. [Lowe, Craig B.; Clawson, Hiram; Raney, Brian J.; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Lowe, Craig B.] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA. [Lowe, Craig B.; Haussler, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Holloway, Alisha K.; Kent, W. James; Kostka, Dennis; Pollard, Katherine S.] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94158 USA. [Clamp, Michele] BioTeam Inc, Middleton, MA 01949 USA. [Cuff, James] Harvard Univ, Fac Arts & Sci, Div Sci, Cambridge, MA 02138 USA. [Hubisz, Melissa J.; Martins, Andre L.; Siepel, Adam] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [Stark, Alexander] Res Inst Mol Pathol IMP, A-1030 Vienna, Austria. [Worley, Kim C.; Kovar, Christie L.; Muzny, Donna M.; Gibbs, Richard A.; Weinstock, George M.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Warren, Wesley C.; Mardis, Elaine R.; Weinstock, George M.; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Margulies, Elliott H.] NHGRI, Genome Informat Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.] NHGRI, NISC Comparat Sequencing Program, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Pollard, Katherine S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Pollard, Katherine S.] Univ Calif San Francisco, Div Biostat, San Francisco, CA 94158 USA. [Pedersen, Jakob S.] Aarhus Univ Hosp, Dept Mol Med MOMA, DK-8200 Aarhus N, Denmark. RP Lindblad-Toh, K (reprint author), Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM kersli@broadinstitute.org; lander@broadinstitute.org; manoli@mit.edu RI Stark, Alexander/D-1473-2012; Pedersen, Jakob/G-3382-2012; Weinstock, George/C-6314-2013; Holloway, Alisha/H-9574-2013; Moltke, Ida/C-6158-2011; OI Goldman, Nick/0000-0001-8486-2211; Flicek, Paul/0000-0002-3897-7955; Birney, Ewan/0000-0001-8314-8497; Herrero, Javier/0000-0001-7313-717X; Stark, Alexander/0000-0003-2611-0841; Pedersen, Jakob/0000-0002-7236-4001; Weinstock, George/0000-0002-2997-4592; Holloway, Alisha/0000-0001-9810-389X; Moltke, Ida/0000-0001-7052-8554; Jordan, Gregory/0000-0002-7655-6000; Ward, Lucas/0000-0002-8017-809X; Siepel, Adam/0000-0002-3557-7219; Vilella, Albert/0000-0002-2005-2516 FU National Human Genome Research Institute (NHGRI) [U54 HG003273]; National Institute for General Medicine (NIGMS) [GM82901]; European Science Foundation; NSF National Science Foundation (NSF) [0905968, 0644282]; NIH [R01 HG004037]; Sloan Foundation; Austrian Fonds zur Forderung der Wissenschaftlichen Forschung; Gates Cambridge Trust; Novo Nordisk Foundation; Department of Mathematical Sciences, University of Copenhagen; David and Lucile Packard Foundation; Danish Council for Independent Research Medical Sciences; Lundbeck Foundation FX We thank O. Ryder, E. Fuchs, D. Haring, A. Walsh, D. Duffield, S. Wong, T. Alvarado, J. Boylan, S. Combes, P. deJong, J. Allman, J. Patton, D. McMullen, D. Hafner, D. Miller, T. Kunz, G. Hewitt, J. Searle, H. Kunzle and D. Williams for providing organismal material. We thank L. Gaffney for help with figures. This work was supported by the National Human Genome Research Institute (NHGRI), including grant U54 HG003273 (R. A. G.), National Institute for General Medicine (NIGMS) grant no. GM82901 (Pollard laboratory) and the European Science Foundation (EURYI award to K.L.-T.), NSF National Science Foundation (NSF) postdoctoral fellowship award 0905968 (J.E.), National Science Foundation CAREER 0644282 and NIH R01 HG004037 and the Sloan Foundation (M. K.), and an Erwin Schrodinger Fellowship of the Austrian Fonds zur Forderung der Wissenschaftlichen Forschung (S. W.), the Gates Cambridge Trust (G.J.), Novo Nordisk Foundation (B.J.P. and J.W.); a Statistics Network Fellowship, Department of Mathematical Sciences, University of Copenhagen (B.J.P.); the David and Lucile Packard Foundation (A. S.); the Danish Council for Independent Research Medical Sciences (J.S.P.); The Lundbeck Foundation (J.S.P.). NR 50 TC 407 Z9 433 U1 12 U2 93 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 476 EP 482 DI 10.1038/nature10530 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200035 PM 21993624 ER PT J AU Kang, HJ Kawasawa, YI Cheng, F Zhu, Y Xu, XM Li, MF Sousa, AMM Pletikos, M Meyer, KA Sedmak, G Guennel, T Shin, Y Johnson, MB Krsnik, Z Mayer, S Fertuzinhos, S Umlauf, S Lisgo, SN Vortmeyer, A Weinberger, DR Mane, S Hyde, TM Huttner, A Reimers, M Kleinman, JE Sestan, N AF Kang, Hyo Jung Kawasawa, Yuka Imamura Cheng, Feng Zhu, Ying Xu, Xuming Li, Mingfeng Sousa, Andre M. M. Pletikos, Mihovil Meyer, Kyle A. Sedmak, Goran Guennel, Tobias Shin, Yurae Johnson, Matthew B. Krsnik, Zeljka Mayer, Simone Fertuzinhos, Sofia Umlauf, Sheila Lisgo, Steven N. Vortmeyer, Alexander Weinberger, Daniel R. Mane, Shrikant Hyde, Thomas M. Huttner, Anita Reimers, Mark Kleinman, Joel E. Sestan, Nenad TI Spatio-temporal transcriptome of the human brain SO NATURE LA English DT Article ID HUMAN PREFRONTAL CORTEX; GENE-EXPRESSION; CEREBRAL-CORTEX; PSYCHIATRIC-DISORDERS; CORTICAL DEVELOPMENT; PYRAMIDAL NEURONS; LIFE-SPAN; SCHIZOPHRENIA; INSIGHTS; DIFFERENTIATION AB Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment. C1 [Kang, Hyo Jung; Kawasawa, Yuka Imamura; Cheng, Feng; Zhu, Ying; Xu, Xuming; Li, Mingfeng; Sousa, Andre M. M.; Pletikos, Mihovil; Meyer, Kyle A.; Sedmak, Goran; Shin, Yurae; Johnson, Matthew B.; Krsnik, Zeljka; Mayer, Simone; Fertuzinhos, Sofia; Sestan, Nenad] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. [Kang, Hyo Jung; Kawasawa, Yuka Imamura; Cheng, Feng; Zhu, Ying; Xu, Xuming; Li, Mingfeng; Sousa, Andre M. M.; Pletikos, Mihovil; Meyer, Kyle A.; Sedmak, Goran; Shin, Yurae; Johnson, Matthew B.; Krsnik, Zeljka; Mayer, Simone; Fertuzinhos, Sofia; Sestan, Nenad] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA. [Sousa, Andre M. M.] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal. [Pletikos, Mihovil; Sedmak, Goran] Univ Zagreb, Sch Med, Croatian Inst Brain Res, Grad Program Neurosci, Zagreb 10000, Croatia. [Guennel, Tobias; Reimers, Mark] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Mayer, Simone] Int Max Planck Res Sch Mol Biol, Msc PhD Mol Biol Program, D-37077 Gottingen, Germany. [Umlauf, Sheila; Mane, Shrikant] Yale Univ, Sch Med, Yale Ctr Genome Anal, New Haven, CT 06510 USA. [Lisgo, Steven N.] Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Vortmeyer, Alexander; Huttner, Anita] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Weinberger, Daniel R.; Hyde, Thomas M.; Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Hyde, Thomas M.] Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Sestan, N (reprint author), Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. EM nenad.sestan@yale.edu RI Fertuzinhos, Sofia /G-8316-2011; Cheng, Feng/A-9760-2009; Sousa, Andre M. M./C-1203-2015; Mayer, Simone/H-1840-2015 OI Sousa, Andre M. M./0000-0003-1740-5066; Mayer, Simone/0000-0002-6381-2474 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD000836]; China Scholarship Council; Portuguese Foundation for Science and Technology; Samsung Scholarship Foundation; German Academic Exchange Service - DAAD; NIDA [DA026119]; US National Institutes of Health [MH081896, MH089929, NS054273]; Kavli Foundation; NARSAD; James S. McDonnell Foundation; [G0700089]; [GR082557] FX We thank A. Belanger, V. Imamovic, R. Johnson, P. Larton, S. Lindsay, B. Poulos, J. Rajan, D. Rimm and R. Zielke for assistance with tissue acquisition, D. Singh for technical assistance, I. Kostovic and Z. Petanjek for dendrite measurements, P. Levitt for suggesting the inclusion of ITC in the study, and D. Karolchik and A. Zweig for help in creating tracks for the UCSC Genome Browser. We also thank A. Beckel-Mitchener, M. Freund, M. Gerstein, D. Geschwind, T. Insel, M. Judas, J. Knowles, E. Lein, P. Levitt, N. Parikshak and members of the Sestan laboratory for discussions and criticism. Tissue was obtained from several sources including the Human Fetal Tissue Repository at the Albert Einstein College of Medicine, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Laboratory of Developmental Biology at the University of Washington (supported by grant HD000836 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development) and the Joint MRC/Wellcome Trust Human Developmental Biology Resource (http://hdbr.org) at the IHG, Newcastle Upon Tyne (UK funding awards G0700089 and GR082557). Support for predoctoral fellowships was provided by the China Scholarship Council (Y.Z.), the Portuguese Foundation for Science and Technology (A. M. M. S.), the Samsung Scholarship Foundation (Y.S.), a Fellowship of the German Academic Exchange Service - DAAD (S. Mayer) and NIDA grant DA026119 (T. G.). This work was supported by grants from the US National Institutes of Health (MH081896, MH089929, NS054273), the Kavli Foundation and NARSAD, and by a James S. McDonnell Foundation Scholar Award (N.S.). NR 49 TC 496 Z9 504 U1 8 U2 76 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 483 EP 489 DI 10.1038/nature10523 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200036 PM 22031440 ER PT J AU Colantuoni, C Lipska, BK Ye, TZ Hyde, TM Tao, R Leek, JT Colantuoni, EA Elkahloun, AG Herman, MM Weinberger, DR Kleinman, JE AF Colantuoni, Carlo Lipska, Barbara K. Ye, Tianzhang Hyde, Thomas M. Tao, Ran Leek, Jeffrey T. Colantuoni, Elizabeth A. Elkahloun, Abdel G. Herman, Mary M. Weinberger, Daniel R. Kleinman, Joel E. TI Temporal dynamics and genetic control of transcription in the human prefrontal cortex SO NATURE LA English DT Article ID HUMAN BRAIN; EXPRESSION; DISEASE; MOUSE; SCHIZOPHRENIA; MICRORNA; CANCER; RNA AB Previous investigations have combined transcriptional and genetic analyses in human cell lines(1-3), but few have applied these techniques to human neural tissue(4-8). To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of post-mortem brains from fetal development through ageing. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half-century later in life, this pattern of reversals is mirrored in ageing and in neurodegeneration. Although we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire data set is freely available (from Gene Expression Omnibus: accession GSE30272; and dbGaP: accession phs000417.v1.p1) and can also be interrogated via a biologist-friendly stand-alone application (http://www.libd.org/braincloud). C1 [Colantuoni, Carlo; Lipska, Barbara K.; Ye, Tianzhang; Hyde, Thomas M.; Tao, Ran; Herman, Mary M.; Weinberger, Daniel R.; Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,IRP,NIH, Bethesda, MD 20892 USA. [Colantuoni, Carlo; Leek, Jeffrey T.; Colantuoni, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Colantuoni, Carlo] Illuminato Biotechnol Inc, Baltimore, MD 21211 USA. [Colantuoni, Carlo; Hyde, Thomas M.; Weinberger, Daniel R.] Johns Hopkins Univ, Med Ctr, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kleinman, JE (reprint author), NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,IRP,NIH, Bethesda, MD 20892 USA. EM kleinmaj@mail.nih.gov RI Tao, Ran/C-2662-2013; Tao, Ran/L-3460-2014; Lipska, Barbara/E-4569-2017; OI Leek, Jeffrey/0000-0002-2873-2671 FU Intramural NIH HHS [ZIC HG200365-02, ZIC HG200365-01, ZIC HG200365-03] NR 27 TC 247 Z9 250 U1 4 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 519 EP U117 DI 10.1038/nature10524 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200044 PM 22031444 ER PT J AU Bergwitz, C Collins, MT Kamath, RS Rosenberg, AE AF Bergwitz, Clemens Collins, Michael T. Kamath, Ravi S. Rosenberg, Andrew E. TI Case 33-2011: A 56-Year-Old Man with Hypophosphatemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUMOR-INDUCED OSTEOMALACIA; OF-THE-LITERATURE; ONCOGENIC OSTEOMALACIA; MESENCHYMAL TUMORS; AMELOBLASTIC FIBROSARCOMA; PHOSPHATE HOMEOSTASIS; CALCIUM-METABOLISM; VITAMIN-D; FIBROBLAST-GROWTH-FACTOR-23; LOCALIZATION C1 [Bergwitz, Clemens] Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA. [Kamath, Ravi S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosenberg, Andrew E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bergwitz, Clemens] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kamath, Ravi S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Rosenberg, Andrew E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA. FU Genzyme FX Dr. Rosenberg reports receiving consulting fees from Genzyme. No other potential conflict of interest relevant to this article was reported. NR 27 TC 8 Z9 9 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 27 PY 2011 VL 365 IS 17 BP 1625 EP 1635 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 837HI UT WOS:000296181800009 PM 22029985 ER PT J AU Castro, O Minniti, CP Nouraie, M AF Castro, Oswaldo Minniti, Caterina P. Nouraie, Mehdi TI Pulmonary Hypertension in Sickle Cell Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Castro, Oswaldo; Nouraie, Mehdi] Howard Univ, Washington, DC 20059 USA. [Minniti, Caterina P.] NHLBI, Bethesda, MD 20892 USA. RP Castro, O (reprint author), Howard Univ, Washington, DC 20059 USA. EM olcastro@aol.com NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 27 PY 2011 VL 365 IS 17 BP 1646 EP 1646 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 837HI UT WOS:000296181800024 PM 22029997 ER PT J AU Shen, H Luo, Y Yu, SJ Wang, Y AF Shen, H. Luo, Y. Yu, S. -J. Wang, Y. TI ENHANCED NEURODEGENERATION AFTER A HIGH DOSE OF METHAMPHETAMINE IN ADENOSINE A3 RECEPTOR NULL MUTANT MICE SO NEUROSCIENCE LA English DT Article DE methamphetamine; Adenosine A3 receptor; neural degeneration; dopamine ID KNOCK-OUT MICE; MOUSE-BRAIN; MICROGLIAL ACTIVATION; INDUCED NEUROTOXICITY; MOLECULAR-CLONING; A(3) RECEPTORS; UP-REGULATION; IN-VIVO; KAPPA-B; RAT AB Previous reports have indicated that adenosine A3 receptor (A3R) knockout mice are more sensitive to ischemic or hypoxic brain injury. The purpose of this study was to examine if suppression of A3R expression is associated with increase in sensitivity to injury induced by a high dose of methamphetamine (Meth). Adult male A3R null mutant (-/-) mice and their controls (+/+) were injected with four doses (2 h apart) of Meth (10 mg/kg) or saline. Animals were placed in a behavioral activity chamber, equipped with food and water, for 52 h starting from one day after injections. The first 4 h were used for studying exploratory behaviors, and the next 48 h were used to measure locomotor activity. High doses of Meth equally reduced the 4-h exploratory behavior in -/- and +/+ mice. Meth suppressed locomotor activity between 4 and 52 h in both groups, with a greater reduction being found in the -/- mice. Brain tissues were collected at 3 days after the Meth or saline injections. Meth treatment reduced striatal dopamine (DA) levels in both +/+ and -/- mice with an increase in 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio being found only in -/- animals. Meth also significantly increased ionized calcium-binding adaptor molecule 1 (lba-1) and cleaved caspase-3 level in striatum, as well as lba-1 and TNF alpha mRNA expression in nigra in -/-, compared to +/+, mice. Previous studies have shown that pharmacological suppression of vesicular monoamine transport 2 (VMAT2) by reserpine enhanced Meth toxicity by increasing cytosolic DA and inflammation. A significant reduction in striatal VMAT2 expression was found in -/- mice compared to +/+ mice, suggesting that increase in sensitivity to Meth injury in -/- mice may be related to a reduction in VMAT2 expression in these mice. In conclusion, our data suggest that A3R -/- mice are more sensitive to high doses of Meth. Published by Elsevier Ltd on behalf of IBRO. C1 [Shen, H.; Luo, Y.; Yu, S. -J.; Wang, Y.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov FU NIDA IRP FX This study was supported by NIDA IRP. We would like to thank Dr. Jean Lud Cadet for his critical suggestions. NR 41 TC 7 Z9 7 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 27 PY 2011 VL 194 BP 170 EP 180 DI 10.1016/j.neuroscience.2011.08.013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 829IN UT WOS:000295571900016 PM 21867746 ER PT J AU Qin, M Xia, Z Huang, T Smith, CB AF Qin, M. Xia, Z. Huang, T. Smith, C. B. TI EFFECTS OF CHRONIC IMMOBILIZATION STRESS ON ANXIETY-LIKE BEHAVIOR AND BASOLATERAL AMYGDALA MORPHOLOGY IN Fmr1 KNOCKOUT MICE SO NEUROSCIENCE LA English DT Article DE fragile X syndrome; FMRP; chronic stress; anxiety; amygdala; dendritic spines ID FRAGILE-X-SYNDROME; TISSUE-PLASMINOGEN ACTIVATOR; MOUSE MODEL; MENTAL-RETARDATION; ENHANCED ANXIETY; SOCIAL-BEHAVIOR; MEMORY; DEFICITS; CONSOLIDATION; HYPERTROPHY AB Several lines of clinical evidence support the idea that fragile X syndrome (FXS) may involve a dysregulation of hypothalamic-pituitary-adrenal axis function [Wisbeck et al. (2000) J Dev Behav Pediatr 21:278-282; Hessl et al. (2002) Psychoneuroendocrinology 27:855-872]. We had tested this idea in a mouse model of FXS (Fmr1 KO) and found that the hormonal response to acute stress was similar to that of wild-type (WT) mice [Qin and Smith (2008) Psychoneuroendocrinology 33:883-889]. We report here responses to chronic stress (CS) in Fmr1 KO mice. Following restraint for 120 min/d, 10 consecutive days, we assessed dendrite and spine morphology in basolateral amygdala (BLA). We also monitored behavior in an elevated plus maze (EPM) and the hormonal response to this novel spatial environment. After CS, mice of both genotypes underwent adrenal hypertrophy, but effects were greater in WT mice. Behavior in the EPM indicated that only WT mice had the expected increase in anxiety following CS. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels were both increased following the spatial novelty of EPM, and there were no differences between genotypes in the hormonal responses. BLA dendritic branching increased proximal to the soma in WT, but in Fmr1 KO mice branching was unaffected close to the soma and slightly decreased at one point distal to the soma. Similarly, spine density on apical and basal dendrites increased in WT but decreased in Fmr1 KO mice. Spine length on apical and basal dendrites increased in WT but was unaffected in Fmr1 KO mice. These differences in behavioral response and effects on neuron morphology in BLA suggest a diminished adaptive response of Fmr1 KO mice. Published by Elsevier Ltd on behalf of IBRO. C1 [Qin, M.; Xia, Z.; Huang, T.; Smith, C. B.] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov FU NIMH, NIH; Fragile X Research Foundation FX We thank Dr. Zhong-Hua Liu for help with the statistical analyses. The research was supported by the Intramural Research Program of the NIMH, NIH and the Fragile X Research Foundation. NR 44 TC 26 Z9 26 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 27 PY 2011 VL 194 BP 282 EP 290 DI 10.1016/j.neuroscience.2011.06.047 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 829IN UT WOS:000295571900028 PM 21723920 ER PT J AU Ferre-D'Amare, AR AF Ferre-D'Amare, Adrian R. TI Use of a coenzyme by the glmS ribozyme-riboswitch suggests primordial expansion of RNA chemistry by small molecules SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE catalytic RNA; enzymatic cofactor; RNA world ID DELTA VIRUS RIBOZYME; ACID-BASE CATALYSIS; IN-VITRO SELECTION; ACTIVE-SITE; CRYSTAL-STRUCTURE; HAIRPIN RIBOZYME; BACTERIAL 2ND-MESSENGER; STRUCTURAL BASIS; GENE-EXPRESSION; MECHANISM AB The glmS ribozyme-riboswitch is the first known example of a naturally occurring catalytic RNA that employs a small molecule as a coenzyme. Binding of glucosamine-6-phosphate (GlcN6P) activates self-cleavage of the bacterial ribozyme, which is part of the mRNA encoding the metabolic enzyme GlcN6P-synthetase. Cleavage leads to negative feedback regulation. GlcN6P binds in the active site of the ribozyme, where its amine could function as a general acid and electrostatic catalyst. The ribozyme is pre-folded but inactive in the absence of GlcN6P, demonstrating it has evolved strict dependence on the exogenous small molecule. The ribozyme showcases the ability of RNA to co-opt non-covalently bound small molecules to expand its chemical repertoire. Analogue studies demonstrate that some molecules other than GlcN6P, such as L-serine (but not D-serine), can function as weak activators. This suggests how coenzyme use by RNA world ribozymes may have led to evolution of proteins. Primordial cofactor-dependent ribozymes may have evolved to bind their cofactors covalently. If amino acids were used as cofactors, this could have driven the evolution of RNA aminoacylation. The ability to make covalently bound peptide coenzymes may have further increased the fitness of such primordial ribozymes, providing a selective pressure for the invention of translation. C1 NHLBI, Lab RNA Biophys & Cellular Physiol, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Lab RNA Biophys & Cellular Physiol, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM ferrea@mail.nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health FX The author thanks past and current members of the Ferre-D'Amare laboratory for their many contributions, and in particular D. Klein for his work on the glmS ribozyme. This research was supported by the intramural programme of the National Heart, Lung and Blood Institute, National Institutes of Health. NR 54 TC 10 Z9 10 U1 1 U2 13 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 27 PY 2011 VL 366 IS 1580 BP 2942 EP 2948 DI 10.1098/rstb.2011.0131 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 821RW UT WOS:000294993100012 PM 21930586 ER PT J AU Bakari, M Aboud, S Nilsson, C Francis, J Buma, D Moshiro, C Aris, EA Lyamuya, EF Janabi, M Godoy-Ramirez, K Joachim, A Polonis, VR Brave, A Earl, P Robb, M Marovich, M Wahren, B Pallangyo, K Biberfeld, G Mhalu, F Sandstrom, E AF Bakari, Muhammad Aboud, Said Nilsson, Charlotta Francis, Joel Buma, Deus Moshiro, Candida Aris, Eric A. Lyamuya, Eligius F. Janabi, Mohamed Godoy-Ramirez, Karina Joachim, Agricola Polonis, Victoria R. Brave, Andreas Earl, Patricia Robb, Merlin Marovich, Mary Wahren, Britta Pallangyo, Kisali Biberfeld, Gunnel Mhalu, Fred Sandstrom, Eric CA HIVIS Study Grp TI Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania SO VACCINE LA English DT Article DE HIV vaccine; DNA prime; MVA boost ID VACCINIA VIRUS ANKARA; T-CELL RESPONSES; DAR-ES-SALAAM; CANDIDATE VACCINE; PHASE-1 SAFETY; IMMUNOGENICITY EVALUATION; MONOCLONAL-ANTIBODIES; SMALLPOX VACCINATION; DOUBLE-BLIND; CLADE-C AB Background: We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Methods: Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1 mg intradermally (id), n = 20, or 3.8 mg intramuscularly (im), n = 20, or placebo, n = 20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B. C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0,4 and 12. Recombinant MVA (10(8) pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. Results: The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-gamma ELISpot responses to 3Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-gamma ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-gamma/IL-2 production showed both CD8(+) and CD4(+) T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01_AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. This vaccine approach is safe and highly immunogenic. Low dose. id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bakari, Muhammad; Pallangyo, Kisali] MUHAS, Dept Internal Med, Dar Es Salaam, Tanzania. [Aboud, Said; Lyamuya, Eligius F.; Joachim, Agricola; Mhalu, Fred] MUHAS, Dept Microbiol & Immunol, Dar Es Salaam, Tanzania. [Moshiro, Candida] MUHAS, Dept Epidemiol & Biostat, Dar Es Salaam, Tanzania. [Aboud, Said; Nilsson, Charlotta; Joachim, Agricola; Wahren, Britta; Biberfeld, Gunnel] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Nilsson, Charlotta; Godoy-Ramirez, Karina; Brave, Andreas; Wahren, Britta; Biberfeld, Gunnel] Swedish Inst Communicable Dis Control SMI, Solna, Sweden. [Francis, Joel] NIMR, Dar Es Salaam, Tanzania. [Aris, Eric A.; Janabi, Mohamed] MNH, Dept Internal Med, Dar Es Salaam, Tanzania. [Buma, Deus] MNH, Dept Pharm, Dar Es Salaam, Tanzania. [Polonis, Victoria R.; Marovich, Mary] WRAIR, Rockville, MD USA. [Earl, Patricia] NIAID, NIH, Bethesda, MD 20892 USA. [Robb, Merlin] Henry M Jackson Fdn, Rockville, MD USA. [Sandstrom, Eric] Karolinska Inst, Sodersjukhuset, Stockholm, Sweden. RP Bakari, M (reprint author), MUHAS, Dept Internal Med, Dar Es Salaam, Tanzania. EM drbakari@yahoo.com FU MUHAS; SMI; European Union; AVIP; Swedish International Development Cooperation Agency {Sida} Sida through the Swedish Embassy, Tanzania; Swedish Research Council; European & Developing Countries Clinical Trials Partnership {EDCTP} FX Conflict of interest statement: The other authors have no potential conflicts of interest to the report. Special thanks to study participants, research assistants and the Government of Tanzania. The trial is dedicated to the volunteers. Sponsors (MUHAS and SMI) and funders of the study (the European Union; AVIP; the Swedish International Development Cooperation Agency {Sida} Sida through the Swedish Embassy, Tanzania; the Swedish Research Council; and the European & Developing Countries Clinical Trials Partnership {EDCTP}) are very much thanked. The Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the National Institute of Health, the US Army Research Program and the US Military HIV Research program, Walter Reed Army Institute for Research (WRAIR) are thanked for the production and provision of MVA vaccine. We are also grateful to BioJect, Tualatin, OR, of USA for the donation of Biojector 2000, syringes and CO2 cartridges. NR 55 TC 50 Z9 51 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 26 PY 2011 VL 29 IS 46 BP 8417 EP 8428 DI 10.1016/j.vaccine.2011.08.001 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 847QV UT WOS:000296988500034 PM 21864626 ER PT J AU Laeyendecker, O Latimore, A Eshleman, SH Summerton, J Oliver, AE Gamiel, J Dobbs, T Mei, J Murphy, G Parry, JV Owen, SM Quinn, TC AF Laeyendecker, Oliver Latimore, Amanda Eshleman, Susan H. Summerton, Jean Oliver, Amy E. Gamiel, Jordyn Dobbs, Trudy Mei, Joanne Murphy, Gary Parry, John V. Owen, S. Michele Quinn, Thomas C. TI The Effect of Sample Handling on Cross Sectional HIV Incidence Testing Results SO PLOS ONE LA English DT Article ID PERFORMANCE-CHARACTERISTICS; ENZYME-IMMUNOASSAY; INFECTION AB Objective(s): To determine if mishandling prior to testing would make a sample from a chronically infected subject appear recently infected when tested by cross-sectional HIV incidence assays. Methods: Serum samples from 31 subjects with chronic HIV infection were tested. Samples were subjected to different handling conditions, including incubation at 4 degrees C, 25 degrees C and 37 degrees C, for 1, 3, 7 or 15 days prior to testing. Samples were also subjected to 1,3, 7 and 15 freeze-thaw cycles prior to testing. Samples were tested using the BED capture enzyme immuno assay (BED-CEIA), Vironostika-less sensitive (V-LS), and an avidity assay using the Genetic Systems HIV-1/HIV-2 plus O EIA (avidity assay). Results: Compared to the sample that was not subjected to any mishandling conditions, for the BED-CEIA, V-LS and avidity assay, there was no significant change in test results for samples incubated at 4 degrees C or 25 degrees C prior to testing. No impact on test results occurred after 15 freeze-thaw cycles. A decrease in assay results was observed when samples were held for 3 days or longer at 37 degrees C prior to testing. Conclusions: Samples can be subjected up to 15 freeze-thaw cycles without affecting the results the BED-CEIA, Vironostika-LS, or avidity assays. Storing samples at 4 degrees C or 25 degrees C for up to fifteen days prior to testing had no impact on test results. However, storing samples at 37 degrees C for three or more days did affect results obtained with these assays. C1 [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Laeyendecker, Oliver; Summerton, Jean; Oliver, Amy E.; Gamiel, Jordyn; Quinn, Thomas C.] Johns Hopkins Univ Sch Med, Dept Med, Div Infect Dis, Baltimore, MD USA. [Latimore, Amanda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Eshleman, Susan H.] Johns Hopkins Univ Sch Med, Dept Pathol, Baltimore, MD USA. [Dobbs, Trudy] Ctr Dis Control & Prevent, Global AIDS Program, Int Lab Branch, Atlanta, GA USA. [Mei, Joanne] Ctr Dis Control & Prevent, Newborn Screening Qual Assurance Program, Atlanta, GA USA. [Murphy, Gary; Parry, John V.] Hlth Protect Agcy, Microbiol Serv, London, England. [Owen, S. Michele] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. RP Laeyendecker, O (reprint author), NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. EM olaeyen1@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU U.S. National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) [R01-DA11602]; Department of Health and Human Services (DHHS) [N01-AI-35173]; Family Health International [contract N01-AI-45200]; Fred Hutchinson Cancer Research Center; Makerere University [NOI-AI-35173-417]; NIAID; National Institutes of Child Health and Human Development (NICH/HD); National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research, of the NIH, DHHS [1UM1AI068613]; Division of Intramural Research, NIAID, NIH; HIV Network for Prevention Trials (HIVNET) FX This work was supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), through contract N01-AI-35173 with Family Health International, contract N01-AI-45200 with Fred Hutchinson Cancer Research Center, and subcontracts with Makerere University (NOI-AI-35173-417), (2) the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS (1UM1AI068613). Additional support was provided in part by the Division of Intramural Research, NIAID, NIH. Samples and data from Baltimore were supplied by Jeanne Keruly and Dr. Richard Moore, supported by NIH grant R01-DA11602. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 12 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 26 PY 2011 VL 6 IS 10 AR e25899 DI 10.1371/journal.pone.0025899 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841NR UT WOS:000296519600007 PM 22046249 ER PT J AU Hafed, ZM Lovejoy, LP Krauzlis, RJ AF Hafed, Ziad M. Lovejoy, Lee P. Krauzlis, Richard J. TI Modulation of Microsaccades in Monkey during a Covert Visual Attention Task SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SACCADIC EYE-MOVEMENTS; PRIMATE SUPERIOR COLLICULUS; SPATIAL ATTENTION; MONOCULAR FIXATION; NEURAL ACTIVITY; SUPPRESSION; SHIFTS; INACTIVATION; PERCEPTION; GENERATION AB The use of awake, fixating monkeys in neuroscience has allowed significant advances in understanding numerous brain functions. However, fixation is an active process, with the occurrence of incessant eye movements, including rapid ones called microsaccades. Even though microsaccades have been shown to be modulated by stimulus and cognitive processes in humans, it is not known to what extent these results are similar in monkeys or why they occur. Here, we analyzed the stimulus-, context-, and attention- related changes in microsaccades while monkeys performed a challenging visual attention task. The distributions of microsaccade times were highly stereotypical across thousands of trials in the task. Moreover, in epochs of the task in which animals anticipated the occurrence of brief stimulus probes, microsaccade frequency decreased to a rate of less than one movement per second even on long multisecond trials. These effects were explained by the observation that microsaccades occurring at the times of the brief probes were sometimes associated with reduced perceptual performance. Microsaccade directions also exhibited temporal modulations related to the attentional demands of the task, like earlier studies in humans, and were more likely to be directed toward an attended location on successfully performed trials than on unsuccessfully completed ones. Our results show that microsaccades in nonhuman primates are correlated with the allocation of stimulus- evoked and sustained covert attention. We hypothesize that involvement of the superior colliculus in microsaccade generation and attentional allocation contributes to these observations. More importantly, our results clarify the potential role of these eye movements in modifying behavior and neural activity. C1 [Hafed, Ziad M.] Werner Reichardt Ctr Integrat Neurosci, D-72076 Tubingen, Germany. [Lovejoy, Lee P.; Krauzlis, Richard J.] Salk Inst Biol Studies, Syst Neurobiol Lab, La Jolla, CA 92037 USA. [Krauzlis, Richard J.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Hafed, ZM (reprint author), Werner Reichardt Ctr Integrat Neurosci, Paul Ehrlich Str 17, D-72076 Tubingen, Germany. EM ziad.m.hafed@cin.uni-tuebingen.de OI Lovejoy, Lee/0000-0002-5732-9224 FU Werner Reichardt Centre for Integrative Neuroscience; Institute for Neural Computation; Aginsky Scholars Award; National Institutes of Health [EY12212] FX This work was supported by the Werner Reichardt Centre for Integrative Neuroscience (Z.M.H.), the Institute for Neural Computation and the Aginsky Scholars Award Program (L.P.L.), and National Institutes of Health Grant EY12212 (R.J.K.). NR 50 TC 36 Z9 36 U1 0 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 26 PY 2011 VL 31 IS 43 BP 15219 EP 15230 DI 10.1523/JNEUROSCI.3106-11.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 840MZ UT WOS:000296446200001 PM 22031868 ER PT J AU Yanovski, SZ Yanovski, JA Horlick, M AF Yanovski, Susan Z. Yanovski, Jack A. Horlick, Mary TI Life-Threatening Childhood Obesity and Legal Intervention SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Yanovski, Susan Z.; Horlick, Mary] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Bethesda, MD USA. RP Yanovski, SZ (reprint author), NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. EM sy29F@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 26 PY 2011 VL 306 IS 16 BP 1763 EP 1764 DI 10.1001/jama.2011.1522 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 837HH UT WOS:000296181600019 PM 22028351 ER PT J AU Imayama, I Alfano, CM Kong, A Foster-Schubert, KE Bain, CE Xiao, LR Duggan, C Wang, CY Campbell, KL Blackburn, GL McTiernan, A AF Imayama, Ikuyo Alfano, Catherine M. Kong, Angela Foster-Schubert, Karen E. Bain, Carolyn E. Xiao, Liren Duggan, Catherine Wang, Ching-Yun Campbell, Kristin L. Blackburn, George L. McTiernan, Anne TI Dietary weight loss and exercise interventions effects on quality of life in overweight/obese postmenopausal women: a randomized controlled trial SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE health-related quality of life; exercise; dietary weight loss; postmenopausal women ID PHYSICAL-ACTIVITY; OLDER-ADULTS; SELF-EFFICACY; SOCIAL SUPPORT; HEALTH; OBESITY; MEN; QUESTIONNAIRE; MEDIATION; FITNESS AB Background: Although lifestyle interventions targeting multiple lifestyle behaviors are more effective in preventing unhealthy weight gain and chronic diseases than intervening on a single behavior, few studies have compared individual and combined effects of diet and/or exercise interventions on health-related quality of life (HRQOL). In addition, the mechanisms of how these lifestyle interventions affect HRQOL are unknown. The primary aim of this study was to examine the individual and combined effects of dietary weight loss and/or exercise interventions on HRQOL and psychosocial factors (depression, anxiety, stress, social support). The secondary aim was to investigate predictors of changes in HRQOL. Methods: This study was a randomized controlled trial. Overweight/obese postmenopausal women were randomly assigned to 12 months of dietary weight loss (n = 118), moderate-to-vigorous aerobic exercise (225 minutes/week, n = 117), combined diet and exercise (n = 117), or control (n = 87). Demographic, health and anthropometric information, aerobic fitness, HRQOL (SF-36), stress (Perceived Stress Scale), depression [Brief Symptom Inventory (BSI)-18], anxiety (BSI-18) and social support (Medical Outcome Study Social Support Survey) were assessed at baseline and 12 months. The 12-month changes in HRQOL and psychosocial factors were compared using analysis of covariance, adjusting for baseline scores. Multiple regression was used to assess predictors of changes in HRQOL. Results: Twelve-month changes in HRQOL and psychosocial factors differed by intervention group. The combined diet + exercise group improved 4 aspects of HRQOL (physical functioning, role-physical, vitality, and mental health), and stress (p <= 0.01 vs. controls). The diet group increased vitality score (p < 0.01 vs. control), while HRQOL did not change differently in the exercise group compared with controls. However, regardless of intervention group, weight loss predicted increased physical functioning, role-physical, vitality, and mental health, while increased aerobic fitness predicted improved physical functioning. Positive changes in depression, stress, and social support were independently associated with increased HRQOL, after adjusting for changes in weight and aerobic fitness. Conclusions: A combined diet and exercise intervention has positive effects on HRQOL and psychological health, which may be greater than that from exercise or diet alone. Improvements in weight, aerobic fitness and psychosocial factors may mediate intervention effects on HRQOL. C1 [Imayama, Ikuyo; Bain, Carolyn E.; Xiao, Liren; Duggan, Catherine; Wang, Ching-Yun; McTiernan, Anne] Fred Hutchison Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Kong, Angela] Univ Illinois, Canc Educ & Career Dev Program, Chicago, IL USA. [Foster-Schubert, Karen E.; McTiernan, Anne] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Wang, Ching-Yun] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Campbell, Kristin L.] Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada. [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg, Boston, MA 02215 USA. [McTiernan, Anne] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP McTiernan, A (reprint author), Fred Hutchison Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute (NCI) [R01 CA105204-01A1, R25CA094880, 2R25CA057699]; National Center for Research Resources (NCRR), a component of the National Institute of Health (NIH) [5KL2RR025015-03]; NIH Roadmap for Medical Research FX The Nutrition and Exercise for Women (NEW) trial was supported by R01 CA105204-01A1 from the National Cancer Institute (NCI). While working on the trial, CMA was employed at the Ohio State University, and located to NCI following completion of her effort on the NEW trial. AK was supported by NCI R25CA094880 at the time of this study and is currently supported by NCI 2R25CA057699. KEF is supported by 5KL2RR025015-03 from National Center for Research Resources (NCRR), a component of the National Institute of Health (NIH) and NIH Roadmap for Medical Research. NR 44 TC 42 Z9 42 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD OCT 25 PY 2011 VL 8 AR 118 DI 10.1186/1479-5868-8-118 PG 12 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 848QB UT WOS:000297066100001 PM 22026966 ER PT J AU Southworth, PM Hyde, JE Sims, PFG AF Southworth, Paul M. Hyde, John E. Sims, Paul F. G. TI A mass spectrometric strategy for absolute quantification of Plasmodium falciparum proteins of low abundance SO MALARIA JOURNAL LA English DT Article DE Absolute quantification of proteins; enzymes of folate metabolism; heavy isotope labelling; malaria parasites; QconCAT ID CONCATENATED SIGNATURE PEPTIDES; UNSTRUCTURED PROTEINS; PROTEOMICS; MALARIA; PARASITE; EXPRESSION AB Selected reaction monitoring mass spectrometry has been combined with the use of an isotopically labelled synthetic protein, made up of proteotypic tryptic peptides selected from parasite proteins of interest. This allows, for the first time, absolute quantification of proteins from Plasmodium falciparum. This methodology is demonstrated to be of sufficient sensitivity to quantify, even within whole cell extracts, proteins of low abundance from the folate pathway as well as more abundant "housekeeping" proteins. C1 [Southworth, Paul M.; Hyde, John E.; Sims, Paul F. G.] Univ Manchester, Fac Life Sci, Manchester Interdisciplinary Bioctr, Manchester M1 7DN, Lancs, England. [Southworth, Paul M.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20814 USA. RP Sims, PFG (reprint author), Univ Manchester, Fac Life Sci, Manchester Interdisciplinary Bioctr, 131 Princess St, Manchester M1 7DN, Lancs, England. EM paul.sims@manchester.ac.uk FU The Wellcome Trust, UK [073896]; BBSRC, UK FX The Wellcome Trust, UK (grant no. 073896) and BBSRC, UK (studentship to PMS) are thanked for their financial support and Drs Ronan O'Cualain and Stephen Holman for assistance with mass spectrometry. NR 20 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 1475-2875 J9 MALARIA J JI Malar. J. PD OCT 25 PY 2011 VL 10 AR 315 DI 10.1186/1475-2875-10-315 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 849EB UT WOS:000297107300001 PM 22027174 ER PT J AU Piller, LB Baraniuk, S Simpson, LM Cushman, WC Massie, BM Einhorn, PT Oparil, S Ford, CE Graumlich, JF Dart, RA Parish, DC Retta, TM Cuyjet, AB Jafri, SZ Furberg, CD Saklayen, MG Thadani, U Probstfield, JL Davis, BR AF Piller, Linda B. Baraniuk, Sarah Simpson, Lara M. Cushman, William C. Massie, Barry M. Einhorn, Paula T. Oparil, Suzanne Ford, Charles E. Graumlich, James F. Dart, Richard A. Parish, David C. Retta, Tamrat M. Cuyjet, Aloysius B. Jafri, Syed Z. Furberg, Curt D. Saklayen, Mohammad G. Thadani, Udho Probstfield, Jeffrey L. Davis, Barry R. CA ALLHAT Collaborative Res Grp TI Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) SO CIRCULATION LA English DT Article DE heart failure; hypertension; diuretics; mortality; ejection fraction ID CONVERTING-ENZYME-INHIBITOR; CARDIOVASCULAR EVENTS; SURVIVAL; HYPERTENSION; RISK; BLOCKER; TRENDS; OLDER AB Background-In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (>= 50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. Methods and Results-With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. Conclusions-Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. C1 [Piller, Linda B.; Baraniuk, Sarah; Simpson, Lara M.; Ford, Charles E.; Davis, Barry R.] Univ Texas Sch Publ Hlth, Houston, TX 77030 USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Einhorn, Paula T.] NHLBI, Bethesda, MD 20892 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Birmingham, AL USA. [Graumlich, James F.] Univ Illinois, Coll Med, Peoria, IL 61656 USA. [Dart, Richard A.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Parish, David C.] Mercer Univ, Sch Med, Macon, GA 31207 USA. [Retta, Tamrat M.] Howard Univ, Coll Med, Washington, DC USA. [Cuyjet, Aloysius B.] Nassau Univ, Med Ctr, E Meadow, NY USA. [Jafri, Syed Z.] Fargo Vet Affairs Med Ctr, Fargo, ND USA. [Furberg, Curt D.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Saklayen, Mohammad G.] Vet Affairs Med Ctr, Dayton, OH USA. [Saklayen, Mohammad G.] Wright State Univ, Dayton, OH 45435 USA. [Thadani, Udho] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Thadani, Udho] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. [Probstfield, Jeffrey L.] Univ Washington, Seattle, WA 98195 USA. RP Piller, LB (reprint author), Univ Texas Sch Publ Hlth, 1200 Pressler St,W-906, Houston, TX 77030 USA. EM Linda.B.Piller@uth.tmc.edu FU National Heart, Lung, and Blood Institute [NO1-HC-35130]; Pfizer, Inc.; GlaxoSmithKline; Merck; Novartis; Corthera; Takeda; Amgen; Daiichi Sankyo; Gilead; Omron Healthcare; Pfizer; Schering Plough; Abbot Laboratories; Boehringer Ingelheim; Sanofi-aventis; Bristol-Myers Squibb; Eisai Medical Research; Eli Lilly; NIH; Schering-Plough FX This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge study medications contributed by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer, Inc.; Dr Cushman has consulted for Daiichi Sankyo, Novartis, Noven, Sanofi-aventis, Takeda, and Theravance; has received honoraria from Bristol-Myers Squibb, and has received research grants from GlaxoSmithKline, Merck, and Novartis. Dr Davis has consulted for Amgen and Takeda. Dr. Massie has consulted for Averion, Bristol-Myers Squibb, Gilead, Merck, Nile Therapeutics, Novartis, and Sanofi-aventis, and has received payments for serving on the DSMB from Corthera and Takeda. Dr Oparil has consulted for Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Forest Pharmaceuticals, NicOx, and Novartis, and has received research grants from Amgen, Daiichi Sankyo, Gilead, Omron Healthcare, Pfizer, Schering Plough, and Takeda. Dr Probstfield has received research grants from Abbot Laboratories, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-aventis. Dr Thadani has consulted for Forest Laboratories, Gilead Colorado, Lilly/ICOS, and Merck; has received honoraria from Daiichi Sankyo and Eli Lilly; and has received research grants from Bristol-Myers Squibb, Eisai Medical Research, Eli Lilly, NIH, Novartis, Pfizer, and Schering-Plough. The other authors report no conflicts. NR 29 TC 17 Z9 19 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 25 PY 2011 VL 124 IS 17 BP 1811 EP U88 DI 10.1161/CIRCULATIONAHA.110.012575 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842EY UT WOS:000296576500012 PM 21969009 ER PT J AU Shurin, SB AF Shurin, Susan B. TI Funding Mechanisms and Program Management at the National Heart, Lung, and Blood Institute Confronting New Challenges and Exploring New Opportunities SO CIRCULATION LA English DT Article DE health care policy; funding C1 NHLBI, Bethesda, MD 20892 USA. RP Shurin, SB (reprint author), NHLBI, 31 Ctr Dr,5A48, Bethesda, MD 20892 USA. EM shurinsb@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 7 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 25 PY 2011 VL 124 IS 17 BP 1894 EP 1896 DI 10.1161/CIRCULATIONAHA.111.065169 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842EY UT WOS:000296576500021 PM 22025639 ER PT J AU Shebl, FM Andreotti, G Meyer, TE Gao, YT Rashid, A Yu, K Shen, MC Wang, BS Han, TQ Zhang, BH Stanczyk, FZ Hsing, AW AF Shebl, F. M. Andreotti, G. Meyer, T. E. Gao, Y-T Rashid, A. Yu, K. Shen, M-C Wang, B-S Han, T-Q Zhang, B-H Stanczyk, F. Z. Hsing, A. W. TI Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China SO BRITISH JOURNAL OF CANCER LA English DT Article DE metabolic syndrome; insulin resistance; biliary tract cancers; biliary stones ID BODY-MASS INDEX; GALLSTONE DISEASE; INFLAMMATION; CHOLESTEROL; SYSTEM; SERUM; RATIO; MEN AB BACKGROUND: Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied. METHODS: In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and beta-cell function were assessed, using homeostasis assessment models. RESULTS: Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR) = 2.75, 95% confidence interval (95% CI) = 1.82-4.15) and biliary stones (OR = 1.64, 95% CI = 1.24-2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend = 0.06). There was a significant inverse association between beta-cell function and gallbladder cancer risk (P trend <0.001). CONCLUSION: Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer. British Journal of Cancer (2011) 105, 1424-1429. doi:10.1038/bjc.2011.363 www.bjcancer.com Published online 13 September 2011 (C) 2011 Cancer Research UK C1 [Shebl, F. M.; Andreotti, G.; Meyer, T. E.; Yu, K.; Hsing, A. W.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Gao, Y-T] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Rashid, A.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Shen, M-C] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, B-S] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, T-Q] Shanghai Jiao Tong Univ, Sch Med, Ruijn Hosp, Shanghai 200030, Peoples R China. [Zhang, B-H] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. [Stanczyk, F. Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, F. Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Shebl, FM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM sheblf@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA FX We thank our collaborators namely, the surgeons and pathologists in Shanghai; Shelley Niwa of Westat for data management; and Chia-Rong Cheng, Lu Sun, and Kai Wu of the Shanghai Cancer Institute for data collection. The Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA funded the current study. NR 30 TC 21 Z9 21 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 25 PY 2011 VL 105 IS 9 BP 1424 EP 1429 DI 10.1038/bjc.2011.363 PG 6 WC Oncology SC Oncology GA 838IR UT WOS:000296282000026 PM 21915122 ER PT J AU Pronk, A Ji, BT Shu, XO Chow, WH Xue, S Yang, G Li, HL Rothman, N Gao, YT Zheng, W Matthews, CE AF Pronk, A. Ji, B-T Shu, X-O Chow, W-H Xue, S. Yang, G. Li, H-L Rothman, N. Gao, Y-T Zheng, W. Matthews, C. E. TI Physical activity and breast cancer risk in Chinese women SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; physical activity; exercise; occupational; critical period ID LEISURE-TIME; COLON CANCER; COHORT; SHANGHAI; HEALTH; COMPENDIUM; SWEDEN AB BACKGROUND: The influence of different types and intensities of physical activity on risk for breast cancer is unclear. METHODS: In a prospective cohort of 73 049 Chinese women (40-70 years), who had worked outside the home, we studied breast cancer risk in relation to specific types of self-reported and work history-related physical activity, including adolescent and adult exercise and household activity and walking and cycling for transportation. Occupational sitting time and physical activity energy expenditure were assigned based on lifetime occupational histories. RESULTS: In all, 717 incident breast cancer cases were diagnosed. Breast cancer risk was lower for women in the lowest quartile of average occupational sitting time and in the highest quartile of average occupational energy expenditure (adjusted hazard ratio (HR): 0.81 and 0.73, respectively, P <= 0.05). Adult exercise at or above the recommended level (8 metabolic equivalent (MET) h per week per year) was associated with lower risk (adjusted HR: 0.73, P<0.05) in post-menopausal women. Analysis of joint effects showed that having both an active job and exercise participation did not confer an additional benefit. Other common daily activities were not associated with lower risk. INTERPRETATION: These findings suggest that both exercise and occupational activity are associated with lower breast cancer risk, which supports current health promotion campaigns promoting exercise. British Journal of Cancer (2011) 105, 1443-1450. doi:10.1038/bjc.2011.370 www.bjcancer.com Published online 20 September 2011 (C) 2011 Cancer Research UK C1 [Pronk, A.; Ji, B-T; Chow, W-H; Xue, S.; Rothman, N.; Matthews, C. E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shu, X-O; Yang, G.; Zheng, W.; Matthews, C. E.] Vanderbilt Univ, Sch Med, Inst Med & Publ Hlth,Dept Med, Vanderbilt Ingram Canc Ctr,Vanderbilt Epidemiol C, Nashville, TN 37203 USA. [Li, H-L; Gao, Y-T] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Matthews, CE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8100,MSC 7240, Bethesda, MD 20892 USA. EM Charles.Matthews2@nih.gov RI matthews, Charles/E-8073-2015 OI matthews, Charles/0000-0001-8037-3103 FU National Institute of Health [R01 CA70867]; Intramural Research Program [N02 CP1101066] FX This research was supported by National Institute of Health research Grant R01 CA70867 and by the Intramural Research Program contract N02 CP1101066. We express their appreciation to Shanghai residents who participated in the study and thank the research staff of the Shanghai Women's Health Study for their dedication and contributions to the study. NR 36 TC 21 Z9 22 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 25 PY 2011 VL 105 IS 9 BP 1443 EP 1450 DI 10.1038/bjc.2011.370 PG 8 WC Oncology SC Oncology GA 838IR UT WOS:000296282000029 PM 21934685 ER PT J AU Wu, YC Ghitani, A Christensen, R Santella, A Du, Z Rondeau, G Bao, ZR Colon-Ramos, D Shroff, H AF Wu, Yicong Ghitani, Alireza Christensen, Ryan Santella, Anthony Du, Zhuo Rondeau, Gary Bao, Zhirong Colon-Ramos, Daniel Shroff, Hari TI Inverted selective plane illumination microscopy (iSPIM) enables coupled cell identity lineaging and neurodevelopmental imaging in Caenorhabditis elegans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fast 4D imaging; axon growth; neuron migration ID C-ELEGANS; MIGRATION; GENES; DIFFERENTIATION; GUIDANCE; SYNAPTOGENESIS; MECHANISMS; RESOLUTION; DIVISION; MOTILITY AB The Caenorhabditis elegans embryo is a powerful model for studying neural development, but conventional imaging methods are either too slow or phototoxic to take full advantage of this system. To solve these problems, we developed an inverted selective plane illumination microscopy (iSPIM) module for noninvasive high-speed volumetric imaging of living samples. iSPIM is designed as a straightforward add-on to an inverted microscope, permitting conventional mounting of specimens and facilitating SPIM use by development and neurobiology laboratories. iSPIM offers a volumetric imaging rate 30x faster than currently used technologies, such as spinning-disk confocal microscopy, at comparable signal-to-noise ratio. This increased imaging speed allows us to continuously monitor the development of C, elegans embryos, scanning volumes every 2 s for the 14-h period of embryogenesis with no detectable phototoxicity. Collecting similar to 25,000 volumes over the entirety of embryogenesis enabled in toto visualization of positions and identities of cell nuclei. By merging two-color iSPIM with automated lineaging techniques we realized two goals: (i) identification of neurons expressing the transcription factor CEH-10/Chx10 and (ii) visualization of their neurodevelopmental dynamics. We found that canal-associated neurons use somal translocation and amoeboid movement as they migrate to their final position in the embryo. We also visualized axon guidance and growth cone dynamics as neurons circumnavigate the nerve ring and reach their targets in the embryo. The high-speed volumetric imaging rate of iSPIM effectively eliminates motion blur from embryo movement inside the egg case, allowing characterization of dynamic neurodevelopmental events that were previously inaccessible. C1 [Wu, Yicong; Ghitani, Alireza; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Christensen, Ryan; Colon-Ramos, Daniel] Yale Univ, Sch Med, Dept Cell Biol, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06536 USA. [Santella, Anthony; Du, Zhuo; Bao, Zhirong] Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA. [Rondeau, Gary] Appl Sci Instrumentat, Eugene, OR 97402 USA. RP Wu, YC (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. EM yicong.wu@gmail.com RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Bao, Zhirong/0000-0002-2201-2745 FU National Institute of Biomedical Imaging and Bioengineering; National Institutes of Health (NIH) [R00 NS057931, R00 HG004643, F32 GM091874]; Klingenstein Foundation; Alfred P. Sloan Foundation [5 T32 GM07499-34]; March of Dimes Basil O'Connor Starter Scholar Research Award [5FY09-526] FX Support for this work was provided by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (Y.W., A. G., and H. S.), National Institutes of Health (NIH) Grant R00 NS057931 (to D.C.-R.), a fellowship from the Klingenstein Foundation, and Alfred P. Sloan Foundation Genetics Training Grant 5 T32 GM07499-34 (to R. C.). Z.B. was partly supported by NIH Grant R00 HG004643 and March of Dimes Basil O'Connor Starter Scholar Research Award 5FY09-526. A. S. was partly supported by NIH Grant F32 GM091874. NR 45 TC 87 Z9 88 U1 4 U2 22 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 OCT 25 PY 2011 VL 108 IS 43 BP 17708 EP 17713 DI 10.1073/pnas.1108494108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100037 PM 22006307 ER PT J AU Wang, W Perovic, I Chittuluru, J Kaganovich, A Nguyen, LTT Liao, JL Auclair, JR Johnson, D Landeru, A Simorellis, AK Ju, SL Cookson, MR Asturias, FJ Agar, JN Webb, BN Kang, CH Ringe, D Petsko, GA Pochapsky, TC Hoang, QQ AF Wang, Wei Perovic, Iva Chittuluru, Johnathan Kaganovich, Alice Nguyen, Linh T. T. Liao, Jingling Auclair, Jared R. Johnson, Derrick Landeru, Anuradha Simorellis, Alana K. Ju, Shulin Cookson, Mark R. Asturias, Francisco J. Agar, Jeffrey N. Webb, Brian N. Kang, ChulHee Ringe, Dagmar Petsko, Gregory A. Pochapsky, Thomas C. Hoang, Quyen Q. TI A soluble alpha-synuclein construct forms a dynamic tetramer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dynamic structure; helical; Parkinson's disease; NMR; heteronuclear single-quantum coherence ID PROTEIN SECONDARY STRUCTURE; PARKINSONS-DISEASE; CIRCULAR-DICHROISM; NEUROTOXICITY; AGGREGATION; MUTATIONS; MODELS; OCCURS AB A heterologously expressed form of the human Parkinson disease-associated protein alpha-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of alpha-helices in the first 100 N-terminal residues of the 140-residue alpha-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated "hairpin" structure of alpha-synuclein. C1 [Simorellis, Alana K.; Ju, Shulin; Ringe, Dagmar; Petsko, Gregory A.; Pochapsky, Thomas C.] Brandeis Univ, Dept Chem & Biochem, Waltham, MA 02454 USA. [Perovic, Iva; Auclair, Jared R.; Simorellis, Alana K.; Ju, Shulin; Agar, Jeffrey N.; Ringe, Dagmar; Petsko, Gregory A.; Pochapsky, Thomas C.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Wang, Wei; Nguyen, Linh T. T.; Liao, Jingling; Johnson, Derrick; Landeru, Anuradha; Hoang, Quyen Q.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Wang, Wei; Nguyen, Linh T. T.; Liao, Jingling; Johnson, Derrick; Landeru, Anuradha; Hoang, Quyen Q.] Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. [Perovic, Iva; Auclair, Jared R.; Agar, Jeffrey N.] Brandeis Univ, Dept Chem, Waltham, MA 02454 USA. [Chittuluru, Johnathan; Asturias, Francisco J.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92307 USA. [Kaganovich, Alice; Cookson, Mark R.] NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [Webb, Brian N.; Kang, ChulHee] Washington State Univ, Dept Chem, Pullman, WA 99164 USA. [Ringe, Dagmar; Petsko, Gregory A.] Brigham & Womens Hosp, Cambridge, MA 02139 USA. [Ringe, Dagmar; Petsko, Gregory A.] Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02139 USA. [Ringe, Dagmar; Petsko, Gregory A.] Harvard Univ, Sch Med, Ctr Neurol Dis, Cambridge, MA 02139 USA. RP Ringe, D (reprint author), Brandeis Univ, Dept Chem & Biochem, Waltham, MA 02454 USA. EM ringe@brandeis.edu; petsko@brandeis.edu; pochapsk@brandeis.edu; qqhoang@iupui.edu RI Wang, Wei/C-1476-2012 OI Wang, Wei/0000-0002-9417-417X FU Michael J. Fox Foundation; Indiana University School of Medicine; Fidelity Biosciences Research Initiative; Ellison Medical Foundation; McKnight Endowment for Neuroscience; National Institutes of Health, National Institute on Aging FX We thank S. Lindquist for yeast expression vectors of alpha Syn; S. Subramanian for help collecting preliminary NMR data; S. Pochapsky for help with NMR experiments and processing data; C. Miller for assistance with liposome assays; M. Georgiadis for providing 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide cross-linker; K. Dunker for access to CD; Clark Wells for the plate reader; N. Agar for use of her MALDI-TOF mass spectrometer; A. Hudmon for spectrofluorimeter access; and J. Sussman for helpful discussions. We also acknowledge the National Resource for Automated Molecular Microscopy. Support for this work was provided by the Michael J. Fox Foundation (Q.Q.H., D.R., and G.A.P.); an Indiana University School of Medicine Biomedical Research grant (to Q.Q.H.); a Fidelity Biosciences Research Initiative (with much useful discussion from Dr. S. Weninger) (to G.A.P. and D.R.); The Ellison Medical Foundation and The McKnight Endowment for Neuroscience; and a Rapid Response grant from the Michael J. Fox Foundation (to T.C.P. and I.P.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 34 TC 136 Z9 138 U1 8 U2 56 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 OCT 25 PY 2011 VL 108 IS 43 BP 17797 EP 17802 DI 10.1073/pnas.1113260108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100052 PM 22006323 ER PT J AU Davis, CA Parniak, MA Hughes, SH AF Davis, Caroline A. Parniak, Michael A. Hughes, Stephen H. TI The effects of RNase H inhibitors and nevirapine on the susceptibility of HIV-1 to AZT and 3TC SO VIROLOGY LA English DT Article DE HIV-1; Reverse transcriptase; NNRTI; RNase H; RNase H Inhibitor (RNHI); AZT resistance ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; CONNECTION DOMAIN; RIBONUCLEASE-H; NONNUCLEOSIDE INHIBITORS; MOLECULAR-MECHANISM; STERIC HINDRANCE; DUAL RESISTANCE; MUTATIONS; NUCLEOSIDE AB It was recently proposed that HIV RT mutations that decrease RNase H activity increase zidovudine (AZT) resistance by delaying the degradation of the RNA template, allowing more time for AZTMP excision from the 3' end of the viral DNA. This predicts that suboptimal concentrations of an RNase H Inhibitor (RNHI), which would decrease RNaseH activity, would decrease AZT susceptibility. Conversely, a suboptimal concentration of a nonnucleoside RT inhibitor (NNRTI) would decrease polymerase activity and increase AZT susceptibility. We determined the effect of several RNHIs and an NNRTI (nevirapine) on AZT and lamivudine (3TC) susceptibility with vectors that replicate using WT or AZT resistant RTs. Susceptibility to 3TC, which is not readily excised, did not change significantly. Nevirapine, and most RNHIs tested, had only small effects on the susceptibility of either HIV vector to AZT and 3TC. One RNHI, F0444-0019, increased the IC50 for AZT for either vector by similar to 5-fold, which may be a concern. Published by Elsevier Inc. C1 [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NCI Frederick, Frederick, MD 21702 USA. [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, NCI Frederick, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institutes of Health [AI073975, AI077424] FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Research in the Parniak laboratory is supported in part by grants AI073975 and AI077424 from the National Institutes of Health. We thank Dwight Nissley for NVP, Andrea Ferris for help with cell maintenance, and also thank Brian Luke for helpful discussions regarding statistical analysis of the data. We also thank AI Kane for assistance with the figures. NR 39 TC 4 Z9 5 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 25 PY 2011 VL 419 IS 2 BP 64 EP 71 DI 10.1016/j.virol.2011.08.010 PG 8 WC Virology SC Virology GA 827IP UT WOS:000295422500002 PM 21907380 ER PT J AU Saribasak, H Maul, RW Cao, Z McClure, RL Yang, W McNeill, DR Wilson, DM Gearhart, PJ AF Saribasak, Huseyin Maul, Robert W. Cao, Zheng McClure, Rhonda L. Yang, William McNeill, Daniel R. Wilson, David M., III Gearhart, Patricia J. TI XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; BASE EXCISION-REPAIR; URACIL-DNA GLYCOSYLASE; RNA-POLYMERASE-II; LIGASE-III; IMMUNOGLOBULIN GENES; DEAMINASE AID; BREAKS; TRANSLOCATIONS; PATHWAYS AB Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer's patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1(+/-) splenic B cells, the length of microhomology at the switch junctions decreased, suggesting that XRCC1 also participates in alternative nonhomologous end joining. Furthermore, Xrcc1(+/-) B cells had reduced Igh/c-myc translocations during CSR, supporting a role for XRCC1 in microhomology-mediated joining. Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways. C1 [Saribasak, Huseyin; Maul, Robert W.; Cao, Zheng; McClure, Rhonda L.; Yang, William; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [McNeill, Daniel R.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov RI Saribasak, Huseyin/C-9331-2012; OI Saribasak, Huseyin/0000-0003-0055-062X; Maul, Robert/0000-0002-6958-8514 FU National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 36 TC 30 Z9 30 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 24 PY 2011 VL 208 IS 11 BP 2209 EP 2216 DI 10.1084/jem.20111135 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841TX UT WOS:000296537800008 PM 21967769 ER PT J AU Kari, L Whitmire, WM Olivares-Zavaleta, N Goheen, MM Taylor, LD Carlson, JH Sturdevant, GL Lu, CX Bakios, LE Randall, LB Parnell, MJ Zhong, GM Caldwell, HD AF Kari, Laszlo Whitmire, William M. Olivares-Zavaleta, Norma Goheen, Morgan M. Taylor, Lacey D. Carlson, John H. Sturdevant, Gail L. Lu, Chunxue Bakios, Lauren E. Randall, Linnell B. Parnell, Michael J. Zhong, Guangming Caldwell, Harlan D. TI A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID OUTER-MEMBRANE PROTEIN; VIRULENCE FACTOR; IMMUNE-RESPONSE; GENITAL-TRACT; ANIMAL-MODEL; INFECTION; PLASMID; STRAINS; COMMUNITIES; DISEASE AB Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease. C1 [Kari, Laszlo; Whitmire, William M.; Olivares-Zavaleta, Norma; Goheen, Morgan M.; Taylor, Lacey D.; Carlson, John H.; Sturdevant, Gail L.; Bakios, Lauren E.; Randall, Linnell B.; Caldwell, Harlan D.] NIAID, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. [Parnell, Michael J.] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Lu, Chunxue; Zhong, Guangming] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, San Antonio, TX 78229 USA. [Lu, Chunxue; Zhong, Guangming] Univ Texas Hlth Sci Ctr San Antonio, Dept Immunol, San Antonio, TX 78229 USA. RP Caldwell, HD (reprint author), NIAID, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, United States National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, United States National Institutes of Health. NR 26 TC 65 Z9 65 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 24 PY 2011 VL 208 IS 11 BP 2217 EP 2223 DI 10.1084/jem.20111266 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841TX UT WOS:000296537800009 PM 21987657 ER PT J AU Matsumoto, M Hikosaka, O AF Matsumoto, Masayuki Hikosaka, Okihide TI Electrical Stimulation of the Primate Lateral Habenula Suppresses Saccadic Eye Movement through a Learning Mechanism SO PLOS ONE LA English DT Article ID ROSTROMEDIAL TEGMENTAL NUCLEUS; MIDBRAIN DOPAMINE NEURONS; NEGATIVE REWARD SIGNALS; DORSAL RAPHE NUCLEUS; SUBSTANTIA-NIGRA; BASAL GANGLIA; SEEKING BEHAVIOR; COMPLEX; RATS; AREA AB The lateral habenula (LHb) is a brain structure which represents negative motivational value. Neurons in the LHb are excited by unpleasant events such as reward omission and aversive stimuli, and transmit these signals to midbrain dopamine neurons which are involved in learning and motivation. However, it remains unclear whether these phasic changes in LHb neuronal activity actually influence animal behavior. To answer this question, we artificially activated the LHb by electrical stimulation while monkeys were performing a visually guided saccade task. In one block of trials, saccades to one fixed direction (e.g., right direction) were followed by electrical stimulation of the LHb while saccades to the other direction (e. g., left direction) were not. The direction-stimulation contingency was reversed in the next block. We found that the post-saccadic stimulation of the LHb increased the latencies of saccades in subsequent trials. Notably, the increase of the latency occurred gradually as the saccade was repeatedly followed by the stimulation, suggesting that the effect of the post-saccadic stimulation was accumulated across trials. LHb stimulation starting before saccades, on the other hand, had no effect on saccade latency. Together with previous studies showing LHb activation by reward omission and aversive stimuli, the present stimulation experiment suggests that LHb activity contributes to learning to suppress actions which lead to unpleasant events. C1 [Matsumoto, Masayuki; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Matsumoto, Masayuki] Kyoto Univ, Primate Res Inst, Inuyama, Aichi 484, Japan. RP Matsumoto, M (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mmatsumoto@pri.kyoto-u.ac.jp FU National Institutes of Health, National Eye Institute FX This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 12 Z9 12 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 24 PY 2011 VL 6 IS 10 AR e26701 DI 10.1371/journal.pone.0026701 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841MA UT WOS:000296515200044 PM 22039537 ER PT J AU Patel, V Boyce, N Collins, PY Saxena, S Horton, R AF Patel, Vikram Boyce, Niall Collins, Pamela Y. Saxena, Shekhar Horton, Richard TI A renewed agenda for global mental health SO LANCET LA English DT Editorial Material ID DISORDERS C1 [Patel, Vikram] Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England. [Boyce, Niall; Collins, Pamela Y.] Lancet, London, England. [Patel, Vikram] Sangath, Goa, India. [Collins, Pamela Y.] NIMH, Bethesda, MD 20892 USA. [Saxena, Shekhar] World Hlth Org, Dept Mental Hlth & Subst Abuse, Geneva, Switzerland. RP Patel, V (reprint author), Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, Keppel St, London WC1E 7HT, England. EM vikram.patel@lshtm.ac.uk OI Patel, Vikram/0000-0003-1066-8584 FU Wellcome Trust [091834] NR 12 TC 54 Z9 55 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD OCT 22 PY 2011 VL 378 IS 9801 BP 1441 EP 1442 DI 10.1016/S0140-6736(11)61385-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 838VC UT WOS:000296319600004 PM 22008422 ER PT J AU Glasgow, RE Dickinson, P Fisher, L Christiansen, S Toobert, DJ Bender, BG Dickinson, LM Jortberg, B Estabrooks, PA AF Glasgow, Russell E. Dickinson, Perry Fisher, Lawrence Christiansen, Steve Toobert, Deborah J. Bender, Bruce G. Dickinson, L. Miriam Jortberg, Bonnie Estabrooks, Paul A. TI Use of RE-AIM to develop a multi-media facilitation tool for the patient-centered medical home SO IMPLEMENTATION SCIENCE LA English DT Article ID PUBLIC-HEALTH IMPACT; COMPUTER-ASSISTED INTERVENTION; IMPROVE DIABETES CARE; CHRONIC ILLNESS CARE; QUALITY-OF-CARE; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; MANAGEMENT; SUPPORT; POPULATION AB Background: Much has been written about how the medical home model can enhance patient-centeredness, care continuity, and follow-up, but few comprehensive aids or resources exist to help practices accomplish these aims. The complexity of primary care can overwhelm those concerned with quality improvement. Methods: The RE-AIM planning and evaluation model was used to develop a multimedia, multiple-health behavior tool with psychosocial assessment and feedback features to facilitate and guide patient-centered communication, care, and follow-up related to prevention and self-management of the most common adult chronic illnesses seen in primary care. Results: The Connection to Health Patient Self-Management System, a web-based patient assessment and support resource, was developed using the RE-AIM factors of reach (e.g., allowing input and output via choice of different modalities), effectiveness (e.g., using evidence-based intervention strategies), adoption (e.g., assistance in integrating the system into practice workflows and permitting customization of the website and feedback materials by practice teams), implementation (e.g., identifying and targeting actionable priority behavioral and psychosocial issues for patients and teams), and maintenance/sustainability (e.g., integration with current National Committee for Quality Assurance recommendations and clinical pathways of care). Connection to Health can work on a variety of input and output platforms, and assesses and provides feedback on multiple health behaviors and multiple chronic conditions frequently managed in adult primary care. As such, it should help to make patient-healthcare team encounters more informed and patient-centered. Formative research with clinicians indicated that the program addressed a number of practical concerns and they appreciated the flexibility and how the Connection to Health program could be customized to their office. Conclusions: This primary care practice tool based on an implementation science model has the potential to guide patients to more healthful behaviors and improved self-management of chronic conditions, while fostering effective and efficient communication between patients and their healthcare team. RE-AIM and similar models can help clinicians and media developers create practical products more likely to be widely adopted, feasible in busy medical practices, and able to produce public health impact. C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Dickinson, Perry; Dickinson, L. Miriam; Jortberg, Bonnie] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Fisher, Lawrence] Univ Calif San Francisco, Ctr Diabet, Dept Family & Community Med, San Francisco, CA 94143 USA. [Christiansen, Steve] Intervis Media, Eugene, OR 97401 USA. [Toobert, Deborah J.] Oregon Res Inst, Eugene, OR 97403 USA. [Bender, Bruce G.] Natl Jewish Hlth, Div Pediat Behav Hlth, Denver, CO 80206 USA. [Estabrooks, Paul A.] Virginia Tech, Dept Human Nutr Foods & Exercise, VT Riverside, Sw Roanoke, VA 24016 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 6144, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov FU The Colorado Health Foundation; Robert Wood Johnson Foundation FX The Colorado Health Foundation and Robert Wood Johnson Foundation provided funding that supported a portion of the planning and development of the Connection to Health Patient Self-management System. NR 65 TC 22 Z9 22 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD OCT 21 PY 2011 VL 6 AR 118 DI 10.1186/1748-5908-6-118 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 857GJ UT WOS:000297705600001 PM 22017791 ER PT J AU Berezhkovskii, AM Shvartsman, SY AF Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI Physical interpretation of mean local accumulation time of morphogen gradient formation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biodiffusion; biological tissues; cellular biophysics; genetics; molecular biophysics; reaction-diffusion systems ID POSITIONAL INFORMATION; DIFFUSION; KINETICS AB The paper deals with a reaction-diffusion problem that arises in developmental biology when describing the formation of the concentration profiles of signaling molecules, called morphogens, which control gene expression and, hence, cell differentiation. The mean local accumulation time, which is the mean time required to reach the steady state at a fixed point of a patterned tissue, is an important characteristic of the formation process. We show that this time is a sum of two times, the conditional mean first-passage time from the source to the observation point and the mean local accumulation time in the situation when the source is localized at the observation point. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3654159] C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Lewis Singler Inst Integrat Genom, Princeton, NJ 08544 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov FU NIH, Center for Information Technology FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 18 TC 11 Z9 11 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 21 PY 2011 VL 135 IS 15 AR 154115 DI 10.1063/1.3654159 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 841MQ UT WOS:000296516800018 PM 22029305 ER PT J AU Bauer, AK Cho, HY Miller-DeGraff, L Walker, C Helms, K Fostel, J Yamamoto, M Kleeberger, SR AF Bauer, Alison K. Cho, Hye-Youn Miller-DeGraff, Laura Walker, Christopher Helms, Katherine Fostel, Jennifer Yamamoto, Masayuki Kleeberger, Steven R. TI Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; PULMONARY INFLAMMATION; KNOCKOUT MICE; MURINE MODEL; CANCER; EXPRESSION; INJURY; CARCINOGENESIS; TUMORIGENESIS; MUTATIONS AB Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2(+/+) and Nrf2(-/-) mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2(-/-) mice compared to Nrf2(+/+) mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2(-/-) mice than in Nrf2(+/+) mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2(+/+) mice relative to Nrf2(-/-) mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy. C1 [Bauer, Alison K.; Helms, Katherine] Michigan State Univ, Coll Vet Med, Dept Pathobiol & Diagnost Invest, E Lansing, MI 48824 USA. [Cho, Hye-Youn; Miller-DeGraff, Laura; Walker, Christopher; Fostel, Jennifer; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Div Med Biochem, Sendai, Miyagi 980, Japan. RP Bauer, AK (reprint author), Michigan State Univ, Coll Vet Med, Dept Pathobiol & Diagnost Invest, E Lansing, MI 48824 USA. EM alison.bauer@ucdenver.edu FU National Institute of Environmental Health Sciences; Michigan State University FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences and Michigan State University internal funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 32 Z9 32 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 21 PY 2011 VL 6 IS 10 AR e26590 DI 10.1371/journal.pone.0026590 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841LG UT WOS:000296513200033 PM 22039513 ER PT J AU Simbaqueba, J Sanchez, P Sanchez, E Zarantes, VMN Chacon, MI Barrero, LS Marino-Ramirez, L AF Simbaqueba, Jaime Sanchez, Pilar Sanchez, Erika Nunez Zarantes, Victor Manuel Isabel Chacon, Maria Stella Barrero, Luz Marino-Ramirez, Leonardo TI Development and Characterization of Microsatellite Markers for the Cape Gooseberry Physalis peruviana SO PLOS ONE LA English DT Article ID EST-SSRS; ANTIINFLAMMATORY ACTIVITY; IN-VITRO; L.; EXTRACTS; GENOMES; PLANTS; WHEAT; RICE; DNA AB Physalis peruviana, commonly known as Cape gooseberry, is an Andean Solanaceae fruit with high nutritional value and interesting medicinal properties. In the present study we report the development and characterization of microsatellite loci from a P. peruviana commercial Colombian genotype. We identified 932 imperfect and 201 perfect Simple Sequence Repeats (SSR) loci in untranslated regions (UTRs) and 304 imperfect and 83 perfect SSR loci in coding regions from the assembled Physalis peruviana leaf transcriptome. The UTR SSR loci were used for the development of 162 primers for amplification. The efficiency of these primers was tested via PCR in a panel of seven P. peruviana accessions including Colombia, Kenya and Ecuador ecotypes and one closely related species Physalis floridana. We obtained an amplification rate of 83% and a polymorphic rate of 22%. Here we report the first P. peruviana specific microsatellite set, a valuable tool for a wide variety of applications, including functional diversity, conservation and improvement of the species. C1 [Simbaqueba, Jaime; Sanchez, Erika; Nunez Zarantes, Victor Manuel; Stella Barrero, Luz; Marino-Ramirez, Leonardo] Colombian Corp Agr Res CORPOICA, CBB, Plant Mol Genet Lab, Bogota, Colombia. [Sanchez, Pilar; Isabel Chacon, Maria] Univ Nacl Colombia, Fac Agron, Bogota, Colombia. [Stella Barrero, Luz; Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. [Marino-Ramirez, Leonardo] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. RP Simbaqueba, J (reprint author), Colombian Corp Agr Res CORPOICA, CBB, Plant Mol Genet Lab, Bogota, Colombia. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; simbaqueba, jaime/0000-0003-4389-9418 FU Colombian Ministry of Agriculture [054/08072-2008L4787-3281, 054/08190-2008L7922-3322]; National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information FX Support for this research was provided by a grant from the Colombian Ministry of Agriculture Contract Nos. 054/08072-2008L4787-3281 to LSB and 054/08190-2008L7922-3322 to VMNZ. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and National Center for Biotechnology Information. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 10 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 21 PY 2011 VL 6 IS 10 AR e26719 DI 10.1371/journal.pone.0026719 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841LG UT WOS:000296513200047 PM 22039540 ER PT J AU Visweswaraiah, J Lageix, S Castilho, BA Izotova, L Kinzy, TG Hinnebusch, AG Sattlegger, E AF Visweswaraiah, Jyothsna Lageix, Sebastien Castilho, Beatriz A. Izotova, Lara Kinzy, Terri Goss Hinnebusch, Alan G. Sattlegger, Evelyn TI Evidence That Eukaryotic Translation Elongation Factor 1A (eEF1A) Binds the Gcn2 Protein C Terminus and Inhibits Gcn2 Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID CONTROL; EIF-2-ALPHA KINASE GCN2; UNCHARGED TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; SUBSTRATE RECOGNITION; NUCLEOTIDE EXCHANGE; EIF2-ALPHA KINASE; STARVED CELLS; ACTIVATION; DOMAIN AB The eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl-tRNAs to the ribosomal A-site during protein synthesis. To ensure a continuous supply of amino acids, cells harbor the kinase Gcn2 and its effector protein Gcn1. The ultimate signal for amino acid shortage is uncharged tRNAs. We have proposed a model for sensing starvation, in which Gcn1 and Gcn2 are tethered to the ribosome, and Gcn1 is directly involved in delivering uncharged tRNAs from the A-site to Gcn2 for its subsequent activation. Gcn1 and Gcn2 are large proteins, and these proteins as well as eEF1A access the A-site, leading us to investigate whether there is a functional or physical link between these proteins. Using Saccharomyces cerevisiae cells expressing His(6)-eEF1A and affinity purification, we found that eEF1A co-eluted with Gcn2. Furthermore, Gcn2 co-immunoprecipitated with eEF1A, suggesting that they reside in the same complex. The purified GST-tagged Gcn2 C-terminal domain (CTD) was sufficient for precipitating eEF1A from whole cell extracts generated from gcn2 Delta cells, independently of ribosomes. Purified GST-Gcn2-CTD and purified His(6)-eEF1A interacted with each other, and this was largely independent of the Lys residues in Gcn2-CTD known to be required for tRNA binding and ribosome association. Interestingly, Gcn2-eEF1A interaction was diminished in amino acid-starved cells and by uncharged tRNAs in vitro, suggesting that eEF1A functions as a Gcn2 inhibitor. Consistent with this possibility, purified eEF1A reduced the ability of Gcn2 to phosphorylate its substrate, eIF2 alpha, but did not diminish Gcn2 autophosphorylation. These findings implicate eEF1A in the intricate regulation of Gcn2 and amino acid homeostasis. C1 [Sattlegger, Evelyn] Massey Univ, Inst Nat Sci, N Shore Mail Ctr, Albany 0745, New Zealand. [Lageix, Sebastien; Hinnebusch, Alan G.; Sattlegger, Evelyn] NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Castilho, Beatriz A.] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, BR-04023062 Sao Paulo, Brazil. [Izotova, Lara; Kinzy, Terri Goss] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Mol Genet Microbiol & Immunol, Piscataway, NJ 08854 USA. RP Sattlegger, E (reprint author), Massey Univ, Inst Nat Sci, N Shore Mail Ctr, POB 102 904, Albany 0745, New Zealand. EM e.sattlegger@massey.ac.nz RI Castilho, Beatriz/C-2503-2012 OI Castilho, Beatriz/0000-0003-4509-5237 FU National Institutes of Health; Fundacao de Apoio a Pesquisa no Estado de Sao Paulo; Marsden Fund Council; Massey University; Royal Society of New Zealand [MAU0607]; [RO1 GM57483] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program (to A.G.H.) and by Grant RO1 GM57483 (to T.G.K.). This work was also supported by a grant from Fundacao de Apoio a Pesquisa no Estado de Sao Paulo (to B.A.C.), The Marsden Fund Council from Government funding, administered by the Royal Society of New Zealand (MAU0607), and a Massey University Technician Award and Research Fund (to E.S.). NR 42 TC 18 Z9 21 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 21 PY 2011 VL 286 IS 42 BP 36568 EP 36579 DI 10.1074/jbc.M111.248898 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841UC UT WOS:000296538300041 PM 21849502 ER PT J AU Lowery, J Szul, T Seetharaman, J Jian, XY Su, M Forouhar, F Xiao, R Acton, TB Montelione, GT Lin, HL Wright, JW Lee, E Holloway, ZG Randazzo, PA Tong, L Sztul, E AF Lowery, Jason Szul, Tomasz Seetharaman, Jayaraman Jian, Xiaoying Su, Min Forouhar, Farhad Xiao, Rong Acton, Thomas B. Montelione, Gaetano T. Lin, Helen Wright, John W. Lee, Eunjoo Holloway, Zoe G. Randazzo, Paul A. Tong, Liang Sztul, Elizabeth TI Novel C-terminal Motif within Sec7 Domain of Guanine Nucleotide Exchange Factors Regulates ADP-ribosylation Factor (ARF) Binding and Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRUCTURAL GENOMICS CONSORTIUM; BREFELDIN-A; FACTOR GBF1; PRODUCTION PLATFORM; PROTEIN-1 BIG1; GOLGI; DYNAMICS; GTPASE; TRAFFICKING; ASSOCIATION AB ADP-ribosylation factors (ARFs) and their activating guanine nucleotide exchange factors (GEFs) play key roles in membrane traffic and signaling. All ARF GEFs share a similar to 200-residue Sec7 domain (Sec7d) that alone catalyzes the GDP to GTP exchange that activates ARF. We determined the crystal structure of human BIG2 Sec7d. A C-terminal loop immediately following helix J (loop>J) was predicted to form contacts with helix H and the switch I region of the cognate ARF, suggesting that loop>J may participate in the catalytic reaction. Indeed, we identified multiple alanine substitutions within loop>J of the full length and/or Sec7d of two large brefeldin A-sensitive GEFs (GBF1 and BIG2) and one small brefeldin A-resistant GEF (ARNO) that abrogated binding of ARF and a single alanine substitution that allowed ARF binding but inhibited GDP to GTP exchange. Loop>J sequences are highly conserved, suggesting that loop>J plays a crucial role in the catalytic activity of all ARF GEFs. Using GEF mutants unable to bind ARF, we showed that GEFs associate with membranes independently of ARF and catalyze ARF activation in vivo only when membrane-associated. Our structural, cell biological, and biochemical findings identify loop>J as a key regulatory motif essential for ARF binding and GDP to GTP exchange by GEFs and provide evidence for the requirement of membrane association during GEF activity. C1 [Lowery, Jason; Szul, Tomasz; Lin, Helen; Wright, John W.; Lee, Eunjoo; Sztul, Elizabeth] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA. [Seetharaman, Jayaraman; Su, Min; Forouhar, Farhad; Tong, Liang] Columbia Univ, NE Struct Genom Consortium, Dept Biol Sci, New York, NY 10027 USA. [Xiao, Rong; Acton, Thomas B.; Montelione, Gaetano T.] Rutgers State Univ, Dept Mol Biol & Biochem, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Xiao, Rong; Acton, Thomas B.; Montelione, Gaetano T.] NE Struct Genom Consortium, Robert Wood Johnson Med Sch, Dept Biochem, Piscataway, NJ 08854 USA. [Jian, Xiaoying; Randazzo, Paul A.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Holloway, Zoe G.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Sztul, E (reprint author), Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA. EM esztul@uab.edu OI Tong, Liang/0000-0002-0563-6468 FU National Science Foundation [NSF0744471] FX This work was supported by National Science Foundation Award NSF0744471 (to E. S.). NR 38 TC 6 Z9 6 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 21 PY 2011 VL 286 IS 42 BP 36898 EP 36906 DI 10.1074/jbc.M111.230631 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841UC UT WOS:000296538300069 PM 21828055 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Equal versus equivalent access to the scientific literature SO RETROVIROLOGY LA English DT Editorial Material ID CHRONIC-FATIGUE-SYNDROME; VIRUS-RELATED VIRUS; MOUSE DNA; XMRV; CONTAMINATION; INFECTION; SEQUENCES; ABSENCE C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 10 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 21 PY 2011 VL 8 AR 83 DI 10.1186/1742-4690-8-83 PG 2 WC Virology SC Virology GA 844FL UT WOS:000296733000001 PM 22018210 ER PT J AU Kang, H Suh, JY Jung, YS Jung, JW Kim, MK Chung, JH AF Kang, Hyeog Suh, Jeong-Yong Jung, Young-Sang Jung, Jae-Won Kim, Myung K. Chung, Jay H. TI Peptide Switch Is Essential for Sirt1 Deacetylase Activity SO MOLECULAR CELL LA English DT Article ID SMALL-MOLECULE ACTIVATORS; CALORIE RESTRICTION; TRANSCRIPTION FACTORS; CELLULAR-RESPONSE; PROSTATE-CANCER; PROTEIN SIR2; DNA-DAMAGE; P53; RESVERATROL; MICE AB In mammals, the Sirtuins are composed of seven Sir2 orthologs (Sirt1-7) with a conserved deacetylase core that utilizes NAD(+) as a cofactor. Interestingly, the deacetylase core of Sirt1 by itself has no catalytic activity. We found within the C-terminal domain a 25 aa sequence that is essential for Sirt1 activity (ESA). Our results indicate that the ESA region interacts with and functions as an "on switch" for the deacetylase core. The endogenous Sirt1 inhibitor DBC1, which also binds to the deacetylase core, competes with and inhibits the ESA region from interacting with the deacetylase core. We discovered an ESA mutant peptide that can bind to the deacetylase core and inhibit Sirt1 in trans. By using this mutant peptide, we were able to inhibit Sirt1 activity and to increase the chemosensitivity of androgen-refractory prostate cancer cells. Therefore, the ESA region is a potential target for development of therapies to regulate Sirt1 C1 [Kang, Hyeog; Jung, Jae-Won; Kim, Myung K.; Chung, Jay H.] NHLBI, NIH, Lab Obes & Aging Res, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. [Suh, Jeong-Yong] Seoul Natl Univ, Dept Agr Biotechnol, WCU Biomodulat Major, Seoul 136701, South Korea. [Jung, Young-Sang] Korea Basic Sci Inst, Seoul 136701, South Korea. RP Chung, JH (reprint author), NHLBI, NIH, Lab Obes & Aging Res, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov RI Jung, Young-Sang/H-1169-2011 FU National Heart Lung and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, National Heart Lung and Blood Institute, National Institutes of Health. We thank Alexandra Brown for help with manuscript preparation. NR 52 TC 48 Z9 48 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 21 PY 2011 VL 44 IS 2 BP 203 EP 213 DI 10.1016/j.molcel.2011.07.038 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837OC UT WOS:000296212100007 PM 22017869 ER PT J AU Azoitei, ML Correia, BE Ban, YEA Carrico, C Kalyuzhniy, O Chen, L Schroeter, A Huang, PS McLellan, JS Kwong, PD Baker, D Strong, RK Schief, WR AF Azoitei, Mihai L. Correia, Bruno E. Ban, Yih-En Andrew Carrico, Chris Kalyuzhniy, Oleksandr Chen, Lei Schroeter, Alexandria Huang, Po-Ssu McLellan, Jason S. Kwong, Peter D. Baker, David Strong, Roland K. Schief, William R. TI Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold SO SCIENCE LA English DT Article ID EPITOPE-SCAFFOLDS; HIV-1 GP120; DESIGN; ANTIBODIES; NEUTRALIZATION; SITE AB The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting. C1 [Azoitei, Mihai L.; Correia, Bruno E.; Ban, Yih-En Andrew; Carrico, Chris; Kalyuzhniy, Oleksandr; Schroeter, Alexandria; Huang, Po-Ssu; Baker, David; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Correia, Bruno E.] Inst Gulbenkian Ciencias, PhD Program Computat Biol, Oeiras, Portugal. [Carrico, Chris; Strong, Roland K.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. [Chen, Lei; McLellan, Jason S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Schief, WR (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA. EM schief@scripps.edu RI McLellan, Jason/A-6874-2010; Baker, David/K-8941-2012; OI Baker, David/0000-0001-7896-6217; Carrico, Chris/0000-0003-0939-9006 FU International AIDS Vaccine Initiative Neutralizing Antibody Consortium; Bill and Melinda Gates Foundation Consortium for AIDS Vaccine Discovery; Portuguese Fundacao para a Ciencia e a Tecnologia [SFRH/774 BD/32958/2006]; PDB [3RPT, 3RU8] FX Supported by grants from the International AIDS Vaccine Initiative Neutralizing Antibody Consortium and the Bill and Melinda Gates Foundation Consortium for AIDS Vaccine Discovery. B.E.C. was supported by a fellowship from the Portuguese Fundacao para a Ciencia e a Tecnologia (SFRH/774 BD/32958/2006). We thank I. Wilson for comments on the manuscript; D. Burton, A. Hessell, and the IAVI Neutralizing Antibody Consortium Reagent Repository for providing b6, b12, and b13; J. Mascola for VRC01 and VRC03; Progenics Inc. for CD4-IgG2; D. Dimitrov for m6, m14, and m18; J. Robinson for 15E; and R. Wyatt for F105 and HxB2 gp120. We thank G. Nabel, M. Kanekiyo, and Z.-Y. Yang for experiments on early generations of b12 scaffolds. Coordinates and structure factors were deposited in the PDB as entries 3RPT and 3RU8. The University of Washington has filed a patent application on the b12 scaffolds and the scaffolding method developed in this study. Materials and information will be provided to noncommercial users under the Uniform Biological Materials Transfer Agreement. The Multigraft software developed in this work is freely available to noncommercial users through the Rosetta Commons agreement (www.rosettacommons.org). NR 23 TC 102 Z9 102 U1 1 U2 51 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 21 PY 2011 VL 334 IS 6054 BP 373 EP 376 DI 10.1126/science.1209368 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835RC UT WOS:000296052500052 PM 22021856 ER PT J AU Proctor, LM AF Proctor, Lita M. TI The Human Microbiome Project in 2011 and Beyond SO CELL HOST & MICROBE LA English DT Editorial Material ID GUT MICROBIOME; INTESTINAL MICROBIOTA; BODY HABITATS; ENTEROTYPES; DISEASE; SHAPES AB The human microbiome comprises the genes and genomes of the microbiota that inhabit the body. We highlight Human Microbiome Project (HMP) resources, including 600 microbial reference genomes, 70 million 16S sequences, 700 metagenomes, and 60 million predicted genes from healthy adult microbiomes. Microbiome studies of specific diseases and future research directions are also discussed. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Proctor, LM (reprint author), NHGRI, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM lita.proctor@nih.gov NR 13 TC 89 Z9 93 U1 2 U2 41 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT 20 PY 2011 VL 10 IS 4 BP 287 EP 291 DI 10.1016/j.chom.2011.10.001 PG 5 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 842LK UT WOS:000296600700002 PM 22018227 ER PT J AU Holmes, EC AF Holmes, Edward C. TI The Evolution of Endogenous Viral Elements SO CELL HOST & MICROBE LA English DT Review ID HEPATITIS-B-VIRUS; RNA VIRUS; MOLECULAR EVOLUTION; MAMMALIAN GENOMES; HIV-1 INFECTION; DNA; SEQUENCES; ORIGINS; ANCIENT; APOBEC3G AB Endogenous retroviruses are a common component of the eukaryotic genome, and their evolution and potential function have attracted considerable interest. More surprising was the recent discovery that eukaryotic genomes contain sequences from RNA viruses that have no DNA stage in their life cycle. Similarly, several single-stranded DNA viruses have left integrated copies in their host genomes. This review explores some major evolutionary aspects arising from the discovery of these endogenous viral elements (EVEs). In particular, the reasons for the bias toward EVEs derived from negative-sense RNA viruses are considered, as well as what they tell us about the long-term "arms races" between hosts and viruses, characterized by episodes of selection and counter-selection. Most dramatically, the presence of orthologous EVEs in divergent hosts demonstrates that some viral families have ancestries dating back almost 100 million years, and hence are far older than expected from the phylogenetic analysis of their exogenous relatives. C1 [Holmes, Edward C.] 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 Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 80 TC 63 Z9 66 U1 0 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT 20 PY 2011 VL 10 IS 4 BP 368 EP 377 DI 10.1016/j.chom.2011.09.002 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 842LK UT WOS:000296600700012 PM 22018237 ER PT J AU Andrei, G Lisco, A Vanpouille, C Introini, A Balestra, E van den Oord, J Cihlar, T Perno, CF Snoeck, R Margolis, L Balzarini, J AF Andrei, Graciela Lisco, Andrea Vanpouille, Christophe Introini, Andrea Balestra, Emanuela van den Oord, Joost Cihlar, Tomas Perno, Carlo-Federico Snoeck, Robert Margolis, Leonid Balzarini, Jan TI Topical Tenofovir, a Microbicide Effective against HIV, Inhibits Herpes Simplex Virus-2 Replication SO CELL HOST & MICROBE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO; TYPE-1; ACYCLOVIR; TRANSMISSION; INFECTION; POTENT; ASSAY; GEL; 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE AB The HIV reverse-transcriptase inhibitor, tenofovir, was recently formulated into a vaginal gel for use as a microbicide. In human trials, a 1% tenofovir gel inhibited HIV sexual transmission by 39% and, surprisingly, herpes simplex virus-2 (HSV-2) transmission by 51%. We demonstrate that the concentration achieved intravaginally with a 1% tenofovir topical gel has direct antiherpetic activity. Tenofovir inhibits the replication of HSV clinical isolates in human embryonic fibroblasts, keratinocytes, and organotypic epithelial 3D rafts, decreases HSV replication in human lymphoid and cervicovaginal tissues ex vivo, and delays HSV-induced lesions and death in topically treated HSV-infected mice. The active tenofovir metabolite inhibits HSV DNA-polymerase and HIV reverse-transcriptase. To exert dual antiviral effects, tenofovir requires topical administration to achieve a drug concentration higher than systemic levels achieved by oral treatment. These findings indicate that a single topical treatment, like tenofovir, can inhibit the transmission of HIV and its copathogens. C1 [Lisco, Andrea; Vanpouille, Christophe; Introini, Andrea; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Andrei, Graciela; Snoeck, Robert; Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. [Balestra, Emanuela; Perno, Carlo-Federico] Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, I-00143 Rome, Italy. [van den Oord, Joost] Katholieke Univ Leuven, Dept Morphol & Mol Pathol, B-3000 Louvain, Belgium. [Cihlar, Tomas] Gilead Sci Inc, Foster City, CA 94404 USA. RP Margolis, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM margolil@mail.nih.gov; jan.balzarini@rega.kuleuven.be RI perno, carlo federico/O-1544-2016; OI Introini, Andrea/0000-0002-9929-8964 FU NICHD; K.U. Leuven [10/014, 10/18]; European Community (CHAARM); Belgian Federal Public Service FX The work of A.L., A.I., C.V., and L.M. was supported by the NICHD Intramural Program. We are grateful to the entire staff of the Department of Anatomic Pathology of Children's National Medical Center in Washington, DC for their generous assistance in obtaining human tonsil tissues. The research of J.B., G.A., and R.S. was supported by K.U. Leuven (GOA no. 10/014 and PF no. 10/18), of J.B. also by the European Community (CHAARM), and of G.A. and R.S. also by the Belgian Federal Public Service "Public Health, Food Chain Safety and Environment, action 29 of the National Cancer Plan." We would also like to thank Robert Strickley and Quynh Iwata (Gilead Sciences) for preparing the gel formulations used in the in vivo testing. We are grateful to the excellent technical assistance of Mrs. Anita Camps, Lies Van den Heurck, Steven Carmans, Lizette van Berckelaer, Ria Van Berwaer, and Dr. Katrien Francois and to Mrs. Christiane Callebaut for dedicated editorial help. NR 34 TC 57 Z9 59 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT 20 PY 2011 VL 10 IS 4 BP 379 EP 389 DI 10.1016/j.chom.2011.08.015 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 842LK UT WOS:000296600700013 PM 22018238 ER PT J AU Brown, PH Balbo, A Zhao, HY Ebel, C Schuck, P AF Brown, Patrick H. Balbo, Andrea Zhao, Huaying Ebel, Christine Schuck, Peter TI Density Contrast Sedimentation Velocity for the Determination of Protein Partial-Specific Volumes SO PLOS ONE LA English DT Article ID HEAVY-OXYGEN WATER; ANALYTICAL ULTRACENTRIFUGATION; MEMBRANE-PROTEINS; DIFFERENTIAL SEDIMENTATION; SOLVENT INTERACTIONS; PHYSICAL PROPERTIES; NEUTRON-SCATTERING; DETERGENT BINDING; MACROMOLECULES; EQUILIBRIUM AB The partial-specific volume of proteins is an important thermodynamic parameter required for the interpretation of data in several biophysical disciplines. Building on recent advances in the use of density variation sedimentation velocity analytical ultracentrifugation for the determination of macromolecular partial-specific volumes, we have explored a direct global modeling approach describing the sedimentation boundaries in different solvents with a joint differential sedimentation coefficient distribution. This takes full advantage of the influence of different macromolecular buoyancy on both the spread and the velocity of the sedimentation boundary. It should lend itself well to the study of interacting macromolecules and/or heterogeneous samples in microgram quantities. Model applications to three protein samples studied in either H(2)O, or isotopically enriched H(2) (18)O mixtures, indicate that partial-specific volumes can be determined with a statistical precision of better than 0.5%, provided signal/noise ratios of 50-100 can be achieved in the measurement of the macromolecular sedimentation velocity profiles. The approach is implemented in the global modeling software SEDPHAT. C1 [Brown, Patrick H.; Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Ebel, Christine] Univ Grenoble 1, Inst Biol Struct, Grenoble, France. [Ebel, Christine] CNRS, Grenoble, France. [Ebel, Christine] Commisariat Energie Atom, Grenoble, France. RP Brown, PH (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov RI Zhao, Huaying/F-5716-2012; OI Schuck, Peter/0000-0002-8859-6966 FU NIBIB, National Institutes of Health, Bethesda, Maryland, U.S.A FX This study was funded by the intramural research program of the NIBIB, National Institutes of Health, Bethesda, Maryland, U.S.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 5 Z9 5 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2011 VL 6 IS 10 AR e26221 DI 10.1371/journal.pone.0026221 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841KI UT WOS:000296510800027 PM 22028836 ER PT J AU Dhasarathy, A Phadke, D Mav, D Shah, RR Wade, PA AF Dhasarathy, Archana Phadke, Dhiral Mav, Deepak Shah, Ruchir R. Wade, Paul A. TI The Transcription Factors Snail and Slug Activate the Transforming Growth Factor-Beta Signaling Pathway in Breast Cancer SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; TGF-BETA-PAR6 POLARITY PATHWAY; REPRESSES E-CADHERIN; GENE-EXPRESSION; TGF-BETA; CLAUDIN-LOW; CELLS; PROGRESSION; CARCINOMA; COMPLEX AB The transcriptional repressors Snail and Slug are situated at the core of several signaling pathways proposed to mediate epithelial to mesenchymal transition or EMT, which has been implicated in tumor metastasis. EMT involves an alteration from an organized, epithelial cell structure to a mesenchymal, invasive and migratory phenotype. In order to obtain a global view of the impact of Snail and Slug expression, we performed a microarray experiment using the MCF-7 breast cancer cell line, which does not express detectable levels of Snail or Slug. MCF-7 cells were infected with Snail, Slug or control adenovirus, and RNA samples isolated at various time points were analyzed across all transcripts. Our analyses indicated that Snail and Slug regulate many genes in common, but also have distinct sets of gene targets. Gene set enrichment analyses indicated that Snail and Slug directed the transcriptome of MCF-7 cells from a luminal towards a more complex pattern that includes many features of the claudin-low breast cancer signature. Of particular interest, genes involved in the TGF-beta signaling pathway are upregulated, while genes responsible for a differentiated morphology are downregulated following Snail or Slug expression. Further we noticed increased histone acetylation at the promoter region of the transforming growth factor beta-receptor II (TGFBR2) gene following Snail or Slug expression. Inhibition of the TGF-beta signaling pathway using selective small-molecule inhibitors following Snail or Slug addition resulted in decreased cell migration with no impact on the repression of cell junction molecules by Snail and Slug. We propose that there are two regulatory modules embedded within EMT: one that involves repression of cell junction molecules, and the other involving cell migration via TGF-beta and/or other pathways. C1 [Dhasarathy, Archana; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Phadke, Dhiral; Mav, Deepak; Shah, Ruchir R.] SRA Int Inc, Res Triangle Pk, NC USA. RP Dhasarathy, A (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU NIEHS, NIH [Z01ES101965]; National Institute of Environmental Health Sciences, National Institute of Health, Department of Health and Human Services [HHSN291200555547C]; GSA Contract [GS-00F-003L] FX Financial support was provided by the Intramural Research Program, NIEHS, NIH (Project number Z01ES101965 to P. A. W.). D. P., D. M. and R. R. S. were supported in whole or in part with federal funds from the National Institute of Environmental Health Sciences, National Institute of Health, Department of Health and Human Services, Delivery Order HHSN291200555547C, GSA Contract GS-00F-003L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 67 Z9 72 U1 3 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 OCT 20 PY 2011 VL 6 IS 10 AR e26514 DI 10.1371/journal.pone.0026514 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841KI UT WOS:000296510800049 PM 22028892 ER PT J AU Jacobsohn, DA Arora, M Klein, JP Hassebroek, A Flowers, ME Cutler, CS Urbano-Ispizua, A Bolwell, BJ Antin, JH Boyiadzis, M Cahn, JY Cairo, MS Herzig, RH Isola, LM Klumpp, TR Lee, SJ Petersdorf, EW Santarone, S Gale, RP Schouten, HC Spellman, SR Weisdorf, DJ Wingard, JR Horowitz, MM Pavletic, SZ AF Jacobsohn, David A. Arora, Mukta Klein, John P. Hassebroek, Anna Flowers, Mary E. Cutler, Corey S. Urbano-Ispizua, Alvaro Bolwell, Brian J. Antin, Joseph H. Boyiadzis, Michael Cahn, Jean-Yves Cairo, Mitchell S. Herzig, Roger H. Isola, Luis M. Klumpp, Thomas R. Lee, Stephanie J. Petersdorf, Effie W. Santarone, Stella Gale, Robert P. Schouten, Harry C. Spellman, Stephen R. Weisdorf, Daniel J. Wingard, John R. Horowitz, Mary M. Pavletic, Steven Z. TI Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; UMBILICAL-CORD BLOOD; UNRELATED DONOR TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE-LEUKEMIA; WEIGHT-LOSS; REGISTRY; THROMBOCYTOPENIA; RECIPIENTS; DIAGNOSIS AB There is a paucity of information regarding the factors that affect nonrelapse mortality (NRM) and overall survival among children that develop chronic graft-versus-host disease (cGVHD). We performed multivariate analyses using data from the Center for International Blood and Marrow Transplant Research to identify risk factors for NRM and survival in 1117 pediatric subjects with leukemia or myelodysplastic syndrome, transplanted from related donors, unrelated donors (URD), or unrelated cord blood between 1995 and 2004. We identified 4 variables associated with higher NRM: HLA partially matched or mismatched URD, peripheral blood cell graft, Karnofsky/Lansky score < 80 at cGVHD diagnosis, and platelets < 100 x 10(9)/L at cGVHD diagnosis. Factors associated with significantly worse survival were: age > 10 years, transplantation from HLA partially matched or mismatched URD, advanced disease at transplantation, Karnofsky/Lansky < 80; and platelets < 100 x 10(9)/L. Cumulative incidence of discontinuation of systemic immune suppression at 1, 3, and 5 years after diagnosis of cGVHD were 22% (20%-25%), 34% (31%-37%), and 37% (34%-40%), respectively. This is the largest study elucidating variables affecting outcome after diagnosis of cGVHD in pediatric allograft recipients. These variables may be useful for risk stratification, development of future clinical trials, and family counseling in children with cGVHD. (Blood. 2011;118(16):4472-4479) C1 [Jacobsohn, David A.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Klein, John P.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Hassebroek, Anna; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Flowers, Mary E.; Lee, Stephanie J.; Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Urbano-Ispizua, Alvaro] Hosp Clin Barcelona, Barcelona, Spain. [Bolwell, Brian J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Boyiadzis, Michael] Univ Pittsburgh, Ctr Canc, Pittsburgh, PA USA. [Cahn, Jean-Yves] Ctr Hosp Univ Grenoble, Hosp A Michallon, Grenoble, France. [Cairo, Mitchell S.] Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY USA. [Herzig, Roger H.] Univ Louisville Hosp, James Brown Canc Ctr, Louisville, KY USA. [Isola, Luis M.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Klumpp, Thomas R.] Temple Univ, Bone Marrow Transplant Program, Philadelphia, PA 19122 USA. [Santarone, Stella] Osped Civile, BMT Ctr Pescara, Pescara, Italy. [Gale, Robert P.] Celgene Corp, Los Angeles, CA USA. [Schouten, Harry C.] Acad Ziekenhuis Maastricht, Maastricht, Netherlands. [Wingard, John R.] Shands HealthCare, Gainesville, FL USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. RP Jacobsohn, DA (reprint author), Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM dajacobs@cnmc.org RI Cahn, Jean-Yves/M-6493-2014 FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID), NHLBI [5U01HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Allos Inc; Amgen Inc; Medical College of Wisconsin; Astellas Pharma US Inc; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai Inc; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Kirin Brewery Co Ltd; Leukemia & Lymphoma Society; Merck Company; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; THERAKOS Inc; Vidacare Corporation; ViraCor Laboratories; ViroPharma Inc; Wellpoint Inc FX CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Allos Inc; Amgen Inc; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai Inc; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Kirin Brewery Co Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; THERAKOS Inc; Vidacare Corporation; ViraCor Laboratories; ViroPharma Inc; and Wellpoint Inc. NR 36 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 20 PY 2011 VL 118 IS 16 BP 4472 EP 4479 DI 10.1182/blood-2011-04-349068 PG 8 WC Hematology SC Hematology GA 838JY UT WOS:000296286500030 PM 21878671 ER PT J AU Hsieh, M Fitzhugh, C Tisdale, JF AF Hsieh, Matthew Fitzhugh, Courtney Tisdale, John F. TI Young adults with sickle cell disease have more transplant options Response SO BLOOD LA English DT Letter ID BONE-MARROW TRANSPLANTATION; ANEMIA C1 [Hsieh, Matthew; Fitzhugh, Courtney; Tisdale, John F.] NIDDK, NHLBI, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDK, NHLBI, NIH, 9000 Rockville Pike,Bdg 10,Rm 9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov NR 8 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 20 PY 2011 VL 118 IS 16 BP 4492 EP 4493 DI 10.1182/blood-2011-08-372201 PG 4 WC Hematology SC Hematology GA 838JY UT WOS:000296286500035 ER PT J AU Tsai, YC Weissman, AM AF Tsai, Yien Che Weissman, Allan M. TI Dissecting the diverse functions of the metastasis suppressor CD82/KAI1 SO FEBS LETTERS LA English DT Review DE Endoplasmic reticulum-associated degradation (ERAD); ubiquitin-proteasome system (UPS); gp78/RNF45; Epidermal growth factor receptor (EGFR); Exosome; Duffy antigen receptor for chemokine (DARC) ID AUTOCRINE MOTILITY FACTOR; CANCER CELL-LINES; TRANSMEMBRANE PROTEIN FAMILY; LEUKEMIA-VIRUS TYPE-1; HUMAN PROSTATE-CANCER; KAI1 GENE; DOWN-REGULATION; TETRASPANIN CD82; DUFFY ANTIGEN/RECEPTOR; ENDOPLASMIC-RETICULUM AB The recent identification of metastasis suppressor genes, the products of which inhibit metastasis but not primary tumor growth, distinguishes oncogenic transformation and tumor suppression from a hallmark of malignancy, the ability of cancer cells to invade sites distant from the primary tumor. The metastasis suppressor CD82/KAI1 is a member of the tetraspanin superfamily of glycoproteins. CD82 suppresses metastasis by multiple mechanisms including inhibition of cell motility and invasion, promotion of cell polarity as well as induction of senescence and apoptosis in response to extracellular stimuli. A common feature of these diverse effects is CD82 regulation of membrane organization as well as protein trafficking and interactions, which affects cellular signaling and intercellular communication. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Tsai, Yien Che; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. RP Tsai, YC (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, 1050 Boyles St,Bldg 560,Room 12-39, Frederick, MD 21702 USA. EM tsaiyien@mail.nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Research in the authors' laboratory is supported by the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 84 TC 33 Z9 37 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 20 PY 2011 VL 585 IS 20 BP 3166 EP 3173 DI 10.1016/j.febslet.2011.08.031 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 841LP UT WOS:000296514100004 PM 21875585 ER PT J AU Lountos, GT Jobson, AG Tropea, JE Self, CR Zhang, GT Pommier, Y Shoemaker, RH Waugh, DS AF Lountos, George T. Jobson, Andrew G. Tropea, Joseph E. Self, Christopher R. Zhang, Guangtao Pommier, Yves Shoemaker, Robert H. Waugh, David S. TI X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket SO FEBS LETTERS LA English DT Article DE Rational drug design; Structure-based drug design; Kinase inhibitors ID CHK2 PROTEIN-KINASE; SELECTIVE INHIBITOR; DNA-DAMAGE; PHOSPHORYLATION; BRCA1; AUTOPHOSPHORYLATION; TRANSCRIPTION; ACTIVATION; RADIATION; APOPTOSIS AB The serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC(50) values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Lountos, George T.; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lountos, George T.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Jobson, Andrew G.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Self, Christopher R.; Zhang, Guangtao] Provid Pharmaceut, Monmouth Jct, NJ 08852 USA. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM waughd@mail.nih.gov RI Lountos, George/B-3983-2015 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Division of Cancer Treatment and Diagnosis; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E, the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis. 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. We thank Dr. Dominic Scudiero, Michael Selby and Julie Laudeman for conducting the kinase inhibition studies. We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick, for use of the LC/ESMS instrument. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamlines 22-ID and 22-BM, Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. NR 33 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 20 PY 2011 VL 585 IS 20 BP 3245 EP 3249 DI 10.1016/j.febslet.2011.08.050 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 841LP UT WOS:000296514100015 PM 21907711 ER PT J AU Parsons, HM Harlan, LC Seibel, NL Stevens, JL Keegan, THM AF Parsons, Helen M. Harlan, Linda C. Seibel, Nita L. Stevens, Jennifer L. Keegan, Theresa H. M. TI Clinical Trial Participation and Time to Treatment Among Adolescents and Young Adults With Cancer: Does Age at Diagnosis or Insurance Make a Difference? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; OLDER ADOLESCENTS; CARE; ENROLLMENT; CHILDREN; IMPACT; PROTOCOLS; SURVIVORS; ACCESS; NEEDS AB Purpose Because adolescent and young adult (AYA) patients with cancer have experienced variable improvement in survival over the past two decades, enhancing the quality and timeliness of cancer care in this population has emerged as a priority area. To identify current trends in AYA care, we examined patterns of clinical trial participation, time to treatment, and provider characteristics in a population-based sample of AYA patients with cancer. Methods Using the National Cancer Institute Patterns of Care Study, we used multivariate logistic regression to evaluate demographic and provider characteristics associated with clinical trial enrollment and time to treatment among 1,358 AYA patients with cancer (age 15 to 39 years) identified through the Surveillance, Epidemiology, and End Results Program. Results In our study, 14% of patients age 15 to 39 years had enrolled onto a clinical trial; participation varied by type of cancer, with the highest participation in those diagnosed with acute lymphoblastic leukemia (37%) and sarcoma (32%). Multivariate analyses demonstrated that uninsured, older patients and those treated by nonpediatric oncologists were less likely to enroll onto clinical trials. Median time from pathologic confirmation to first treatment was 3 days, but this varied by race/ethnicity and cancer site. In multivariate analyses, advanced cancer stage and outpatient treatment alone were associated with longer time from pathologic confirmation to treatment. Conclusion Our study identified factors associated with low clinical trial participation in AYA patients with cancer. These findings support the continued need to improve access to clinical trials and innovative treatments for this population, which may ultimately translate into improved survival. C1 [Parsons, Helen M.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Syst, Silver Spring, MD USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Parsons, HM (reprint author), NCI, Appl Res Program, Execut Plaza N,61230 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM helen.parsons@nih.gov FU National Cancer Institute [N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404, N01-PC-54405] FX Supported by National Cancer Institute Grants No. N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404, and N01-PC-54405. NR 38 TC 53 Z9 53 U1 2 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2011 VL 29 IS 30 BP 4045 EP 4053 DI 10.1200/JCO.2011.36.2954 PG 9 WC Oncology SC Oncology GA 841YS UT WOS:000296551700021 PM 21931022 ER PT J AU Renton, AE Majounie, E Waite, A Simon-Sanchez, J Rollinson, S Gibbs, JR Schymick, JC Laaksovirta, H van Swieten, JC Myllykangas, L Kalimo, H Paetau, A Abramzon, Y Remes, AM Kaganovich, A Scholz, SW Duckworth, J Ding, JH Harmer, DW Hernandez, DG Johnson, JO Mok, K Ryten, M Trabzuni, D Guerreiro, RJ Orrell, RW Neal, J Murray, A Pearson, J Jansen, IE Sondervan, D Seelaar, H Blake, D Young, K Halliwell, N Callister, JB Toulson, G Richardson, A Gerhard, A Snowden, J Mann, D Neary, D Nalls, MA Peuralinna, T Jansson, L Isoviita, VM Kaivorinne, AL Holtta-Vuori, M Ikonen, E Sulkava, R Benatar, M Wuu, J Chio, A Restagno, G Borghero, G Sabatelli, M Heckerman, D Rogaeva, E Zinman, L Rothstein, JD Sendtner, M Drepper, C Eichler, EE Alkan, C Abdullaev, Z Pack, SD Dutra, A Pak, E Hardy, J Singleton, A Williams, NM Heutink, P Pickering-Brown, S Morris, HR Tienari, PJ Traynor, BJ AF Renton, Alan E. Majounie, Elisa Waite, Adrian Simon-Sanchez, Javier Rollinson, Sara Gibbs, J. Raphael Schymick, Jennifer C. Laaksovirta, Hannu van Swieten, John C. Myllykangas, Liisa Kalimo, Hannu Paetau, Anders Abramzon, Yevgeniya Remes, Anne M. Kaganovich, Alice Scholz, Sonja W. Duckworth, Jamie Ding, Jinhui Harmer, Daniel W. Hernandez, Dena G. Johnson, Janel O. Mok, Kin Ryten, Mina Trabzuni, Danyah Guerreiro, Rita J. Orrell, Richard W. Neal, James Murray, Alex Pearson, Justin Jansen, Iris E. Sondervan, David Seelaar, Harro Blake, Derek Young, Kate Halliwell, Nicola Callister, Janis Bennion Toulson, Greg Richardson, Anna Gerhard, Alex Snowden, Julie Mann, David Neary, David Nalls, Michael A. Peuralinna, Terhi Jansson, Lilja Isoviita, Veli-Matti Kaivorinne, Anna-Lotta Holtta-Vuori, Maarit Ikonen, Elina Sulkava, Raimo Benatar, Michael Wuu, Joanne Chio, Adriano Restagno, Gabriella Borghero, Giuseppe Sabatelli, Mario Heckerman, David Rogaeva, Ekaterina Zinman, Lorne Rothstein, Jeffrey D. Sendtner, Michael Drepper, Carsten Eichler, Evan E. Alkan, Can Abdullaev, Ziedulla Pack, Svetlana D. Dutra, Amalia Pak, Evgenia Hardy, John Singleton, Andrew Williams, Nigel M. Heutink, Peter Pickering-Brown, Stuart Morris, Huw R. Tienari, Pentti J. Traynor, Bryan J. CA ITALSGEN Consortium TI A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD SO NEURON LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; HUMAN GENOME; MUTATIONS; TDP-43; DEMENTIA; SUSCEPTIBILITY; ASSOCIATION; POPULATION; COMMON AB The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date. C1 [Renton, Alan E.; Schymick, Jennifer C.; Abramzon, Yevgeniya; Johnson, Janel O.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Majounie, Elisa; Scholz, Sonja W.; Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Waite, Adrian; Pearson, Justin; Blake, Derek; Williams, Nigel M.; Morris, Huw R.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiatr Genet & Genom, Cardiff CF14 4XN, Wales. [Simon-Sanchez, Javier; van Swieten, John C.; Jansen, Iris E.; Sondervan, David; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Depat Clin Genet, Sect Med Genom, NL-1081 HV Amsterdam, Netherlands. [Simon-Sanchez, Javier; van Swieten, John C.; Jansen, Iris E.; Sondervan, David; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Alzheimer Dis Ctr, NL-1081 HV Amsterdam, Netherlands. [Simon-Sanchez, Javier; van Swieten, John C.; Seelaar, Harro] Erasmus MC Univ Med Ctr Rotterdam, Dept Neurol, NL-3015 CE Rotterdam, Netherlands. [Rollinson, Sara; Young, Kate; Halliwell, Nicola; Callister, Janis Bennion; Toulson, Greg; Pickering-Brown, Stuart] Univ Manchester, Fac Human & Med Sci, Manchester M13 9PT, Lancs, England. [Gibbs, J. Raphael; Hernandez, Dena G.; Johnson, Janel O.; Mok, Kin; Ryten, Mina; Trabzuni, Danyah; Guerreiro, Rita J.; Hardy, John] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Gibbs, J. Raphael; Hernandez, Dena G.; Johnson, Janel O.; Mok, Kin; Ryten, Mina; Trabzuni, Danyah; Guerreiro, Rita J.; Hardy, John] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1N 3BG, England. [Laaksovirta, Hannu; Peuralinna, Terhi; Jansson, Lilja; Isoviita, Veli-Matti; Tienari, Pentti J.] Univ Helsinki, Dept Neurol, Cent Hosp, FIN-02900 Helsinki, Finland. [Laaksovirta, Hannu; Peuralinna, Terhi; Jansson, Lilja; Isoviita, Veli-Matti; Tienari, Pentti J.] Univ Helsinki, Mol Neurol Programme, Biomedicum, FIN-02900 Helsinki, Finland. [Myllykangas, Liisa; Kalimo, Hannu; Paetau, Anders] Univ Helsinki, Dept Pathol, Haartman Inst HUSLAB, FIN-02900 Helsinki, Finland. [Myllykangas, Liisa; Kalimo, Hannu; Paetau, Anders] Folkhalsan Res Ctr LM, FIN-02900 Helsinki, Finland. [Remes, Anne M.; Kaivorinne, Anna-Lotta] Univ Oulu, Inst Clin Med, FIN-90014 Oulu, Finland. [Remes, Anne M.; Kaivorinne, Anna-Lotta] Oulu Univ Hosp, Clin Res Ctr, FIN-90014 Oulu, Finland. [Kaganovich, Alice] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Scholz, Sonja W.; Rothstein, Jeffrey D.; Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21287 USA. [Harmer, Daniel W.] Illumina Inc, Hayward, CA 94545 USA. [Orrell, Richard W.] UCL, Dept Clin Neurosci, Inst Neurol, London NW3 2PG, England. [Neal, James] Cardiff Univ, Sch Med, Dept Pathol, Cardiff CF14 4XN, S Glam, Wales. [Murray, Alex] Univ Wales Hosp, Inst Med Genet, Cardiff CF14 4XW, S Glam, Wales. [Richardson, Anna; Gerhard, Alex; Snowden, Julie; Mann, David; Neary, David] Univ Manchester, Neurodegenerat & Mental Hlth Res Grp, Cerebral Funct Unit, Sch Community Based Med, Manchester M6 8HD, Lancs, England. [Holtta-Vuori, Maarit; Ikonen, Elina] Univ Helsinki, Inst Biomed Anat, FIN-00014 Helsinki, Finland. [Sulkava, Raimo] Univ Eastern Finland, Sect Geriatr, Inst Publ Hlth & Clin Nutr, FIN-70211 Kuopio, Finland. [Benatar, Michael] Univ Miami, Miller Sch Med, Neuromuscular Div, Dept Neurol, Miami, FL 33136 USA. [Wuu, Joanne] Univ Miami, Miller Sch Med, Clin Translat Res Div, Dept Neurol, Miami, FL 33136 USA. [Chio, Adriano] Univ Turin, Dept Neurosci, I-10126 Turin, Italy. [Restagno, Gabriella] ASOOIRM S Anna, Mol Genet Unit, Dept Clin Pathol, I-10126 Turin, Italy. [Borghero, Giuseppe] Azienda Univ Osped Cagliari, Dept Neurol, I-09042 Cagliari, Italy. [Borghero, Giuseppe] Univ Cagliari, I-09042 Cagliari, Italy. [Sabatelli, Mario] Catholic Univ, Neurol Inst, I-10100 Rome, Italy. [Sabatelli, Mario] ICOMM Assoc ALS Res, I-10100 Rome, Italy. [Heckerman, David] Microsoft Res, Los Angeles, CA 90024 USA. [Rogaeva, Ekaterina] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. [Rogaeva, Ekaterina] Univ Toronto, Toronto Western Hosp, Div Neurol, Dept Med, Toronto, ON M5S 3H2, Canada. [Zinman, Lorne] Univ Toronto, Div Neurol, Dept Internal Med, Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Sendtner, Michael; Drepper, Carsten] Univ Wurzburg, Inst Clin Neurobiol, D-97078 Wurzburg, Germany. [Eichler, Evan E.; Alkan, Can] Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Eichler, Evan E.; Alkan, Can] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Abdullaev, Ziedulla; Pack, Svetlana D.] NCI, Chromosome Pathol Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Dutra, Amalia; Pak, Evgenia] NHGRI, NIH, Bethesda, MD 20892 USA. [Morris, Huw R.] Aneurin Bevan Local Hlth Board, Dept Neurol, Royal Gwent Hosp, Newport NP20 2UB, Gwent, Wales. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI LOGROSCINO, GIANCARLO/K-5148-2016; Spataro, Rossella/B-3656-2016; Lunetta, Christian/K-9214-2016; Sendtner, Michael/J-1542-2012; MANDRIOLI, JESSICA/K-7235-2016; Conforti, Francesca Luisa/K-8877-2016; Alkan, Can/D-2982-2009; Tienari, Pentti/A-4893-2012; Hardy, John/C-2451-2009; Pickering-Brown, Stuart/D-4008-2009; Morris, Huw/B-8527-2008; Mok, Kin/F-5860-2012; Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010; rothstein, jeffrey/C-9470-2013; Orrell, Richard/L-2123-2013; Pack, Svetlana/C-2020-2014; Trabzuni, Daniah/C-4034-2012; Battistini, Stefania/N-2596-2015 OI Holtta-Vuori, Maarit/0000-0002-0488-4486; Scholz, Sonja/0000-0002-6623-0429; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Spataro, Rossella/0000-0002-8910-3131; Lunetta, Christian/0000-0002-4788-1875; Sendtner, Michael/0000-0002-4737-2974; Mandich, Paola/0000-0003-3123-3512; Simone, Isabella Laura/0000-0002-7429-3091; MANDRIOLI, JESSICA/0000-0002-9244-9782; Sabatelli, Mario/0000-0001-6635-4985; Conforti, Francesca Luisa/0000-0001-8364-1783; Chio, Adriano/0000-0001-9579-5341; Snowden, Julie/0000-0002-3976-4310; Alkan, Can/0000-0002-5443-0706; Pickering-Brown, Stuart/0000-0003-1561-6054; Morris, Huw/0000-0002-5473-3774; Trabzuni, Daniah/0000-0003-4826-9570; Battistini, Stefania/0000-0003-2887-7624 FU NIH, National Institute on Aging [Z01-AG000949-02]; NINDS; Packard Center for ALS Research at Hopkins; ALS Association; Microsoft Research; Ontario Research Fund; Hersenstichting Nederland Fellowship [B08.03]; Neuroscience Campus Amsterdam; Nuts Ohra Fonds; Stichting Dioraphte [09020300]; UK MND Association [6057]; The Medical Research Council UK; Wellcome Trust; Helsinki University Central Hospital; Finnish Academy; Finnish Medical Society Duodecim, Kuopio University; Italian Health Ministry (Ricerca Sanitaria Finalizzata); Fondazione Vialli e Mauro ONLUS; Federazione Italians Giuoco Calcio; Compagnia di San Paolo; European Community [259867]; Deutsche Forschungsgemeinschaft [SFB 581, TP4]; Muscular Dystrophy Association; Emory Woodruff Health Sciences Center; Oulu University Hospital; Finnish Medical Foundation FX This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02), and NINDS. The work was also supported by the Packard Center for ALS Research at Hopkins (B.J.T.), the ALS Association (B.J.T., A.C.), Microsoft Research (B.J.T.. P.J.T.), Ontario Research Fund (E.R.), Hersenstichting Nederland Fellowship project B08.03 and the Neuroscience Campus Amsterdam (J.S-S.), Nuts Ohra Fonds (J.v.S.), Stichting Dioraphte (J.v.S. - Grant 09020300), the UK MND Association (H.M. - MNDA Grant 6057, J.H., R.W.O.), The Medical Research Council UK (J.H., S.P.B.), the Wellcome Trust (J.H.), the Helsinki University Central Hospital, the Finnish Academy (P.J.T.), the Finnish Medical Society Duodecim, Kuopio University, the Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007, to A.C.), Fondazione Vialli e Mauro ONLUS (A.C.). Federazione Italians Giuoco Calcio (A.C., M.S., B.J.T.) and Compagnia di San Paolo (A.C., G.R.). the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreements 259867 (A.G.) and 259867 (M.S., C.D.), Deutsche Forschungsgemeinschaft (M.S. - Grant SFB 581, TP4), the Muscular Dystrophy Association (M.B., J.W.), the Emory Woodruff Health Sciences Center (M.B., J.W.), EVO grants from Oulu University Hospital (A.M.R.) and the Finnish Medical Foundation (A.M.R.). DNA samples for this study were obtained in part from the NINDS repository at the Coriell Cell Repositories (http://www.coriell.org/), and the National Cell Repository for Alzheimer's Disease (http://ncrad.iu.edu). We thank the DNA extraction and storage facility of the National Institute for Health and Welfare/FIMM, Helsinki, Finland and Dr Tuomo Polvikoski, Institute for Ageing and Health. Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK for their help in extraction of DNA from ALS patients. We also thank Nayia Nicolaou for her assistance. J.R. is Director of the Packard Center for ALS Research at Hopkins, D. Harmer is an employee of Illumina. E.E.E. is on the scientific advisory board of Pacific Biosciences, and D. Heckerman is an employee of Microsoft Research. We thank the patients and research subjects who contributed samples for this study. NR 34 TC 1267 Z9 1293 U1 24 U2 147 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 20 PY 2011 VL 72 IS 2 BP 257 EP 268 DI 10.1016/j.neuron.2011.09.010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 837SR UT WOS:000296224000009 PM 21944779 ER PT J AU Holmes, EC AF Holmes, Edward C. TI The Viral Storm: The Dawn of a New Pandemic Age SO NATURE LA English DT Book Review C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, University Pk, PA 16802 USA. EM echolmes@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 1 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 0028-0836 J9 NATURE JI Nature PD OCT 20 PY 2011 VL 478 IS 7369 BP 319 EP 320 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835FO UT WOS:000296021100022 ER PT J AU Blanc, FX Sok, T Laureillard, D Borand, L Rekacewicz, C Nerrienet, E Madec, Y Marcy, O Chan, S Prak, N Kim, C Lak, KK Hak, C Dim, B Sin, CI Sun, S Guillard, B Sar, B Vong, S Fernandez, M Fox, L Delfraissy, JF Goldfeld, AE AF Blanc, Francois-Xavier Sok, Thim Laureillard, Didier Borand, Laurence Rekacewicz, Claire Nerrienet, Eric Madec, Yoann Marcy, Olivier Chan, Sarin Prak, Narom Kim, Chindamony Lak, Khemarin Kim Hak, Chanroeurn Dim, Bunnet Sin, Chhun Im Sun, Sath Guillard, Bertrand Sar, Borann Vong, Sirenda Fernandez, Marcelo Fox, Lawrence Delfraissy, Jean-Francois Goldfeld, Anne E. CA CAMELIA ANRS 1295-CIPRA KH001 TI Earlier versus Later Start of Antiretroviral Therapy in HIV-Infected Adults with Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUB-SAHARAN AFRICA; MORTALITY; CAMBODIA; OUTCOMES; PROGRAM; PREVALENCE; DIAGNOSIS; SURVIVAL; THAILAND; IMPACT AB Background Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy. Methods We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. Results A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P = 0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. Conclusions Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.) C1 [Blanc, Francois-Xavier; Delfraissy, Jean-Francois] Hop Bicetre, AP HP, Dept Internal Med, Pneumol Unit, Le Kremlin Bicetre, France. [Delfraissy, Jean-Francois] Univ Paris 11, INSERM, U1012, Le Kremlin Bicetre, France. [Sok, Thim; Laureillard, Didier; Marcy, Olivier; Chan, Sarin; Lak, Khemarin Kim; Dim, Bunnet; Sun, Sath; Fernandez, Marcelo; Goldfeld, Anne E.] Khmer Soviet Friendship Hosp, Cambodian Hlth Comm, Phnom Penh, Cambodia. [Borand, Laurence; Nerrienet, Eric; Guillard, Bertrand; Sar, Borann; Vong, Sirenda] Khmer Soviet Friendship Hosp, Inst Pasteur Cambodia, Phnom Penh, Cambodia. [Prak, Narom] Khmer Soviet Friendship Hosp, Dept Infect Dis, Phnom Penh, Cambodia. [Sin, Chhun Im] Khmer Soviet Friendship Hosp, Dept Pneumol, Phnom Penh, Cambodia. [Kim, Chindamony; Dim, Bunnet] Med Sans Frontieres, Phnom Penh, Cambodia. [Hak, Chanroeurn] Calmette Hosp, Phnom Penh, Cambodia. [Kim, Chindamony] Donkeo Prov Hosp, Takeo, Cambodia. [Lak, Khemarin Kim; Sun, Sath] Svay Rieng Prov Hosp, Svay Rieng, Cambodia. [Dim, Bunnet] Siem Reap Prov Hosp, Siem Reap, Cambodia. [Laureillard, Didier] Georges Pompidou European Hosp, AP HP, Dept Clin Immunol, Paris, France. [Rekacewicz, Claire; Delfraissy, Jean-Francois] Agence Natl Rech Sida & Hepatites Virales, Paris, France. [Madec, Yoann] Inst Pasteur, Unite Epidemiol Malad Emergentes, Paris, France. [Fox, Lawrence] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Goldfeld, Anne E.] Harvard Univ, Sch Med, Childrens Hosp, Immune Dis Inst, Boston, MA USA. [Goldfeld, Anne E.] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. RP Blanc, FX (reprint author), CHU Bicetre, Unite Fonct Pneumol, 78 Rue Gen Leclerc, F-94275 Le Kremlin Bicetre, France. EM xavier.blanc@bct.aphp.fr; goldfeld@idi.harvard.edu RI Blanc, Francois-Xavier/D-7425-2015 FU French National Agency for Research on AIDS and Viral Hepatitis [ANRS 1295]; National Institutes of Health; National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS [CIPRA KH001/DAID-ES ID 10425]; Annenberg Foundation; Aeras Global TB Vaccine Foundation; scientific team of the ANRS; logistic team of the ANRS; Organisation Franco-Cambodgienne de Pneumologie FX Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.; Supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS 1295) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (CIPRA KH001/DAID-ES ID 10425).; Dr. Delfraissy reports serving on the international board for HIV treatment of GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Gilead, and Bristol-Myers Squibb; and Dr. Goldfeld, receiving funds from the Annenberg Foundation to her laboratory and to the Cambodian Health Committee to conduct studies and serving as a consultant for the Aeras Global TB Vaccine Foundation, which provides funds to the Cambodian Health Committee to conduct studies. No other potential conflict of interest relevant to this article was reported.; We thank the patients for their participation in the trial; Franoise Barre-Sinoussi for her help with initiating the CIPRA project and the CAMELIA trial and for her support throughout the trial; H. E. Eng Huot for his early and continuing support; Philippe Glaziou for providing the initial design of the study; Charles Mayaud for his clinical mentorship; Jean-Louis Sarthou for ensuring high-quality laboratory and basic scientific support during the trial; H. E. Mean Chhivun and H. E. Mao Tan Eang for the support of the Cambodian National AIDS and Tuberculosis Programs, respectively; Takmao, Kossamak, and Kampong Trach Hospitals for referring patients to the study sites; Bart Janssens, Petros Isaakidis, and Tony Reid for the support from Medecins sans Frontieres Belgium to two of our study sites (Donkeo and Siem Reap Provincial Hospitals); the data and safety monitoring board, chaired by John Modlin, and the scientific advisory board, chaired by Charles Mayaud, for their significant contributions to the study; the scientific and logistic teams of the ANRS (Brigitte Bazin, Severine Blesson, Alpha Diallo, Annie Metro, Saphonn Vonthanak, Isabelle Fournier-Nicolle, and Michel Kazatchkine) and the National Institutes of Health (Jane E. Bupp, Ray Y. Chen, Margaret Matula, Rod Hoff, Sandra Nusinoff Lehrman, Karen Near, Barbara Laughon, Mike Ussery, Trinh Ly, Mary Fanning, and Ana Martinez) for their support and intellectual contributions; and Pierre L'Her, Etienne Leroy-Terquem, the Organisation Franco-Cambodgienne de Pneumologie, Pean Polidy, Sylvia Taylor, Josephine Braun, Vincent Guillemet, Adrienne Shapiro, Catherine Quillet, Jean-Paul Dousset, Anne-Marie Taburet, Wayne Wilson, and Vincent Deubel for their support. NR 33 TC 297 Z9 304 U1 2 U2 19 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 20 PY 2011 VL 365 IS 16 BP 1471 EP 1481 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 835BW UT WOS:000296009500001 PM 22010913 ER PT J AU Bressler, NM Beck, RW Ferris, FL AF Bressler, Neil M. Beck, Roy W. Ferris, Frederick L., III TI Panretinal Photocoagulation for Proliferative Diabetic Retinopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; IRIS NEOVASCULARIZATION; LASER PHOTOCOAGULATION; INTRAVITREAL INJECTION; BEVACIZUMAB AVASTIN; RETINAL NEOVASCULARIZATION; NONHUMAN PRIMATE; TRANSIENT MYOPIA; MACULAR EDEMA; FOLLOW-UP AB A 55-year-old man with a 20-year history of type 2 diabetes mellitus was referred to a retina specialist after noticing a few black floaters in his left eye for the preceding week. His glycated hemoglobin level was 8.2%. He had no history of laser treatment for proliferative diabetic retinopathy in either eye. Ophthalmoscopic examination of the right eye showed venous beading, intraretinal microvascular abnormalities, and no macular edema. Ophthalmoscopic examination of the left eye showed extensive neovascularization of the disk, consisting of new vessels extending beyond the optic disk in all directions (Fig. 1A). The retina specialist diagnosed severe nonproliferative diabetic retinopathy in the right eye and high-risk proliferative diabetic retinopathy in the left eye, with no macular edema in either eye. The specialist recommended prompt initiation of panretinal photocoagulation in the left eye. C1 [Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL USA. RP Ferris, FL (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM ferrisf@nei.nih.gov FU Abbott Medical Optics; Alimera Sciences; Allergan; Bausch Lomb; ForSight Labs; Genzyme; Lumenis; Notal Vision; Novartis; QLT; Regeneron; Genentech FX Dr. Bressler reports that his institution has received grant support from Abbott Medical Optics, Alimera Sciences, Allergan, Bausch & Lomb, ForSight Labs, Genzyme, Lumenis, Notal Vision, Novartis, QLT, Regeneron, and Genentech. No other potential conflict of interest relevant to this article was reported. NR 46 TC 30 Z9 31 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 20 PY 2011 VL 365 IS 16 BP 1520 EP 1526 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 835BW UT WOS:000296009500006 PM 22010918 ER PT J AU DeRouchey, JE Rau, DC AF DeRouchey, Jason E. Rau, Donald C. TI Salt Effects on Condensed Protamine-DNA Assemblies: Anion Binding and Weakening of Attraction SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID X-RAY-DIFFRACTION; DOUBLE HELICES; INTERMOLECULAR FORCES; HYDRATION FORCES; MOUSE SPERM; BEHAVIOR; CATION; PHOSPHORYLATION; SPERMATOZOA; POLYAMINES AB Using osmotic stress coupled with X-ray scattering, we have directly examined the salt sensitivity of the intermolecular forces between helices in condensed protamine DNA arrays. Thermodynamic forces are measured from the dependence of DNA helical interaxial spacings on external salt concentration or the osmotic pressure applied by neutral polymer solutions in equilibrium with the condensed phase. Force curves of salmon protamine DNA condensates are highly dependent on salt species and concentration, indicating salt binding to protamine-DNA complexes. This dependence of the forces on salt species follows the Hofmeister series for anions. Chaotropic anions bind more tightly to protamine - DNA arrays than kosmotropic anions, thus more greatly disrupting the attractive thermodynamic forces. Variations with cation type are small compared with those observed for anions. Further, osmotic stress is used to estimate the number of ions bound in the condensed phase through a Gibbs-Duhem relationship. We estimate that at equilibrium, similar to 1 Br(-) is bound per protamine molecule at 200 mM NaBr concentration. Remarkably, this one bound anion results in a change of similar to 12% in the surface-to-surface distance between DNA helices. Potential biological implications of this attractive force salt sensitivity are discussed. C1 [DeRouchey, Jason E.] Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. [Rau, Donald C.] NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP DeRouchey, JE (reprint author), Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. EM derouchey@uky.edu; raud@mail.nih.gov RI DeRouchey, Jason/C-5907-2011 OI DeRouchey, Jason/0000-0002-3624-4432 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 30 TC 4 Z9 4 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 20 PY 2011 VL 115 IS 41 BP 11888 EP 11894 DI 10.1021/jp203834z PG 7 WC Chemistry, Physical SC Chemistry GA 831AI UT WOS:000295700700015 PM 21894933 ER PT J AU Abraham, D Hess, JA Mejia, R Nolan, TJ Lok, JB Lustigman, S Nutman, TB AF Abraham, David Hess, Jessica A. Mejia, Rojelio Nolan, Thomas J. Lok, James B. Lustigman, Sara Nutman, Thomas B. TI Immunization with the recombinant antigen Ss-IR induces protective immunity to infection with Strongyloides stercoralis in mice SO VACCINE LA English DT Article DE Strongyloides stercoralis; Ss-IR; Recombinant vaccine ID ANCYLOSTOMA-CEYLANICUM; ONCHOCERCA-VOLVULUS; HOOKWORM INFECTION; SECRETED PROTEIN; BALB/CBYJ MICE; LARVAE; VACCINE; IDENTIFICATION; SPECIFICITY; COMPLEMENT AB Human intestinal infections with the nematode Strongyloides stercoralis remain a significant problem worldwide and a vaccine would be a useful addition to the tools available to prevent and control this infection. The goal of this study was to test single antigens for their efficacy in a vaccine against S. stercoralis larvae in mice. Alum was used as the adjuvant in these studies and antigens selected for analysis were either recognized by protective human IgG (Ss-TMY-1, Ss-EAT-6, and Ss-LEC-5) or were known to be highly immunogenic in humans (Ss-NIE-1 and Ss-IR). Only mice immunized with the Ss-IR antigen demonstrated a significant decrease of approximately 80% in the survival of larval parasites in the challenge infection. Antibodies, recovered from mice with protective immunity to S. stercoralis after immunization with Ss-IR, were used to locate the antigen in the larvae. Confocal microscopy revealed that IgG from mice immunized with Ss-IR bound to the surface of the parasites and observations by electron microscopy indicated that IgG bound to granules in the glandular esophagus. Serum collected from mice immunized with Ss-IR passively transferred immunity to naive mice. These studies demonstrate that Ss-IR, in combination with alum, induces high levels of protective immunity through an antibody dependent mechanism and may therefore be suitable for further development as a vaccine against human strongyloidiasis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Abraham, David; Hess, Jessica A.] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Mejia, Rojelio; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Nolan, Thomas J.; Lok, James B.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Lustigman, Sara] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10065 USA. RP Abraham, D (reprint author), Thomas Jefferson Univ, Dept Microbiol & Immunol, 233 S 10th St, Philadelphia, PA 19107 USA. EM David.Abraham@jefferson.edu OI Nolan, Thomas/0000-0002-6860-7947 FU NIH [1R56 AI076345, RO1 AI 22662, RO1 AI 50668, RO1 AI082548, P40 RR02512]; Division of Intramural Research, NAID FX We thank Sandra Bonne-Annee, Laura Kerepesi and Eric Wong for their expert and enthusiastic technical support. Special thanks to Yelena Oskov for assistance with the electron microscopy. This work was supported in part by NIH grants 1R56 AI076345 (to DA), RO1 AI 22662 (to JBL), RO1 AI 50668 (to JBL), RO1 AI082548 (to JBL), and P40 RR02512 (to JBL) and the Division of Intramural Research, NAID (to TBN). NR 35 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 19 PY 2011 VL 29 IS 45 BP 8134 EP 8140 DI 10.1016/j.vaccine.2011.08.030 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 843PF UT WOS:000296683700035 PM 21856350 ER PT J AU Ascierto, ML Worschech, A Yu, ZY Adams, S Reinboth, J Chen, NG Pos, Z Roychoudhuri, R Di Pasquale, G Bedognetti, D Uccellini, L Rossano, F Ascierto, PA Stroncek, DF Restifo, NP Wang, E Szalay, AA Marincola, FM AF Ascierto, Maria Libera Worschech, Andrea Yu, Zhiya Adams, Sharon Reinboth, Jennifer Chen, Nanhai G. Pos, Zoltan Roychoudhuri, Rahul Di Pasquale, Giovanni Bedognetti, Davide Uccellini, Lorenzo Rossano, Fabio Ascierto, Paolo A. Stroncek, David F. Restifo, Nicholas P. Wang, Ena Szalay, Aladar A. Marincola, Francesco M. TI Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68 SO BMC CANCER LA English DT Article ID GENE-THERAPY; ADENOVIRUS; RECEPTOR; IDENTIFICATION; INFECTION; PANEL; CD9 AB Background: Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo. Methods: In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection. Results: We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection. Conclusions: Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection. C1 [Ascierto, Maria Libera; Worschech, Andrea; Reinboth, Jennifer; Pos, Zoltan; Bedognetti, Davide; Uccellini, Lorenzo; Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ascierto, Maria Libera; Worschech, Andrea; Reinboth, Jennifer; Pos, Zoltan; Bedognetti, Davide; Uccellini, Lorenzo; Wang, Ena; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Ascierto, Maria Libera; Bedognetti, Davide] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Ascierto, Maria Libera] Univ Genoa, CEBR, I-16126 Genoa, Italy. [Worschech, Andrea; Reinboth, Jennifer; Chen, Nanhai G.; Szalay, Aladar A.] Genelux Corp, San Diego Sci Ctr, San Diego, CA USA. [Yu, Zhiya; Roychoudhuri, Rahul; Restifo, Nicholas P.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Adams, Sharon] NIH, Warren G Magnuson Clin Ctr, HLA Lab, Bethesda, MD 20892 USA. [Worschech, Andrea] Univ Wurzburg, Dept Internal Med 2, D-97074 Wurzburg, Germany. [Worschech, Andrea; Reinboth, Jennifer; Szalay, Aladar A.] Univ Wurzburg, Dept Biochem, Bioctr, D-97074 Wurzburg, Germany. [Di Pasquale, Giovanni] NIH, NIDCR Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Rossano, Fabio] Univ Naples Federico 2, Dept Mol Pathol, Naples, Italy. [Ascierto, Maria Libera; Ascierto, Paolo A.] Fdn G Pascale, Natl Canc Inst, Naples, Italy. [Stroncek, David F.] NIH, Cell Therapy Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide] Univ Genoa, Dept Oncol Biol & Genet, I-16126 Genoa, Italy. [Bedognetti, Davide] Natl Inst Canc Res, Dept Med Oncol, Genoa, Italy. [Uccellini, Lorenzo] Univ Milan, L Sacco Hosp, Inst Infect & Trop Dis, Milan, Italy. [Chen, Nanhai G.; Szalay, Aladar A.] Univ Calif San Diego, Dept Radiat Oncol, Rebecca & John Moores Comprehens Canc Ctr, San Diego, CA 92103 USA. RP Ascierto, ML (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM asciertoml@cc.nih.gov; Fmarincola@mail.cc.nih.gov RI Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012; Worschech, Andrea/I-3919-2012; Restifo, Nicholas/A-5713-2008; Roychoudhuri, Rahul/A-7442-2010; Pos, Zoltan/C-3623-2014; OI Worschech, Andrea/0000-0002-4303-8653; Roychoudhuri, Rahul/0000-0002-5392-1853; Pos, Zoltan/0000-0002-2574-7616; Bedognetti, Davide/0000-0002-5857-773X; Restifo, Nicholas P./0000-0003-4229-4580 FU Infectious Disease and Immunogenetics Section (IDIS), National Institutes of Health (Bethesda, MD, USA); Genelux Corporation (R&D facility in San Diego, CA, USA); Genelux Corporation FX This work was supported by Infectious Disease and Immunogenetics Section (IDIS), National Institutes of Health (Bethesda, MD, USA) and from grant derived from Genelux Corporation (R&D facility in San Diego, CA, USA). Ms. A. Worschech and Ms. J. Reinboth, visitors at NIH, are graduate students in Dr. Szalay's laboratory in the Department of Biochemistry, University of Wurzburg, Germany, and are supported by a graduate stipend and foreign travel grant from Genelux Corporation. Nanhai G. Chen and Aladar A. Szalay are affiliated with Genelux Corporation. No competing financial interests exist for other authors. NR 36 TC 12 Z9 12 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 19 PY 2011 VL 11 AR 451 DI 10.1186/1471-2407-11-451 PG 14 WC Oncology SC Oncology GA 844QG UT WOS:000296761800001 PM 22011439 ER PT J AU Bystrom, J Wray, JA Sugden, MC Holness, MJ Swales, KE Warner, TD Edin, ML Zeldin, DC Gilroy, DW Bishop-Bailey, D AF Bystrom, Jonas Wray, Jessica A. Sugden, Mary C. Holness, Mark J. Swales, Karen E. Warner, Timothy D. Edin, Matthew L. Zeldin, Darryl C. Gilroy, Derek W. Bishop-Bailey, David TI Endogenous Epoxygenases Are Modulators of Monocyte/Macrophage Activity SO PLOS ONE LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; KAPPA-B ACTIVITY; ENDOTHELIAL-CELLS; LAMINAR-FLOW; IN-VITRO; CYTOCHROME-P450; ACID; EXPRESSION; CYP2J2; GAMMA AB Background: Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known. Methodology/Principal Findings: When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha. Human monocytes and macrophages contain PPAR alpha and here we show they express the epoxygenases CYP2J2 and CYP2C8. Inhibition of constitutive monocyte epoxygenases using the epoxygenase inhibitor SKF525A induces cyclooxygenase (COX)-2 expression and activity, and the release of TNF alpha, and can be reversed by either add back of the endogenous epoxygenase products and PPAR alpha ligand 11,12-epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPAR alpha ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNF alpha release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNF alpha by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNF alpha mRNA and further decreases M2 macrophage TNF alpha. Conclusions/Significance: In conclusion, epoxygenase activity represents an important endogenous pathway which limits monocyte activation. Moreover endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state. C1 [Bystrom, Jonas; Wray, Jessica A.; Swales, Karen E.; Warner, Timothy D.; Bishop-Bailey, David] Queen Mary Univ London, William Harvey Res Inst, London, England. [Sugden, Mary C.; Holness, Mark J.] Queen Mary Univ London, Blizzard Inst Cell & Mol Sci, London, England. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Gilroy, Derek W.] UCL, Div Med, London, England. RP Bystrom, J (reprint author), Queen Mary Univ London, William Harvey Res Inst, London, England. EM d.bishop-bailey@qmul.ac.uk RI Warner, Timothy/A-1980-2009; OI Warner, Timothy/0000-0003-3988-4408; Edin, Matthew/0000-0002-7042-500X FU British Heart Foundation [FS/04/075, BS/02/002, PG/08/070/25464]; Wellcome Trust [074361/Z/04/Z]; National Institutes of Health, NIEHS; European Community [LSHM-CT-2004-0050333]; National Institute of Health Research FX This work was partly funded by grants from the British Heart Foundation (FS/04/075; BS/02/002; PG/08/070/25464), the Wellcome Trust (074361/Z/04/Z) and the Intramural Research Programs of the National Institutes of Health, NIEHS (to DZ), and European Community FP6 funding (LSHM-CT-2004-0050333). Derek Gilroy holds a Wellcome Trust Senior Fellowship. This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 28 Z9 29 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 19 PY 2011 VL 6 IS 10 AR e26591 DI 10.1371/journal.pone.0026591 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841JB UT WOS:000296507500092 PM 22028915 ER PT J AU Gibson, TM Brennan, P Han, S Karami, S Zaridze, D Janout, V Kollarova, H Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Slamova, A Pfeiffer, RM Stolzenberg-Solomon, RZ Mayne, ST Yeager, M Chanock, S Rothman, N Chow, WH Rosenberg, PS Boffetta, P Moore, LE AF Gibson, Todd M. Brennan, Paul Han, Summer Karami, Sara Zaridze, David Janout, Vladimir Kollarova, Helen Bencko, Vladimir Navratilova, Marie Szeszenia-Dabrowska, Neonila Mates, Dana Slamova, Alena Pfeiffer, Ruth M. Stolzenberg-Solomon, Rachael Z. Mayne, Susan T. Yeager, Meredith Chanock, Stephen Rothman, Nat Chow, Wong-Ho Rosenberg, Philip S. Boffetta, Paolo Moore, Lee E. TI Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk SO PLOS ONE LA English DT Article ID REDUCED FOLATE CARRIER; CASE-CONTROL ASSOCIATION; CENTRAL-EUROPE; METHYLENETETRAHYDROFOLATE REDUCTASE; MTHFR POLYMORPHISMS; COLORECTAL-CANCER; PANCREATIC-CANCER; VEGETABLE INTAKE; COMMON MUTATION; KIDNEY CANCER AB Introduction: Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Methods: Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. Results: The strongest associations with RCC risk were observed for SLC19A1 (Pmin-P = 0.03) and MTHFR (Pmin-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. Conclusions: To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings. C1 [Gibson, Todd M.; Han, Summer; Karami, Sara; Pfeiffer, Ruth M.; Stolzenberg-Solomon, Rachael Z.; Yeager, Meredith; Chanock, Stephen; Rothman, Nat; Chow, Wong-Ho; Rosenberg, Philip S.; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gibson, Todd M.; Mayne, Susan T.] Yale Sch Publ Hlth, New Haven, CT USA. [Brennan, Paul; Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Janout, Vladimir; Kollarova, Helen] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir; Slamova, Alena] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Navratilova, Marie] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, Gaithersburg, MD USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Canc Prevent Res Inst, Lyon, France. RP Gibson, TM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM gibsontm@mail.nih.gov RI Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; OI mates, dana/0000-0002-6219-9807 FU US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [TU2-CA-105666] FX This work was supported in part by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and by grant TU2-CA-105666. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 19 PY 2011 VL 6 IS 10 AR e26165 DI 10.1371/journal.pone.0026165 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841JB UT WOS:000296507500036 PM 22039442 ER PT J AU Bossart, KN Geisbert, TW Feldmann, H Zhu, ZY Feldmann, F Geisbert, JB Yan, LY Feng, YR Brining, D Scott, D Wang, YP Dimitrov, AS Callison, J Chan, YP Hickey, AC Dimitrov, DS Broder, CC Rockx, B AF Bossart, Katharine N. Geisbert, Thomas W. Feldmann, Heinz Zhu, Zhongyu Feldmann, Friederike Geisbert, Joan B. Yan, Lianying Feng, Yan-Ru Brining, Doug Scott, Dana Wang, Yanping Dimitrov, Antony S. Callison, Julie Chan, Yee-Peng Hickey, Andrew C. Dimitrov, Dimiter S. Broder, Christopher C. Rockx, Barry TI A Neutralizing Human Monoclonal Antibody Protects African Green Monkeys from Hendra Virus Challenge SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NIPAH VIRUS; INFECTION; RECEPTOR; HENIPAVIRUS; BINDING; MODEL AB Hendra virus (HeV) is a recently emerged zoonotic paramyxovirus that can cause a severe and often fatal disease in horses and humans. HeV is categorized as a biosafety level 4 agent, which has made the development of animal models and testing of potential therapeutics and vaccines challenging. Infection of African green monkeys (AGMs) with HeV was recently demonstrated, and disease mirrored fatal HeV infection in humans, manifesting as a multisystemic vasculitis with widespread virus replication in vascular tissues and severe pathologic manifestations in the lung, spleen, and brain. Here, we demonstrate that m102.4, a potent HeV-neutralizing human monoclonal antibody (hmAb), can protect AGMs from disease after infection with HeV. Fourteen AGMs were challenged intratracheally with a lethal dose of HeV, and 12 subjects were infused twice with a 100-mg dose of m102.4 beginning at either 10, 24, or 72 hours after infection and again about 48 hours later. The presence of viral RNA, infectious virus, and HeV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease on day 8 after infection. Animals in the 72-hour treatment group exhibited neurological signs of disease, but all animals started to recover by day 16 after infection. These results represent successful post-exposure in vivo efficacy by an investigational drug against HeV and highlight the potential impact a hmAb can have on human disease. C1 [Yan, Lianying; Feng, Yan-Ru; Chan, Yee-Peng; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Bossart, Katharine N.; Hickey, Andrew C.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Bossart, Katharine N.; Hickey, Andrew C.] Boston Univ, Sch Med, Natl Emerging Infect Dis Labs Inst, Boston, MA 02118 USA. [Geisbert, Thomas W.; Geisbert, Joan B.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Geisbert, Thomas W.; Geisbert, Joan B.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Feldmann, Heinz; Callison, Julie; Rockx, Barry] NIAID, Rocky Mt Labs, Virol Lab, NIH, Hamilton, MT 59840 USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3T 2N2, Canada. [Zhu, Zhongyu; Wang, Yanping; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,NIH, Frederick, MD 21702 USA. [Zhu, Zhongyu; Wang, Yanping] Frederick Inc, Sci Applicat Int Corp, Behav Res Program, Ft Detrick, MD 21702 USA. [Feldmann, Friederike] NIAID, Rocky Mt Labs, Operat Off, NIH, Hamilton, MT 59840 USA. [Feldmann, Friederike] NIAID, Rocky Mt Labs, Off Management, NIH, Hamilton, MT 59840 USA. [Brining, Doug; Scott, Dana] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, NIH, Hamilton, MT 59840 USA. [Dimitrov, Antony S.] Profectus BioSci Inc, Baltimore, MD 21224 USA. RP Broder, CC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM cbroder@usuhs.mil OI Bossart, Katharine/0000-0001-6886-6896 FU National Institute of Allergy and Infectious Diseases, NIH; Department of Health and Human Services, NIH [AI082121, AI057159, AI054715, AI077995]; National Institute of Allergy and Infectious Diseases; National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [N01-CO-12400] FX These studies were supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, and in part by the Department of Health and Human Services, NIH, grants AI082121 and AI057159 (to T. W. G.) and AI054715 and AI077995 (to C. C. B.), and the Intramural Biodefense Program of the National Institute of Allergy and Infectious Diseases, the Intramural Program of the National Cancer Institute, Center for Cancer Research, and by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. NR 33 TC 38 Z9 39 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 19 PY 2011 VL 3 IS 105 AR 105ra103 DI 10.1126/scitranslmed.3002901 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 842CL UT WOS:000296565100004 PM 22013123 ER PT J AU Christopherson, GT Nesti, LJ AF Christopherson, Gregory T. Nesti, Leon J. TI Stem cell applications in military medicine SO STEM CELL RESEARCH & THERAPY LA English DT Review ID SPINAL-CORD-INJURY; TISSUE-ENGINEERED SKIN; PRIMARY BLAST INJURY; MESENCHYMAL STEM; PROGENITOR CELLS; REPLACEMENT THERAPY; VASCULAR TRAUMA; CARDIAC REPAIR; GENE-THERAPY; BONE-MARROW AB There are many similarities between health issues affecting military and civilian patient populations, with the exception of the relatively small but vital segment of active soldiers who experience high-energy blast injuries during combat. A rising incidence of major injuries from explosive devices in recent campaigns has further complicated treatment and recovery, highlighting the need for tissue regenerative options and intensifying interest in the possible role of stem cells for military medicine. In this review we outline the array of tissue-specific injuries typically seen in modern combat - as well as address a few complications unique to soldiers - and discuss the state of current stem cell research in addressing each area. Embryonic, induced-pluripotent and adult stem cell sources are defined, along with advantages and disadvantages unique to each cell type. More detailed stem cell sources are described in the context of each tissue of interest, including neural, cardiopulmonary, musculoskeletal and sensory tissues, with brief discussion of their potential role in regenerative medicine moving forward. Additional commentary is given to military stem cell applications aside from regenerative medicine, such as blood pharming, immunomodulation and drug screening, with an overview of stem cell banking and the unique opportunity provided by the military and civilian overlap of stem cell research. C1 [Christopherson, Gregory T.; Nesti, Leon J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Nesti, Leon J.] McDonald Army Med Hlth Ctr, Hand & Upper Extrem Reconstruct Surg Serv, Dept Orthopaed Surg, Ft Eustis, VA 23604 USA. RP Nesti, LJ (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM leon.nesti@nih.gov FU Military Amputee Research Program [PO5-A011]; NIH/NIAMS FX The authors thank LCDR Jared Vogler, MD, and Wesley Jackson, PhD, for their helpful discussion and manuscript review. Work in the Nesti lab is supported by the Military Amputee Research Program (PO5-A011) and the NIH/NIAMS intramural program. NR 108 TC 5 Z9 6 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD OCT 19 PY 2011 VL 2 AR 40 DI 10.1186/scrt81 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 844GH UT WOS:000296735200001 PM 22011454 ER PT J AU Pickens, CL Calu, DJ AF Pickens, Charles L. Calu, Donna J. TI Alcohol Reward, Dopamine Depletion, and GDNF SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID VENTRAL TEGMENTAL AREA; RELAPSE; ABSTINENCE; ETHANOL; SEEKING; COCAINE; STRESS; DRUG; RATS C1 [Pickens, Charles L.; Calu, Donna J.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pickens, CL (reprint author), 251 Bayview Blvd, Baltimore, MD 21224 USA. EM pickensc@mail.nih.gov OI Calu, Donna/0000-0003-2377-9494 FU Intramural NIH HHS [Z99 DA999999] NR 11 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 19 PY 2011 VL 31 IS 42 BP 14833 EP 14834 DI 10.1523/JNEUROSCI.4222-11.2011 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 838FY UT WOS:000296274000001 PM 22016515 ER PT J AU Glass, RI Patel, M Parashar, U AF Glass, Roger I. Patel, Manish Parashar, Umesh TI Lessons From the US Rotavirus Vaccination Program SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID UNITED-STATES; CHILDREN; GASTROENTERITIS; DISEASE; MEXICO C1 [Patel, Manish; Parashar, Umesh] Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Patel, M (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, 1600 Clifton Rd,MS A34, Atlanta, GA 30333 USA. EM mpatel@cdc.gov NR 10 TC 8 Z9 8 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 19 PY 2011 VL 306 IS 15 BP 1701 EP 1702 DI 10.1001/jama.2011.1475 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 834MA UT WOS:000295963200030 PM 22009102 ER PT J AU Turkbey, EB Backlund, JYC Genuth, S Jain, A Miao, CL Cleary, PA Lachin, JM Nathan, DM van der Geest, RJ Soliman, EZ Liu, CY Lima, JAC Bluemke, DA AF Turkbey, Evrim B. Backlund, Jye-Yu C. Genuth, Saul Jain, Aditya Miao, Cuilian Cleary, Patricia A. Lachin, John M. Nathan, David M. van der Geest, Rob J. Soliman, Elsayed Z. Liu, Chia-Ying Lima, Joao A. C. Bluemke, David A. CA DCCT EDIC Res Grp TI Myocardial Structure, Function, and Scar in Patients With Type 1 Diabetes Mellitus SO CIRCULATION LA English DT Article DE cardiovascular diseases; diabetes mellitus, type 1; magnetic resonance imaging; risk factors ID LEFT-VENTRICULAR MASS; CARDIAC MAGNETIC-RESONANCE; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; COMPLICATIONS TRIAL/EPIDEMIOLOGY; ARTERY-DISEASE; BODY-SIZE; FOLLOW-UP; INFARCTION AB Background-We report relationships between cardiovascular disease risk factors and myocardial structure, function, and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods and Results-Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus. Gadolinium cardiac magnetic resonance was also obtained in 741 patients. The mean age was 49 +/- 7 years; 52% were men; and mean duration of diabetes mellitus was 28 +/- 5 years. Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models. History of macroalbuminuria was positively associated with left ventricular mass (by 14.8 g), leading to a significantly higher ratio of left ventricular mass to end-diastolic volume (by 8%). Mean hemoglobin A(1c) levels over the preceding 22 years were inversely associated with end-diastolic volume (-3.0 mL per unit mean hemoglobin A(1c) percent) and stroke volume (-2.3 mL per unit mean hemoglobin A(1c) percent) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume (0.02 g/mL per unit). The overall prevalence of myocardial scar was 4.3% by cardiac magnetic resonance and 1.4% by clinical adjudication of myocardial infarction. Both mean hemoglobin A(1c) (odds ratio, 1.5 [95% confidence interval, 1.0-2.2] per unit) and macroalbuminuria (odds ratio, 3.5 [95% confidence interval, 1.2-9.9]) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors. Conclusions-In addition to traditional cardiovascular disease risk factors, elevated mean hemoglobin A(1c) and macroalbuminuria were significantly associated with alterations in left ventricular structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function. C1 [Turkbey, Evrim B.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Backlund, Jye-Yu C.; Cleary, Patricia A.; Lachin, John M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Genuth, Saul] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Div Cardiol, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Miao, Cuilian] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [van der Geest, Rob J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI van der Geest, Rob/J-8193-2015; OI van der Geest, Rob/0000-0002-9084-5597; Lachin, John/0000-0001-9838-2841; Bluemke, David/0000-0002-8323-8086 FU Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers Program; National Center for Research Resources; Genentech; National Institute of Diabetes and Digestive and Kidney Diseases; NIH FX The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; the General Clinical Research Centers Program; and the Clinical and Translation Science Centers Program, National Center for Research Resources, as well as by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Drs Bluemke and Turkbey are supported by the NIH Intramural research program. NR 42 TC 30 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 18 PY 2011 VL 124 IS 16 BP 1737 EP U112 DI 10.1161/CIRCULATIONAHA.111.022327 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842BW UT WOS:000296562900018 PM 21947298 ER PT J AU Rajamannan, NM Evans, FJ Aikawa, E Grande-Allen, KJ Demer, LL Heistad, DD Simmons, CA Masters, KS Mathieu, P O'Brien, KD Schoen, FJ Towler, DA Yoganathan, AP Otto, CM AF Rajamannan, Nalini M. Evans, Frank J. Aikawa, Elena Grande-Allen, K. Jane Demer, Linda L. Heistad, Donald D. Simmons, Craig A. Masters, Kristyn S. Mathieu, Patrick O'Brien, Kevin D. Schoen, Frederick J. Towler, Dwight A. Yoganathan, Ajit P. Otto, Catherine M. TI Calcific Aortic Valve Disease: Not Simply a Degenerative Process A Review and Agenda for Research From the National Heart and Lung and Blood Institute Aortic Stenosis Working Group SO CIRCULATION LA English DT Review DE aortic valve; aortic valve calcification; aortic valve stenosis; calcification; cardiac calcifications ID LOW-DENSITY-LIPOPROTEIN; INTERSTITIAL CELL CALCIFICATION; ANGIOTENSIN-CONVERTING ENZYME; RISK-FACTORS; FAMILIAL HYPERCHOLESTEROLEMIA; BONE-FORMATION; EXTRACELLULAR-MATRIX; METABOLIC SYNDROME; DIABETES-MELLITUS; VALVULAR LESIONS C1 [Rajamannan, Nalini M.] Northwestern Univ, Feinberg Sch Med, Div Cardiol & Pathol, Chicago, IL 60611 USA. [Evans, Frank J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Aikawa, Elena] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Grande-Allen, K. Jane] Rice Univ, Houston, TX USA. [Demer, Linda L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Heistad, Donald D.] Univ Iowa, Ctr Cardiovasc, Carver Coll Med, Iowa City, IA 52242 USA. [Heistad, Donald D.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Simmons, Craig A.] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON, Canada. [Masters, Kristyn S.] Univ Wisconsin, Dept Biomed Engn, Madison, WI USA. [Mathieu, Patrick] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [O'Brien, Kevin D.; Otto, Catherine M.] Univ Washington, Seattle, WA 98195 USA. [Schoen, Frederick J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Schoen, Frederick J.] Harvard Univ, Sch Med, Boston, MA USA. [Towler, Dwight A.] Washington Univ, Dept Med, St Louis, MO USA. [Yoganathan, Ajit P.] Georgia Inst Technol, Atlanta, GA 30332 USA. RP Rajamannan, NM (reprint author), Northwestern Univ, Feinberg Sch Med, Div Cardiol & Pathol, 303 E Chicago,Tarry 12-717, Chicago, IL 60611 USA. EM n-rajamannan@northwestern.edu RI Simmons, Craig/A-5880-2008; Grande-Allen, Kathryn/P-4042-2014; OI Simmons, Craig/0000-0001-7729-1772; Grande-Allen, Kathryn/0000-0003-1533-3767; Otto, Catherine/0000-0002-0527-9392 FU Amgen Corporation; Division of Engineering Education and Centers (EEC) at NSF [9731643]; NIH [5R01HL085591, 3R01HL085591S1, HL069229, HL081138, HL088651, 1R21HL081558, HL 62984, 1R01 HL081202]; Barnes-Jewish Hospital Foundation; Canadian Institutes of Health Research [MOP-102721]; Heart and Stroke Foundation of Ontario [NA6654]; Canadian Research Chair; Whitaker Foundation; American Heart Association [0835460N]; Carver Research Program of Excellence; Amgen Inc; [1R01 HL093281] FX The working group was commissioned by the National Heart, Lung, and Blood Institute, and support for the meeting was directly from the National Institutes of Health (NIH). Dr Schoen is a consultant for Edwards LifeSciences, Medtronic, Pi-R-Sq, Sadra Medical, Sorin Medical, St. Jude Medical, and Sulver Carbomedics. Dr Rajamannan is the inventor of a patent for methods to slow progression of valvular heart disease. This patent is owned by the Mayo Clinic, and the author does not receive any royalties from this patent. Dr Heistad receives funding from a grant from Amgen Corporation. The other authors report no conflicts.; Dr Yoganathan is supported by the Division of Engineering Education and Centers (EEC) at NSF-9731643. Dr Rajamannan is supported by NIH grants 5R01HL085591 and 3R01HL085591S1. Dr Towler is supported by NIH grants HL069229, HL081138, and HL088651, and by the Barnes-Jewish Hospital Foundation. Dr Simmons is supported by the Canadian Institutes of Health Research (MOP-102721) and the Heart and Stroke Foundation of Ontario (NA6654) and the Canadian Research Chair. Dr Grande-Allen is supported by NIH grant 1R21HL081558 and Whitaker Foundation Biomedical Engineering Grant the Human Frontiers Science Program. Dr O'Brien is supported by NIH grant 1R21HL081558. Dr Aikawa is supported by the American Heart Association 0835460N. Dr Heistad is supported by Carver Research Program of Excellence, Amgen Inc (Industry Grant), and HL 62984 (NIH). Dr Demer is supported by NIH grant 1R01 HL081202. Dr Masters is supported by 1R01 HL093281. NR 89 TC 225 Z9 232 U1 6 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 18 PY 2011 VL 124 IS 16 BP 1783 EP 1791 DI 10.1161/CIRCULATIONAHA.110.006767 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842BW UT WOS:000296562900023 PM 22007101 ER PT J AU Lizunov, V Chlanda, P Kraft, M Zimmerberg, J AF Lizunov, Vladimir Chlanda, Petr Kraft, Mary Zimmerberg, Joshua TI Long, Saturated Chains: Tasty Domains for Kinases of Insulin Resistance SO DEVELOPMENTAL CELL LA English DT Editorial Material ID FATTY-ACIDS C1 [Lizunov, Vladimir; Chlanda, Petr; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Kraft, Mary] Univ Illinois, Sch Chem Sci, Urbana, IL 61801 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov FU Intramural NIH HHS [ZIA HD001415-22] NR 10 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT 18 PY 2011 VL 21 IS 4 BP 604 EP 606 DI 10.1016/j.devcel.2011.10.001 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 839LA UT WOS:000296366000004 PM 22014518 ER PT J AU Ferretti, E Li, BS Zewdu, R Wells, V Hebert, JM Karner, C Anderson, MJ Williams, T Dixon, J Dixon, MJ Depew, MJ Selleri, L AF Ferretti, Elisabetta Li, Bingsi Zewdu, Rediet Wells, Victoria Hebert, Jean M. Karner, Courtney Anderson, Matthew J. Williams, Trevor Dixon, Jill Dixon, Michael J. Depew, Michael J. Selleri, Licia TI A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis SO DEVELOPMENTAL CELL LA English DT Article ID CLEFT-PALATE; MIDFACIAL MORPHOGENESIS; LIP; EXPRESSION; MICE; HOX; PROLIFERATION; WNT9B; IRF6; DIFFERENTIATION AB Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CUP), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CUP in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CUP and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CUP. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair. C1 [Ferretti, Elisabetta; Li, Bingsi; Zewdu, Rediet; Wells, Victoria; Selleri, Licia] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [Hebert, Jean M.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. [Hebert, Jean M.] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Karner, Courtney] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Karner, Courtney] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Anderson, Matthew J.] NCI, Genet Vertebrate Dev Sect, Frederick, MD 21701 USA. [Williams, Trevor] Univ Colorado Denver, Dept Craniofacial Biol, Aurora, CO 80045 USA. [Williams, Trevor] Univ Colorado Denver, Dept Cell & Dev Biol, Aurora, CO 80045 USA. [Dixon, Jill; Dixon, Michael J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Manchester M13 9PT, Lancs, England. [Depew, Michael J.] Kings Coll London, Dept Craniofacial Dev, London SE1 9RT, England. RP Selleri, L (reprint author), Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. EM lis2008@med.cornell.edu FU Marie Curie Fellowship [OIF-CT-2005-022003]; MRC UK [G0901539]; Royal Society; King's College London; March of Dimes and Birth Defects Foundation [6-FY03-071]; National Institutes of Health [RO1 HD43997, 2RO1 HD061403, R21 DE18031]; Cleft Palate Foundation; Alice Bohmfalk Trust FX We are grateful to Drs. M. Lewandoski and T. Carroll for generously providing Fgf8 hypomorph embryos, Wnt9b-deficient mice, and Rosa-Wnt1 mice. We also thank Dr. D. Kingsley for the SfiHsp68LacZ plasmid; Dr. B. Wang for proliferation assays; Drs. E. Lacy, A. Foley, T. Capellini, and D. Noden for important discussions; and Cyagen for transgenic embryos. Work was supported by Marie Curie Fellowship (OIF-CT-2005-022003) to E.F., grants from MRC UK (G0901539) to J.D. and M.J. Dixon, the Royal Society and King's College London to M.J. Depew, and March of Dimes and Birth Defects Foundation (6-FY03-071), National Institutes of Health (RO1 HD43997, 2RO1 HD061403, and R21 DE18031), Cleft Palate Foundation, and Alice Bohmfalk Trust to L.S. L.S. is a Hirschl Scholar. NR 54 TC 61 Z9 61 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT 18 PY 2011 VL 21 IS 4 BP 627 EP 641 DI 10.1016/j.devcel.2011.08.005 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 839LA UT WOS:000296366000008 PM 21982646 ER PT J AU Kerlikowske, K Hubbard, RA Miglioretti, DL Geller, BM Yankaskas, BC Lehman, CD Taplin, SH Sickles, EA AF Kerlikowske, Karla Hubbard, Rebecca A. Miglioretti, Diana L. Geller, Berta M. Yankaskas, Bonnie C. Lehman, Constance D. Taplin, Stephen H. Sickles, Edward A. CA Breast Canc Surveillance Consortiu TI Comparative Effectiveness of Digital Versus Film-Screen Mammography in Community Practice in the United States A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CANCER SURVEILLANCE CONSORTIUM; CARCINOMA IN-SITU; BREAST-CANCER; THERAPY USE; POPULATION; ACCURACY; DENSITY; PROGRAM; PERFORMANCE; WOMEN AB Background: Few studies have examined the comparative effectiveness of digital versus film-screen mammography in U. S. community practice. Objective: To determine whether the interpretive performance of digital and film-screen mammography differs. Design: Prospective cohort study. Setting: Mammography facilities in the Breast Cancer Surveillance Consortium. Participants: 329 261 women aged 40 to 79 years underwent 869 286 mammograms (231 034 digital; 638 252 film-screen). Measurements: Invasive cancer or ductal carcinoma in situ diagnosed within 12 months of a digital or film-screen examination and calculation of mammography sensitivity, specificity, cancer detection rates, and tumor outcomes. Results: Overall, cancer detection rates and tumor characteristics were similar for digital and film-screen mammography, but the sensitivity and specificity of each modality varied by age, tumor characteristics, breast density, and menopausal status. Compared with film-screen mammography, the sensitivity of digital mammography was significantly higher for women aged 60 to 69 years (89.9% vs. 83.0%; P = 0.014) and those with estrogen receptor-negative cancer (78.5% vs. 65.8%; P = 0.016); borderline significantly higher for women aged 40 to 49 years (82.4% vs. 75.6%; P = 0.071), those with extremely dense breasts (83.6% vs. 68.1%; P = 0.051), and pre- or perimenopausal women (87.1% vs. 81.7%; P = 0.057); and borderline significantly lower for women aged 50 to 59 years (80.5% vs. 85.1%; P = 0.097). The specificity of digital and film-screen mammography was similar by decade of age, except for women aged 40 to 49 years (88.0% vs. 89.7%; P < 0.001). Limitation: Statistical power for subgroup analyses was limited. Conclusion: Overall, cancer detection with digital or film-screen mammography is similar in U. S. women aged 50 to 79 years undergoing screening mammography. Women aged 40 to 49 years are more likely to have extremely dense breasts and estrogen receptor-negative tumors; if they are offered mammography screening, they may choose to undergo digital mammography to optimize cancer detection. C1 [Kerlikowske, Karla] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Washington, Sch Publ Hlth & Community Med, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98195 USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Vermont, Coll Med, Burlington, VT USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Appl Res Program, Rockville, MD USA. RP Kerlikowske, K (reprint author), San Francisco VA Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM Karla.Kerlikowske@ucsf.edu OI Hubbard, Rebecca/0000-0003-0879-0994 FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, R03CA150007, RC2CA148577] FX By the National Cancer Institute-funded BCSC cooperative agreement (grants U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040) and National Cancer Institute grants R03CA150007 and RC2CA148577. The collection of cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the United States; for a full description of these sources, see http://breastscreening.cancer.gov/work/acknowledgement.html. NR 30 TC 93 Z9 94 U1 1 U2 14 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 18 PY 2011 VL 155 IS 8 BP 493 EP U64 DI 10.7326/0003-4819-155-8-201110180-00005 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 835WB UT WOS:000296066300014 PM 22007043 ER PT J AU Kim, HS Vassilopoulos, A Wang, RH Lahusen, T Xiao, Z Xu, XL Li, CL Veenstra, TD Li, B Yu, HT Ji, JF Wang, XW Park, SH Cha, YI Gius, D Deng, CX AF Kim, Hyun-Seok Vassilopoulos, Athanassios Wang, Rui-Hong Lahusen, Tyler Xiao, Zhen Xu, Xiaoling Li, Cuiling Veenstra, Timothy D. Li, Bing Yu, Hongtao Ji, Junfang Wang, Xin Wei Park, Seong-Hoon Cha, Yong I. Gius, David Deng, Chu-Xia TI SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity SO CANCER CELL LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; SPINDLE ASSEMBLY CHECKPOINT; TUMOR AMPLIFIED KINASE; AURORA-A; HEPATOCELLULAR-CARCINOMA; CELL-CYCLE; CENTROSOME AMPLIFICATION; TUBULIN DEACETYLASE; GENETIC INSTABILITY; MAMMALIAN SIRTUINS AB Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity. C1 [Kim, Hyun-Seok; Vassilopoulos, Athanassios; Wang, Rui-Hong; Lahusen, Tyler; Xu, Xiaoling; Li, Cuiling; Deng, Chu-Xia] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Ji, Junfang; Wang, Xin Wei] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Xiao, Zhen; Veenstra, Timothy D.] NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick, Frederick, MD 20170 USA. [Li, Bing; Yu, Hongtao] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Kim, Hyun-Seok; Park, Seong-Hoon; Cha, Yong I.; Gius, David] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37232 USA. [Kim, Hyun-Seok; Park, Seong-Hoon; Cha, Yong I.; Gius, David] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Kim, Hyun-Seok; Park, Seong-Hoon; Cha, Yong I.; Gius, David] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA. RP Deng, CX (reprint author), Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI Wang, Xin/B-6162-2009; deng, chuxia/N-6713-2016 FU NIDDK; NCI [1R01CA152601-01, 1R01CA152799-01]; CCR, NIH; DOD [BC093803]; National Institutes of Health; DHHS [HHSN261200800001E]; [SPORE P50CA98131] FX We thank members of Dr. Deng's lab for their critical discussion of this work. This research was supported (in part) by the Intramural Research Program of the NIDDK, NCI, and CCR, NIH. D.G. is supported by 1R01CA152601-01 and 1R01CA152799-01 from the NCI, BC093803 from the DOD, and SPORE P50CA98131. This project was also supported with federal funds from the National Cancer Institute, National Institutes of Health, DHHS, 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 the mention of trade names, commercial products, or organization imply endorsement by the U.S. government. All investigators have no research conflict. NR 66 TC 175 Z9 185 U1 1 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 18 PY 2011 VL 20 IS 4 BP 487 EP 499 DI 10.1016/j.ccr.2011.09.004 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 836OP UT WOS:000296121300010 PM 22014574 ER PT J AU Liao, JY Thakur, SA Zalinger, ZB Gerrish, KE Imani, F AF Liao, Jie-ying Thakur, Sheetal A. Zalinger, Zachary B. Gerrish, Kevin E. Imani, Farhad TI Inosine-Containing RNA Is a Novel Innate Immune Recognition Element and Reduces RSV Infection SO PLOS ONE LA English DT Article ID DOUBLE-STRANDED-RNA; NF-KAPPA-B; TOLL-LIKE RECEPTOR-3; PROTEIN-KINASE; ADENOSINE-DEAMINASE; VIRUS-REPLICATION; EPITHELIAL-CELLS; BIASED HYPERMUTATION; MESSENGER-RNA; RIG-I AB During viral infections, single-and double-stranded RNA (ssRNA and dsRNA) are recognized by the host and induce innate immune responses. The cellular enzyme ADAR-1 (adenosine deaminase acting on RNA-1) activation in virally infected cells leads to presence of inosine-containing RNA (Ino-RNA). Here we report that ss-Ino-RNA is a novel viral recognition element. We synthesized unmodified ssRNA and ssRNA that had 6% to16% inosine residues. The results showed that in primary human cells, or in mice, 10% ss-Ino-RNA rapidly and potently induced a significant increase in inflammatory cytokines, such as interferon (IFN)-beta (35 fold), tumor necrosis factor (TNF)-alpha (9.7 fold), and interleukin (IL)-6 (11.3 fold) (p<0.01). Flow cytometry data revealed a corresponding 4-fold increase in influx of neutrophils into the lungs by ss-Ino-RNA treatment. In our in vitro experiments, treatment of epithelial cells with ss-Ino-RNA reduced replication of respiratory syncytial virus (RSV). Interestingly, RNA structural analysis showed that ss-Ino-RNA had increased formation of secondary structures. Our data further revealed that extracellular ss-Ino-RNA was taken up by scavenger receptor class-A (SR-A) which activated downstream MAP Kinase pathways through Toll-like receptor 3 (TLR3) and dsRNA-activated protein kinase (PKR). Our data suggests that ss-Ino-RNA is an as yet undescribed virus-associated innate immune stimulus. C1 [Liao, Jie-ying; Thakur, Sheetal A.; Zalinger, Zachary B.] NIEHS, Lab Resp Biol, NIH, Durham, NC USA. [Gerrish, Kevin E.] NIEHS, Gene Array Core Facil, NIH, Durham, NC USA. [Imani, Farhad] ViraSource Labs, Durham, NC USA. RP Liao, JY (reprint author), NIEHS, Lab Resp Biol, NIH, Durham, NC USA. EM fimani@virasource.com FU Intramural National Institute of Health (NIH) FX This research was fully funded by Intramural National Institute of Health (NIH) funding, and the authors are NIH employees. The funders had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. NR 50 TC 10 Z9 11 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2011 VL 6 IS 10 AR e26463 DI 10.1371/journal.pone.0026463 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900068 PM 22028885 ER PT J AU Pierron, D Opazo, JC Heiske, M Papper, Z Uddin, M Chand, G Wildman, DE Romero, R Goodman, M Grossman, LI AF Pierron, Denis Opazo, Juan C. Heiske, Margit Papper, Zack Uddin, Monica Chand, Gopi Wildman, Derek E. Romero, Roberto Goodman, Morris Grossman, Lawrence I. TI Silencing, Positive Selection and Parallel Evolution: Busy History of Primate Cytochromes c SO PLOS ONE LA English DT Article ID PHOSPHORYLATED IN-VIVO; MOLECULAR EVOLUTION; ANTHROPOID PRIMATES; OXIDASE SUBUNIT; ADAPTIVE EVOLUTION; LIKELIHOOD METHOD; DIVERGENCE TIME; HOX CLUSTERS; BINDING-SITE; MITOCHONDRIAL AB Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades. C1 [Pierron, Denis; Opazo, Juan C.; Papper, Zack; Uddin, Monica; Chand, Gopi; Wildman, Derek E.; Romero, Roberto; Goodman, Morris; Grossman, Lawrence I.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. [Pierron, Denis; Chand, Gopi; Wildman, Derek E.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. [Pierron, Denis; Chand, Gopi; Wildman, Derek E.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Opazo, Juan C.] Univ Austral Chile, Fac Ciencias, Inst Ecol & Evoluc, Valdivia, Chile. [Heiske, Margit] Univ Victor Segalen Bordeaux 2, INSERM, Lab Physiopathol Mitochondriale, Bordeaux, France. [Uddin, Monica] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Goodman, Morris] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. RP Pierron, D (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. EM lgrossman@wayne.edu RI Opazo, Juan/A-9363-2009; OI Opazo, Juan/0000-0001-7938-4083 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [GM65580]; Department of Health and Human Services; National Science Foundation [BCS-0550209, BCS0827546, BCS 9910679]; Wayne State Research Excellence fund FX Supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, by NIH GM65580, and by the National Science Foundation (grants BCS-0550209, BCS0827546 and BCS 9910679) and the Wayne State Research Excellence fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 6 Z9 6 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2011 VL 6 IS 10 AR e26269 DI 10.1371/journal.pone.0026269 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900040 PM 22028846 ER PT J AU Zhang, Y Thomas, GL Swat, M Shirinifard, A Glazier, JA AF Zhang, Ying Thomas, Gilberto L. Swat, Maciej Shirinifard, Abbas Glazier, James A. TI Computer Simulations of Cell Sorting Due to Differential Adhesion SO PLOS ONE LA English DT Article ID HOMOPHILIC CADHERIN ADHESION; N-CADHERIN; ACTIN CYTOSKELETON; FORCE MEASUREMENTS; MEDIATED ADHESION; STRUCTURAL BASIS; WOUND CLOSURE; CHICK LIMB; MORPHOGENESIS; SPECIFICITY AB The actions of cell adhesion molecules, in particular, cadherins during embryonic development and morphogenesis more generally, regulate many aspects of cellular interactions, regulation and signaling. Often, a gradient of cadherin expression levels drives collective and relative cell motions generating macroscopic cell sorting. Computer simulations of cell sorting have focused on the interactions of cells with only a few discrete adhesion levels between cells, ignoring biologically observed continuous variations in expression levels and possible nonlinearities in molecular binding. In this paper, we present three models relating the surface density of cadherins to the net intercellular adhesion and interfacial tension for both discrete and continuous levels of cadherin expression. We then use then the Glazier-Graner-Hogeweg (GGH) model to investigate how variations in the distribution of the number of cadherins per cell and in the choice of binding model affect cell sorting. We find that an aggregate with a continuous variation in the level of a single type of cadherin molecule sorts more slowly than one with two levels. The rate of sorting increases strongly with the interfacial tension, which depends both on the maximum difference in number of cadherins per cell and on the binding model. Our approach helps connect signaling at the molecular level to tissue-level morphogenesis. C1 [Zhang, Ying] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. [Thomas, Gilberto L.] Univ Fed Rio Grande do Sul, Inst Fis, Porto Alegre, RS, Brazil. [Swat, Maciej; Shirinifard, Abbas; Glazier, James A.] Indiana Univ, Biocomplex Inst, Bloomington, IN USA. [Swat, Maciej; Shirinifard, Abbas; Glazier, James A.] Indiana Univ, Dept Phys, Bloomington, IN 47405 USA. RP Zhang, Y (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. EM zhangy14@mail.nih.gov RI Thomas, Gilberto/H-8944-2012; Zhang, Ying/Q-6956-2016 OI Zhang, Ying/0000-0002-8045-3821 FU Indiana University; Biocomplexity Institute at Indiana University; National Institutes of Health [NIGMS R01-GM76692, R01-GM077138]; EPA; Brazilian agencies Conselho Nacional de Pesquisa e Desenvolvimento (CNPq); Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS) [PRONEX-10/0008-0] FX The authors acknowledge support from Indiana University and The Biocomplexity Institute at Indiana University and National Institutes of Health grants NIGMS R01-GM76692 and R01-GM077138 and The EPA grant "Texas-Indiana Virtual STAR Center.'' GLT acknowledges support from the Brazilian agencies Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) and Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS) under the grant PRONEX-10/0008-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 11 Z9 11 U1 2 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2011 VL 6 IS 10 AR e24999 DI 10.1371/journal.pone.0024999 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900004 PM 22028771 ER PT J AU Bhaumik, P Xiao, HG Hidaka, K Gustchina, A Kiso, Y Yada, RY Wlodawer, A AF Bhaumik, Prasenjit Xiao, Huogen Hidaka, Koushi Gustchina, Alla Kiso, Yoshiaki Yada, Rickey Y. Wlodawer, Alexander TI Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum SO BIOCHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURES; ACTIVE-SITE; PLASMEPSIN-II; HISTOASPARTIC PROTEASE; PORCINE PEPSINOGEN; PROTEINASE ZYMOGEN; CATALYTIC SITE; MECHANISM; MALARIA; ALLOPHENYLNORSTATINE AB Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 angstrom resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p-38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A' of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP. C1 [Bhaumik, Prasenjit; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Xiao, Huogen; Yada, Rickey Y.] Univ Guelph, Dept Food Sci, Guelph, ON N1G 2W1, Canada. [Hidaka, Koushi; Kiso, Yoshiaki] Kyoto Pharmaceut Univ, Dept Med Chem, Yamashina Ku, Kyoto 6078412, Japan. [Hidaka, Koushi; Kiso, Yoshiaki] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Yamashina Ku, Kyoto 6078412, Japan. [Hidaka, Koushi; Kiso, Yoshiaki] Kobe Gakuin Univ, Med Chem Lab, Chuo Ku, Kobe, Hyogo 6508586, Japan. [Kiso, Yoshiaki] Nagahama Inst Biosci & Technol, Lab Peptide Sci, Shiga 5260829, Japan. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, MCL Bldg 536,Rm 5, Frederick, MD 21702 USA. EM wlodawer@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Natural Sciences and Engineering Research Council of Canada; Canada Research Chairs Program; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Financial support from the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chairs Program is also gratefully acknowledged.; Diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-ID, located at the Advanced Photon Source. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 55 TC 6 Z9 6 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 18 PY 2011 VL 50 IS 41 BP 8862 EP 8879 DI 10.1021/bi201118z PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830MN UT WOS:000295661200010 PM 21928835 ER PT J AU Yardeni, T Choekyi, T Jacobs, K Ciccone, C Patzel, K Anikster, Y Gahl, WA Kurochkina, N Huizing, M AF Yardeni, Tal Choekyi, Tsering Jacobs, Katherine Ciccone, Carla Patzel, Katherine Anikster, Yair Gahl, William A. Kurochkina, Natalya Huizing, Marjan TI Identification, Tissue Distribution, and Molecular Modeling of Novel Human Isoforms of the Key Enzyme in Sialic Acid Synthesis, UDP-GIcNAc 2-Epimerase/ManNAc Kinase SO BIOCHEMISTRY LA English DT Article ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; SECONDARY STRUCTURE PREDICTION; INCLUSION-BODY MYOPATHY; CRYSTAL-STRUCTURE; BIFUNCTIONAL ENZYME; SUBSTRATE-SPECIFICITY; FRAGMENT DATABASE; GOR-V; BIOSYNTHESIS; DOMAIN AB UDP-GIcNAc 2-epimerase/ManNAc kinase (GNE) catalyzes the first two committed steps in sialic acid synthesis. In addition to the three previously described human GNE isoforms (hGNE1-hGNE3), our database and polymerase chain reaction analysis yielded five additional human isoforms (hGNE4-hGNE8). hGNE1 is the ubiquitously expressed major isoform, while the hGNE2-hGNE8 isoforms are differentially expressed and may act as tissue-specific regulators of sialylation. hGNE2 and hGNE7 display a 31-residue N-terminal extension compared to hGNE1. On the basis of similarities to kinases and helicases, this extension does not seem to hinder the epimerase enzymatic active site. hGNE3 and hGNE8 contain a 55-residue N-terminal deletion and a 50-residue N-terminal extension compared to hGNE1. The size and secondary structures of these fragments are similar, and modeling predicted that these modifications do not affect the overall fold compared to that of hGNE1. However, the epimerase enzymatic activity of GNE3 and GNE8 is likely absent, because the deleted fragment contains important substrate binding residues in homologous bacterial epimerases. hGNE5-hGNE8 have a 53-residue deletion, which was assigned a role in substrate (UDP-GIcNAc) binding. Deletion of this fragment likely eliminates epimerase enzymatic activity. Our findings imply that GNE is subject to evolutionary mechanisms to improve cellular functions, without increasing the number of genes. Our expression and modeling data contribute to elucidation of the complex functional and regulatory mechanisms of human GNE and may contribute to further elucidating the pathology and treatment strategies of the human GNE-opathies sialuria and hereditary inclusion body myopathy. C1 [Yardeni, Tal; Jacobs, Katherine; Ciccone, Carla; Patzel, Katherine; Gahl, William A.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yardeni, Tal; Anikster, Yair] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Choekyi, Tsering; Kurochkina, Natalya] Sch Theoret Modeling, Chevy Chase, MD 20825 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health; School of Theoretical Modeling FX This study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (T.Y., K.J., C.C., K.P., W.A.G., and M.H.) and Research Funds of The School of Theoretical Modeling (T.C. and N.K.). NR 42 TC 12 Z9 12 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 18 PY 2011 VL 50 IS 41 BP 8914 EP 8925 DI 10.1021/bi201050u PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830MN UT WOS:000295661200014 PM 21910480 ER PT J AU Fozzatti, L Lu, CX Kim, DW Park, JW Astapova, I Gavrilova, O Willingham, MC Hollenberg, AN Cheng, SY AF Fozzatti, Laura Lu, Changxue Kim, Dong Wook Park, Jeong Won Astapova, Inna Gavrilova, Oksana Willingham, Mark C. Hollenberg, Anthony N. Cheng, Sheue-yann TI Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE thyroid hormone receptor mutant; mouse models; dominant negative activity ID DOMINANT-NEGATIVE ACTIVITY; BETA-RECEPTOR; MOUSE MODEL; MICE; GENE; TUMORIGENESIS; MUTATIONS; CARCINOMA; MUTANTS; BINDING AB Mutations in the ligand-binding domain of the thyroid hormone receptor beta (TR beta) lead to resistance to thyroid hormone (RTH). These TR beta mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TR beta mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed Thrb(PV) mice (a model of RTH) expressing a human TR beta mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1(Delta ID) mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1 Delta ID, the abnormally elevated thyroid-stimulating hormone and TH levels found in Thrb(PV) mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1 Delta ID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TR beta mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH. C1 [Fozzatti, Laura; Lu, Changxue; Kim, Dong Wook; Park, Jeong Won; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Astapova, Inna; Hollenberg, Anthony N.] Harvard Univ, Sch Med, Beth Israel Med Ctr, Div Endocrinol Metab & Diabet, Boston, MA 02215 USA. [Gavrilova, Oksana] Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Willingham, Mark C.] Wake Forest Univ, Dept Pathol, Winston Salem, NC 27157 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [DK-056123, DK-078090] FX We thank Won Gu Kim of the National Cancer Institute for assistance in statistical analyses using regression models, and the programs from the Statistical Package for the Social Science (http://www-01.ibm.com/software/analytics/spss/). The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by extramural Grants DK-056123 and DK-078090 from the National Institutes of Health (to A.N.H.). NR 27 TC 23 Z9 24 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2011 VL 108 IS 42 BP 17462 EP 17467 DI 10.1073/pnas.1107474108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PP UT WOS:000295975300049 PM 21987803 ER PT J AU Gal, N Kolusheva, S Kedei, N Telek, A Naeem, TA Lewin, NE Lim, L Mannan, P Garfield, SH El Kazzouli, S Sigano, DM Marquez, VE Blumberg, PM Jelinek, R AF Gal, Noga Kolusheva, Sofiya Kedei, Noemi Telek, Andrea Naeem, Taiyabah A. Lewin, Nancy E. Lim, Langston Mannan, Poonam Garfield, Susan H. El Kazzouli, Said Sigano, Dina M. Marquez, Victor E. Blumberg, Peter M. Jelinek, Raz TI N-Methyl-Substituted Fluorescent DAG-Indololactone Isomers Exhibit Dramatic Differences in Membrane Interactions and Biological Activity SO CHEMBIOCHEM LA English DT Article DE diacylglycerol-lactones; FRET; kinases; phorbol esters; vesicles ID PROTEIN-KINASE-C; CONFORMATIONALLY CONSTRAINED ANALOGS; PLASMA-MEMBRANE; PHORBOL ESTERS; DIACYLGLYCEROL; RASGRP3; LACTONES; DOMAINS; DELTA; TRANSLOCATION AB N-methyl-substituted diacylglycerol-indololactones (DAG-indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCa. We present a comprehensive analysis of membrane interactions and biological activities of several DAG-indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG-indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands. C1 [Gal, Noga; Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Kedei, Noemi; Telek, Andrea; Naeem, Taiyabah A.; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Lim, Langston; Mannan, Poonam; Garfield, Susan H.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [El Kazzouli, Said; Sigano, Dina M.; Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Jelinek, R (reprint author), Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. EM razj@bgu.ac.il RI JELINEK, RAZ/F-2023-2012; Sigano, Dina/M-6144-2014; OI Sigano, Dina/0000-0001-7489-9555; jelinek, raz/0000-0002-0336-1384 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005270). NR 30 TC 5 Z9 5 U1 0 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD OCT 17 PY 2011 VL 12 IS 15 BP 2331 EP 2340 DI 10.1002/cbic.201100246 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 845XF UT WOS:000296859900016 PM 23106081 ER PT J AU Zamora-Ros, R Rabassa, M Cherubini, A Urpi-Sarda, M Llorach, R Bandinelli, S Ferrucci, L Andres-Lacueva, C AF Zamora-Ros, Raul Rabassa, Montserrat Cherubini, Antonio Urpi-Sarda, Mireia Llorach, Rafael Bandinelli, Stefania Ferrucci, Luigi Andres-Lacueva, Cristina TI Comparison of 24-h volume and creatinine-corrected total urinary polyphenol as a biomarker of total dietary polyphenols in the Invecchiare InCHIANTI study SO ANALYTICA CHIMICA ACTA LA English DT Article DE Polyphenols; Urine 24-h; Creatinine normalization; Biomarker; InCHIANTI study ID GLOMERULAR-FILTRATION-RATE; RESVERATROL METABOLITES; PHENOLIC-ACIDS; VEGETABLES; FRUITS; FLAVONOIDS; EXCRETION; QUESTIONNAIRE; POPULATION; CLEARANCE AB Polyphenols have beneficial effects on several chronic diseases but assessing polyphenols intake from self-reported dietary questionnaires tends to be inaccurate and not very reliable. A promising alternative is to use urinary excretion of polyphenols as a proxy measure of intake. The best method to assess urinary excretion is to collect 24-h urine. However, since collecting 24-h urine method is expensive, time consuming and may be difficult to implement in large population-based studies, measures obtained from spot urine normalized by creatinine are commonly used. The purpose of the study was to evaluate the correlation between polyphenols dietary intake and total urinary polyphenol excretion (TPE), expressed by both 24-h volume and urinary creatinine normalization in 928 participants from the InCHIANTI study. Dietary intake data were collected using a validated food frequency questionnaire. Urinary TPE was analyzed by Folin-Ciocalteau assay. Both urinary TPE expression models were statistically correlated (r = 0.580), and the partial correlation coefficient improved (pr = 0.722) after adjusting for the variables that modify the urinary creatinine excretion (i.e. gender, age, BMI, physical activity and renal function). In crude models, polyphenol intake was associated with TPE corrected by 24-h volume (r = 0.211; P < 0.001), but not with creatinine normalization (r = 0.014; P = 0.692). However, urinary TPE expressed by creatinine correction was significantly correlated with dietary polyphenols after adjusting for covariates (pr = 0.113; P = 0.002). We conclude that urinary TPE expressed by 24-h volume is a better biomarker of polyphenol dietary intake than by urinary creatinine normalization. After covariate adjustment, both can be used for studying the relationships between polyphenol intake and health in large-scale epidemiological studies. (C) 2011 Elsevier B.V. All rights reserved. C1 [Cherubini, Antonio] Univ Perugia, Inst Gerontol & Geriatr, Dept Clin & Expt Med, Sch Med, I-06100 Perugia, Italy. [Zamora-Ros, Raul; Rabassa, Montserrat; Urpi-Sarda, Mireia; Llorach, Rafael; Andres-Lacueva, Cristina] Univ Barcelona, Nutr & Food Sci Dept, Sch Pharm,XaRTA INSA, INGENIO CONSOLIDER Program, E-08028 Barcelona, Spain. [Zamora-Ros, Raul] IDIBELL, Catalan Inst Oncol, Unit Nutr Environm & Canc, Canc Epidemiol Res Programme, Barcelona, Spain. [Urpi-Sarda, Mireia] Hosp Clin Barcelona, Dept Internal Med, Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr 06 03, E-08036 Barcelona, Spain. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Cherubini, A (reprint author), Univ Perugia, Inst Gerontol & Geriatr, Dept Clin & Expt Med, Sch Med, I-06100 Perugia, Italy. EM acherub@unipg.it RI llorach, rafael/D-4729-2014; Urpi-Sarda, Mireia/D-5937-2013; Andres-Lacueva, Cristina/J-3377-2012; OI llorach, rafael/0000-0002-5215-4445; Urpi-Sarda, Mireia/0000-0002-4064-5175; Andres-Lacueva, Cristina/0000-0002-8494-4978; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health; United States National Institute on Aging (NIA); Spanish Ministry of Science and Innovation [FUN-C-Food CSD2007-063, AGL2009-13906-C02-01]; ISCIII [CD09/00134]; [CD09/00133] FX The InCHIANTI study is supported in part by the Italian Ministry of Health and by the United States National Institute on Aging (NIA). This study was also supported by grants from the Spanish Ministry of Science and Innovation (Ingenio-CONSOLIDER program, FUN-C-Food CSD2007-063; and AGL2009-13906-C02-01), R.Ll. thanks to the Ramon y Cajal program from this Ministry and Fondo Social Europeo (FSE). R.Z.-R. and M.U.-S. are grateful to the Spanish postdoctoral program Sara Borrell from this Ministry and ISCIII (CD09/00133 and CD09/00134, respectively). NR 40 TC 26 Z9 26 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD OCT 17 PY 2011 VL 704 IS 1-2 BP 110 EP 115 DI 10.1016/j.aca.2011.07.035 PG 6 WC Chemistry, Analytical SC Chemistry GA 845LQ UT WOS:000296824600011 PM 21907027 ER PT J AU Hogerkorp, CM Nishimura, Y Song, KM Martin, MA Roederer, M AF Hogerkorp, Carl-Magnus Nishimura, Yoshiaki Song, Kaimei Martin, Malcolm A. Roederer, Mario TI The Simian Immunodeficiency Virus Targets Central Cell Cycle Functions through Transcriptional Repression In vivo SO PLOS ONE LA English DT Article ID CD4(+) T-CELLS; GENE-EXPRESSION PROFILES; BLOOD MONONUCLEAR-CELLS; HUMAN PERIPHERAL-BLOOD; TOLL-LIKE RECEPTOR; IMMUNE ACTIVATION; TYPE-1 INFECTION; HIV-1 INFECTION; DENDRITIC CELLS; INDUCIBLE GENES AB A massive and selective loss of CD4+ memory T cells occurs during the acute phase of immunodeficiency virus infections. The mechanism of this depletion is poorly understood but constitutes a key event with implications for progression. We assessed gene expression of purified T cells in Rhesus Macaques during acute SIVmac239 infection in order to define mechanisms of pathogenesis. We observe a general transcriptional program of over 1,600 interferon- stimulated genes induced in all T cells by the infection. Furthermore, we identify 113 transcriptional changes that are specific to virally infected cells. A striking downregulation of several key cell cycle regulator genes was observed and shared promotor-region E2F binding sites in downregulated genes suggested a targeted transcriptional control of an E2F regulated cell cycle program. In addition, the upregulation of the gene for the fundamental regulator of RNA polymerase II, TAF7, demonstrates that viral interference with the cell cycle and transcriptional regulation programs may be critical components during the establishment of a pathogenic infection in vivo. C1 [Hogerkorp, Carl-Magnus; Song, Kaimei; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nishimura, Yoshiaki; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Hogerkorp, CM (reprint author), Novo Nordisk AS, Dept Mol Genet, Malov, Denmark. EM CMGH@novonordisk.com; Roederer@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) FX All work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2011 VL 6 IS 10 AR e25684 DI 10.1371/journal.pone.0025684 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834SM UT WOS:000295984400018 PM 22043290 ER PT J AU Singleton, A Hardy, J AF Singleton, Andrew Hardy, John TI A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci SO HUMAN MOLECULAR GENETICS LA English DT Review ID FAMILIAL PARKINSONS-DISEASE; GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; COMPLEX DISEASES; RARE VARIANTS; MUTATIONS; SUSCEPTIBILITY AB The dominant and sometimes competing theories for the aetiology of complex human disease have been the common disease, common variant (CDCV) hypothesis, and the multiple rare variant (MRV) hypothesis. With the advent of genome wide association studies and of second-generation sequencing, we are fortunate in being able to test these ideas. The results to date suggest that these hypotheses are not mutually exclusive. Further, initial evidence suggests that both MRV and CDCV can be true at the same loci, and that other disease-related genetic mechanisms also exist at some of these loci. We propose calling these, pleomorphic risk loci, and discuss here how such loci not only offer understanding of the genetic basis of disease, but also provide mechanistic biological insight into disease processes. C1 [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM j.hardy@ion.ucl.ac.uk RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000957-07]; Wellcome Trust; MRC 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 AG000957-07 (A.S.) and by the Wellcome Trust and MRC (J.H.). NR 34 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2011 VL 20 SI 2 BP R158 EP R162 DI 10.1093/hmg/ddr358 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 893FI UT WOS:000300340600007 PM 21875901 ER PT J AU Li, CY Zhou, WZ Zhang, PW Johnson, C Wei, LP Uhl, GR AF Li, Chuan-Yun Zhou, Wei-Zhen Zhang, Ping-Wu Johnson, Catherine Wei, Liping Uhl, George R. TI Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction SO BMC GENOMICS LA English DT Article ID MOLECULAR-GENETICS; NICOTINE DEPENDENCE; SYSTEMATIC METAANALYSES; INTERACTION DATABASE; ALCOHOL DEPENDENCE; SMOKING-CESSATION; 2008 UPDATE; ASSOCIATION; EXPRESSION; DISEASE AB Background: Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results: Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions: These results appear to offer new insights into the genetic factors underlying drug addiction. C1 [Li, Chuan-Yun] Peking Univ, Inst Mol Med, Lab Bioinformat & Genom Med, Beijing 100871, Peoples R China. [Li, Chuan-Yun; Zhou, Wei-Zhen; Wei, Liping] Peking Univ, Coll Life Sci, Natl Lab Prot Engn & Plant Genet Engn, Ctr Bioinformat, Beijing 100871, Peoples R China. [Zhang, Ping-Wu] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Johnson, Catherine; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, IRP, Bethesda, MD 20892 USA. RP Li, CY (reprint author), Peking Univ, Inst Mol Med, Lab Bioinformat & Genom Med, Beijing 100871, Peoples R China. EM lichuanyun@gmail.com FU National Basic Research Program of China [2011CB518000]; National Natural Science Foundation of China [31171269]; NIH IRP (NIDA); China National High-tech 863 Programs [2007AA02Z165]; 973 Programs [2007CB946904]; Merck FX We thank Dr. Antonio M. Persico at University Campus, Ms. Xiao-Mo Li at Peking University and Dr. Yong Zhang at the University of Chicago for insightful suggestions. All five pooling-based GWAS datasets used in the meta-analyses came from the Molecular Neurobiology Branch, NIH-IRP (NIDA) led by Dr. George Uhl. We acknowledge support to CYL from the National Basic Research Program of China [2011CB518000], The National Natural Science Foundation of China [31171269] and a scholarship in NIH IRP (NIDA), and support to LW from China National High-tech 863 Programs [2007AA02Z165] and 973 Programs [2007CB946904] and a Merck scholarship. NR 64 TC 14 Z9 14 U1 3 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 15 PY 2011 VL 12 AR 508 DI 10.1186/1471-2164-12-508 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 847IB UT WOS:000296965500001 PM 21999673 ER PT J AU Park, JE Erikson, RL Lee, KS AF Park, Jung-Eun Erikson, Raymond L. Lee, Kyung S. TI A self-propelled biological process Plk1-dependent, product-activated feedforward mechanism SO CELL CYCLE LA English DT Editorial Material ID MOTIF C1 [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Erikson, Raymond L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2011 VL 10 IS 20 BP 3411 EP 3412 DI 10.4161/cc.10.20.17522 PG 2 WC Cell Biology SC Cell Biology GA 842DR UT WOS:000296570700002 ER PT J AU McCulley, J Myung, K AF McCulley, Jennifer Myung, Kyungjae TI Multiple roles of ELG1 with different interactions determine various cellular processes Comment on: Parnas O, et al. Cell Cycle 2011; 10:2894-903 SO CELL CYCLE LA English DT Editorial Material ID S-PHASE; PCNA; SUBUNIT; COMPLEX C1 [McCulley, Jennifer; Myung, Kyungjae] NHGRI, NIH, Bethesda, MD 20892 USA. RP McCulley, J (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM kmyung@mail.nih.gov NR 9 TC 1 Z9 1 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 OCT 15 PY 2011 VL 10 IS 20 BP 3434 EP 3434 DI 10.4161/cc.10.20.17670 PG 1 WC Cell Biology SC Cell Biology GA 842DR UT WOS:000296570700018 PM 22024927 ER PT J AU FitzGerald, DJ Wayne, AS Kreitman, RJ Pastan, I AF FitzGerald, David J. Wayne, Alan S. Kreitman, Robert J. Pastan, Ira TI Treatment of Hematologic Malignancies with Immunotoxins and Antibody-Drug Conjugates SO CANCER RESEARCH LA English DT Review ID ACUTE MYELOID-LEUKEMIA; T-CELL LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; PHASE-II TRIAL; RECOMBINANT IMMUNOTOXIN; GEMTUZUMAB OZOGAMICIN; DENILEUKIN DIFTITOX; CYTOTOXIC ACTIVITY; RFB4(DSFV)-PE38 BL22 AB To enable antibodies to function as cytotoxic anticancer agents, they are modified either via attachment to protein toxins or highly potent, low-molecular-weight drugs. Such molecules, termed immunotoxins and antibody-drug conjugates, respectively, represent a second revolution in antibody-mediated cancer therapy. Thus, highly toxic compounds are delivered to the interior of cancer cells based on antibody specificity for cell-surface target antigens. Cancer Res; 71( 20); 6300-9. (C) 2011 AACR. C1 [FitzGerald, David J.; Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU NIH, NCI, Center for Cancer Research; MedImmune, LLC FX This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and under a Cooperative Research and Development Agreement with MedImmune, LLC. NR 76 TC 72 Z9 74 U1 2 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2011 VL 71 IS 20 BP 6300 EP 6309 DI 10.1158/0008-5472.CAN-11-1374 PG 10 WC Oncology SC Oncology GA 836WT UT WOS:000296148900002 PM 21998010 ER PT J AU Matsumoto, S Batra, S Saito, K Yasui, H Choudhuri, R Gadisetti, C Subramanian, S Devasahayam, N Munasinghe, JP Mitchell, JB Krishna, MC AF Matsumoto, Shingo Batra, Sonny Saito, Keita Yasui, Hironobu Choudhuri, Rajani Gadisetti, Chandramouli Subramanian, Sankaran Devasahayam, Nallathamby Munasinghe, Jeeva P. Mitchell, James B. Krishna, Murali C. TI Antiangiogenic Agent Sunitinib Transiently Increases Tumor Oxygenation and Suppresses Cycling Hypoxia SO CANCER RESEARCH LA English DT Article ID ANTI-ANGIOGENIC THERAPY; VASCULAR NORMALIZATION; FREE-RADICALS; RADIATION; REOXYGENATION; MICROENVIRONMENT; INHIBITION; IMPACT; CANCER; MICE AB Structural and functional abnormalities in tumor blood vessels impact the delivery of oxygen and nutrients to solid tumors, resulting in chronic and cycling hypoxia. Although chronically hypoxic regions exhibit treatment resistance, more recently it has been shown that cycling hypoxic regions acquire prosurvival pathways. Angiogenesis inhibitors have been shown to transiently normalize the tumor vasculatures and enhance tumor response to treatments. However, the effect of antiangiogenic therapy on cycling tumor hypoxia remains unknown. Using electron paramagnetic resonance imaging and MRI in tumor-bearing mice, we have examined the vascular renormalization process by longitudinally mapping tumor partial pressure of oxygen (pO(2)) and microvessel density during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation was visualized by electron paramagnetic resonance imaging 2 to 4 days following antiangiogenic treatments, accompanied by a 45% decrease in microvessel density. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth. In addition, dynamic oxygen imaging obtained every 3 minutes was conducted to distinguish tumor regions with chronic and cycling hypoxia. Sunitinib treatment suppressed the extent of temporal fluctuations in tumor pO(2) during the vascular normalization window, resulting in the decrease of cycling tumor hypoxia. Overall, the findings suggest that longitudinal and noninvasive monitoring of tumor pO(2) makes it possible to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs. Cancer Res; 71(20); 6350-9. (C) 2011 AACR. C1 [Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva P.] Natl Inst Neurol Disorder & Stroke, NIH, Bethesda, MD USA. [Batra, Sonny] NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. [Yasui, Hironobu] Hokkaido Univ, Grad Sch Vet Med, Dept Environm Vet Sci, Lab Radiat Biol, Sapporo, Hokkaido, Japan. [Gadisetti, Chandramouli] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Yasui, Hironobu/E-3794-2010 FU Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 34 TC 44 Z9 47 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2011 VL 71 IS 20 BP 6350 EP 6359 DI 10.1158/0008-5472.CAN-11-2025 PG 10 WC Oncology SC Oncology GA 836WT UT WOS:000296148900007 PM 21878530 ER PT J AU Teicher, BA Chari, RVJ AF Teicher, Beverly A. Chari, Ravi V. J. TI Antibody Conjugate Therapeutics: Challenges and Potential SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; MULTIPLE-MYELOMA CELLS; CARBONIC-ANHYDRASE-IX; IN-VIVO ACTIVITY; DRUG CONJUGATE; CANCER-THERAPY; INOTUZUMAB OZOGAMICIN; MONOCLONAL-ANTIBODIES; ANTITUMOR-ACTIVITY; PHASE-II AB Antibody conjugates are a diverse class of therapeutics consisting of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates is marked by hurdles that have been identified and overcome. Early conjugates used mouse antibodies; cytotoxic agents that were immunogenic (proteins), too toxic, or not sufficiently potent; and linkers that were not sufficiently stable in circulation. Investigators have explored 4 main avenues using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small-molecule drug conjugates, and antibody-enzyme conjugates administered along with small-molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and nearly 20 antibody conjugates are currently in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for cancer patients. Clin Cancer Res; 17(20); 6389-97. (C) 2011 AACR. C1 [Chari, Ravi V. J.] ImmunoGen Inc, Waltham, MA USA. [Teicher, Beverly A.] NCI, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. RP Teicher, BA (reprint author), NCI, Mol Pharmacol Branch, Dev Therapeut Program, MSC 7458,Room 8156,6130 Execut Blvd, Rockville, MD 20852 USA. EM Beverly.Teicher@nih.gov NR 86 TC 136 Z9 145 U1 5 U2 56 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2011 VL 17 IS 20 BP 6389 EP 6397 DI 10.1158/1078-0432.CCR-11-1417 PG 9 WC Oncology SC Oncology GA 839IR UT WOS:000296359400005 PM 22003066 ER PT J AU Kreitman, RJ Pastan, I AF Kreitman, Robert J. Pastan, Ira TI Antibody Fusion Proteins: Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox SO CLINICAL CANCER RESEARCH LA English DT Article ID PSEUDOMONAS EXOTOXIN-A; SINGLE-CHAIN IMMUNOTOXIN; B-CELL MALIGNANCIES; PHASE-I TRIAL; RFB4(DSFV)-PE38 BL22; CYTOTOXIC ACTIVITY; DIPHTHERIA-TOXIN; HEMATOLOGIC MALIGNANCIES; COMPLETE REGRESSION; DISULFIDE BONDS AB Recombinant immunotoxins are fusion proteins that contain the cytotoxic portion of a protein toxin fused to the Fv portion of an antibody. The Fv binds to an antigen on a target cell and brings the toxin into the cell interior, where it arrests protein synthesis and initiates the apoptotic cascade. Moxetumomab pasudotox, previously called HA22 or CAT-8015, is a recombinant immunotoxin composed of the Fv fragment of an antiCD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. Moxetumomab pasudotox is an improved, more active form of a predecessor recombinant immunotoxin, BL22 (also called CAT-3888), which produced complete remission in relapsed/refractory hairy cell leukemia(HCL), but it had a < 20% response rate in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), diseases in which the leukemic cells contain much lower numbers of CD22 target sites. Compared with BL22, moxetumomab pasudotox is up to 50-fold more active on lymphoma cell lines and leukemic cells from patients with CLL and HCL. A phase I trial was recently completed in HCL patients, who achieved response rates similar to those obtained with BL22 but without dose-limiting toxicity. In addition to further testing in HCL, moxetumomab pasudotox is being evaluated in phase I trials in patients with CLL, B-cell lymphomas, and childhood ALL. Moreover, protein engineering is being used to increase its activity, decrease nonspecific side effects, and remove B-cell epitopes. Clin Cancer Res; 17(20); 6398-405. (C) 2011 AACR. C1 [Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU National Cancer Institute; MedImmune, LLC. FX National Cancer Institute Intramural Program; development of BL22 and moxetumomab was supported in part by MedImmune, LLC. NR 61 TC 70 Z9 71 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2011 VL 17 IS 20 BP 6398 EP 6405 DI 10.1158/1078-0432.CCR-11-0487 PG 8 WC Oncology SC Oncology GA 839IR UT WOS:000296359400006 PM 22003067 ER PT J AU Katz, J Janik, JE Younes, A AF Katz, Jessica Janik, John E. Younes, Anas TI Brentuximab Vedotin (SGN-35) SO CLINICAL CANCER RESEARCH LA English DT Article ID LARGE-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; PHASE-I/II; IDEC-Y2B8 RADIOIMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; I-131 TOSITUMOMAB; T-CELLS; CD30; DISEASE; IMMUNOCONJUGATE AB Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed-Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration. Clin Cancer Res; 17(20); 6428-36. (C) 2011 AACR. C1 [Katz, Jessica] Lankenau Med Ctr, Dept Hematol Oncol, Wynnewood, PA USA. [Katz, Jessica] Lankenau Inst Med Res, Wynnewood, PA USA. [Janik, John E.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Younes, Anas] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Janik, JE (reprint author), Route 206 & Prov Line Rd, Lawrenceville, NJ 08543 USA. EM john.janik@bms.com FU Seattle Genetics FX Drs. Katz and Janik are employed by Bristol-Myers Squibb. Dr. Younes received research support and hororaria from Seattle Genetics. The opinions expressed reflect those of the authors. NR 48 TC 116 Z9 121 U1 3 U2 19 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2011 VL 17 IS 20 BP 6428 EP 6436 DI 10.1158/1078-0432.CCR-11-0488 PG 9 WC Oncology SC Oncology GA 839IR UT WOS:000296359400009 PM 22003070 ER PT J AU Tarhini, AA Frankel, P Margolin, KA Christensen, S Ruel, C Shipe-Spotloe, J Gandara, DR Chen, A Kirkwood, JM AF Tarhini, Ahmad A. Frankel, Paul Margolin, Kim A. Christensen, Scott Ruel, Christopher Shipe-Spotloe, Janice Gandara, David R. Chen, Alice Kirkwood, John M. TI Aflibercept (VEGF Trap) in Inoperable Stage III or Stage IV Melanoma of Cutaneous or Uveal Origin SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED PHASE-III; MALIGNANT-MELANOMA; CANCER-PATIENTS; TUMOR ANGIOGENESIS; COLORECTAL-CANCER; BEVACIZUMAB; HYPERTENSION; PACLITAXEL; TRIAL AB Purpose: Aflibercept is a soluble decoy VEGF receptor and angiogenesis inhibitor with potent preclinical antitumor activity in melanoma. We conducted a multicenter phase II study in patients with inoperable stage III or IV melanoma and no prior chemotherapy. Experimental Design: A two-stage design was adopted to evaluate 4-month progression-free survival rate (PFSR) and response rate. Aflibercept was given at 4 mg/kg intravenously every 2 weeks. Response was assessed every 8 weeks. First-stage accrual of 21 patients was specified and with an adequate 4-month PFSR accrual continued to a total of 41. Results: Forty-one patients of ages 23 to 84 (median = 57) were enrolled. Thirty-nine had American Joint Committee on Cancer stage IV (5 M1a, 7 M1b, and 27 M1c) and 2 had inoperable stage IIIC (N3). Eastern Cooperative Oncology Group (ECOG) performance status was 0 (27 patients) or 1 (14 patients). Ten patients had primary uveal melanoma, 28 cutaneous, and 3 had unknown primaries. A median of 7 cycles were initiated (range: 1-56). Grade 3 and 4 toxicities included hypertension in 9 patients (22%) and proteinuria in 6 (15%). Among 40 patients evaluable for efficacy (those who initiated aflibercept), 3 (7.5%) had a confirmed partial response and 20 had progression-free survival of 4 months or above. The predicted 1-year survival rate derived from the Korn meta-analysis model is 36% (N = 39), whereas we observed a corresponding 56.4% survival rate at 1 year (95% CI, 43-74, P < 0.005). Median overall survival in this trial is 16.3 months (95% CI, 9.2 to not reached). We observed a significant association between severity of hypertension following aflibercept and survival improvement. Conclusions: Aflibercept showed promising activity in patients with metastatic melanoma of cutaneous or uveal origin. Further evaluation of aflibercept as a single agent and in combination is warranted. Clin Cancer Res; 17(20); 6574-81. (C) 2011 AACR. C1 [Tarhini, Ahmad A.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA. [Frankel, Paul; Ruel, Christopher] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Margolin, Kim A.] Univ Washington, Seattle, WA 98195 USA. [Christensen, Scott; Gandara, David R.] UC Davis Canc Ctr, Sacramento, CA USA. [Chen, Alice] NCI, Rockville, MD USA. RP Tarhini, AA (reprint author), Univ Pittsburgh, Inst Canc, UPMC Canc Pavil,5150 Ctr Ave,5th Floor, Pittsburgh, PA 15232 USA. EM tarhiniaa@upmc.edu FU National Cancer Institute (California and Pittsburgh Cancer Consortium), Sanofi-Aventis, and Regeneron FX This investigator initiated study was supported by the National Cancer Institute (NO1 grant; California and Pittsburgh Cancer Consortium), Sanofi-Aventis, and Regeneron. NR 41 TC 29 Z9 29 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2011 VL 17 IS 20 BP 6574 EP 6581 DI 10.1158/1078-0432.CCR-11-1463 PG 8 WC Oncology SC Oncology GA 839IR UT WOS:000296359400023 PM 21880788 ER PT J AU Nahid, P Saukkonen, J Mac Kenzie, WR Johnson, JL Phillips, PPJ Andersen, J Bliven-Sizemore, E Belisle, JT Boom, WH Luetkemeyer, A Campbell, TB Eisenach, KD Hafner, R Lennox, JL Makhene, M Swindells, S Villarino, ME Weiner, M Benson, C Burman, W AF Nahid, Payam Saukkonen, Jussi Mac Kenzie, William R. Johnson, John L. Phillips, Patrick P. J. Andersen, Janet Bliven-Sizemore, Erin Belisle, John T. Boom, W. Henry Luetkemeyer, Annie Campbell, Thomas B. Eisenach, Kathleen D. Hafner, Richard Lennox, Jeffrey L. Makhene, Mamodikoe Swindells, Susan Villarino, M. Elsa Weiner, Marc Benson, Constance Burman, William TI Tuberculosis Biomarker and Surrogate Endpoint Research Roadmap SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID CLINICAL-TRIALS; TREATMENT RESPONSE; DISEASE-ACTIVITY; RELAPSE; DRUGS; PROGRESS; THERAPY; URINE; CURE AB The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation of a specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation. C1 [Nahid, Payam] Univ Calif San Francisco, San Francisco Gen Hosp, Div Pulm & Crit Care, Curry Int TB Ctr, San Francisco, CA 94110 USA. [Saukkonen, Jussi] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Mac Kenzie, William R.; Bliven-Sizemore, Erin; Villarino, M. Elsa] Ctr Dis Control & Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Div TB Eliminat, Clin Res Branch, Atlanta, GA USA. [Johnson, John L.; Boom, W. Henry] Case Western Reserve Univ, Div Infect Dis, Dept Med, TB Res Unit, Cleveland, OH 44106 USA. [Phillips, Patrick P. J.] British Med Res Council Clin Trials Unit, London, England. [Andersen, Janet] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Belisle, John T.] Colorado State Univ, Mycobacteria Res Labs, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Luetkemeyer, Annie] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA 94110 USA. [Campbell, Thomas B.] Univ Colorado, Dept Med, Div Infect Dis, Denver, CO USA. [Eisenach, Kathleen D.] Univ Arkansas Med Sci, Dept Microbiol, Little Rock, AR 72205 USA. [Eisenach, Kathleen D.] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. [Hafner, Richard] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Lennox, Jeffrey L.] Emory Univ, Sch Med, Dept Internal Med, Div Infect Dis, Atlanta, GA USA. [Makhene, Mamodikoe] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Swindells, Susan] Univ Nebraska Med Ctr, Dept Internal Med, Div Infect Dis, Omaha, NE USA. [Weiner, Marc] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Benson, Constance] Univ Calif San Diego, San Diego Sch Med, Div Infect Dis, San Diego, CA 92103 USA. [Burman, William] Denver Publ Hlth, Denver, CO USA. RP Nahid, P (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div Pulm & Crit Care, Curry Int TB Ctr, 1001 Potrero Ave,5K1, San Francisco, CA 94110 USA. EM pnahid@ucsf.edu RI Mac Kenzie, William /F-1528-2013; Lennox, Jeffrey/D-1654-2014; Belisle, John/B-8944-2017; OI Mac Kenzie, William /0000-0001-7723-0339; Lennox, Jeffrey/0000-0002-2064-5565; Belisle, John/0000-0002-2539-2798; Phillips, Patrick/0000-0002-6336-7024 FU National Institutes of Health through National Heart, Lung, and Blood Institute [K23HL092629]; National Institute of Allergy and Infectious Diseases [AI068636, AI068634]; Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, Tuberculosis Trials Consortium FX Supported partially by the National Institutes of Health through National Heart, Lung, and Blood Institute funding K23HL092629 (P.N.), National Institute of Allergy and Infectious Diseases funding AI068636 (A. L., T. B. C., J.L.L., S. S. and C. B.) and AI068634 (J.A.), and also through the Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, Tuberculosis Trials Consortium. NR 33 TC 26 Z9 26 U1 1 U2 7 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 OCT 15 PY 2011 VL 184 IS 8 BP 972 EP 979 DI 10.1164/rccm.201105-0827WS PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 835PG UT WOS:000296047700018 PM 21737585 ER PT J AU Shim, MS Kim, JY Lee, KH Jung, HK Carlson, BA Xu, XM Hatfield, DL Lee, BJ AF Shim, Myoung Sup Kim, Jin Young Lee, Kwang Hee Jung, Hee Kyoung Carlson, Bradley A. Xu, Xue-Ming Hatfield, Dolph L. Lee, Byeong Jae TI 1(2)01810 is a novel type of glutamate transporter that is responsible for megamitochondrial formation SO BIOCHEMICAL JOURNAL LA English DT Article DE glutamate transporter; 1(2)01810; megamitochondrion; nutritional stress; signal peptide ID HUMAN CYSTINE/GLUTAMATE TRANSPORTER; INORGANIC-PHOSPHATE COTRANSPORTER; AMINO-ACID TRANSPORTERS; CAENORHABDITIS-ELEGANS; MOLECULAR-CLONING; GLIOMA-CELLS; FUNCTIONAL-CHARACTERIZATION; DROSOPHILA-MELANOGASTER; PLASMA-MEMBRANE; SYSTEM X(C)(-) AB 1(2)01810 causes glutamine-,dependent megamitochondrial formation when it is overexpressed in Drosophila cells. In the present study, we elucidated the function of 1(2)01810 during megamitochondrial formation. The overexpression of 1(2)01810 and. the inhibition of glutamine synthesis showed that 1(2)01810 is involved in the accumulation of glutamate. 1(2)01810 was predicted to contain transmembrane domains and was found to be localized to the plasma membrane. By using 14C-labelled glutamate, 1(2)01810 was confirmed to uptake glutamate into Drosophila cells with high affinity (K(m) = 69.4 mu M). Also, 1(2)01810 uptakes glutamate in a Na(+)-independent manner. Interestingly, however, this uptake was not inhibited by cystine, which is a competitive inhibitor of Na(+)-independent glutamate transporters, but by aspartate. A signal peptide consisting of 34 amino acid residues targeting to endoplasmic reticulum was predicted at the N-terminus of 1(2)01810 and this signal peptide is essential for the protein's localization to the plasma membrane. In addition, 1(2)01810 has a conserved functional domain of a vesicular-type glutamate transporter, and Arg(146) in this domain was found to play a key role in glutamate transport and megamitochondrial formation. These results indicate that 1(2)01810 is a novel type of glutamate transporter and that glutamate uptake is a rate-limiting step for megamitochondrial formation. C1 [Shim, Myoung Sup; Kim, Jin Young; Lee, Kwang Hee; Jung, Hee Kyoung; Lee, Byeong Jae] Seoul Natl Univ, Lab Mol Genet & Genom, Sch Biol Sci, Inst Mol Biol & Genet, Seoul 151742, South Korea. [Carlson, Bradley A.; Xu, Xue-Ming; Hatfield, Dolph L.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Lab Mol Genet & Genom, Sch Biol Sci, Inst Mol Biol & Genet, Seoul 151742, South Korea. EM imbglmg@snu.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2009-0094020, 2011-0012947]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Korea Ministry of Education and Human Resources Development FX This work was supported by the Priority Research Centers Program and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant numbers 2009-0094020 and 2011-0012947 (to B.J.L.)] and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. M.S.S., J.Y.K., K.H.L. and H.K.J. were supported by a Brain Korea 21 Research Fellowship from the Korea Ministry of Education and Human Resources Development. NR 60 TC 3 Z9 3 U1 0 U2 3 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD OCT 15 PY 2011 VL 439 BP 277 EP 286 DI 10.1042/BJ20110582 PN 2 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836PO UT WOS:000296123800010 PM 21728998 ER PT J AU Zhang, XD Santini, F Lacson, R Marine, SD Wu, Q Benetti, L Yang, RJ McCampbell, A Berger, JP Toolan, DM Stec, EM Holder, DJ Soper, KA Heyse, JF Ferrer, M AF Zhang, Xiaohua Douglas Santini, Francesca Lacson, Raul Marine, Shane D. Wu, Qian Benetti, Luca Yang, Ruojing McCampbell, Alex Berger, Joel P. Toolan, Dawn M. Stec, Erica M. Holder, Daniel J. Soper, Keith A. Heyse, Joseph F. Ferrer, Marc TI cSSMD: assessing collective activity for addressing off-target effects in genome-scale RNA interference screens SO BIOINFORMATICS LA English DT Article ID FALSE NONDISCOVERY RATES; MEDIATED ENDOCYTOSIS; HIT SELECTION; REVEALS; GENE; DISCOVERY; POSITIVES; CELLS AB Motivation: Off-target activity commonly exists in RNA interference (RNAi) screens and often generates false positives. Existing analytic methods for addressing the off-target effects are demonstrably inadequate in RNAi confirmatory screens. Results: Here, we present an analytic method assessing the collective activity of multiple short interfering RNAs (siRNAs) targeting a gene. Using this method, we can not only reduce the impact of off-target activities, but also evaluate the specific effect of an siRNA, thus providing information about potential off-target effects. Using in-house RNAi screens, we demonstrate that our method obtains more reasonable and sensible results than current methods such as the redundant siRNA activity (RSA) method, the RNAi gene enrichment ranking (RIGER) method, the frequency approach and the t-test. C1 [Zhang, Xiaohua Douglas; Heyse, Joseph F.] Merck Res Labs, BARDS, West Point, PA 19486 USA. [Santini, Francesca; Lacson, Raul; Marine, Shane D.; Stec, Erica M.] Merck Res Labs, N Wales, PA 19454 USA. [Wu, Qian] Univ Penn, Philadelphia, PA 19104 USA. [Benetti, Luca] Merck Mfg Div, West Point, PA 19486 USA. [Yang, Ruojing; Berger, Joel P.] Merck Res Labs, Rahway, NJ 07065 USA. [Ferrer, Marc] NIH, Chem Genom Ctr, Rockville, MD USA. RP Zhang, XD (reprint author), Merck Res Labs, BARDS, West Point, PA 19486 USA. EM xiaohua_zhang@merck.com RI Wu, Qian/M-2802-2015; OI Wu, Qian/0000-0002-3550-7923; Zhang, Xiaohua Douglas/0000-0002-2486-7931 NR 25 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD OCT 15 PY 2011 VL 27 IS 20 BP 2775 EP 2781 DI 10.1093/bioinformatics/btr474 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 830TR UT WOS:000295680600001 PM 21846737 ER PT J AU Bielejec, F Rambaut, A Suchard, MA Lemey, P AF Bielejec, Filip Rambaut, Andrew Suchard, Marc A. Lemey, Philippe TI SPREAD: spatial phylogenetic reconstruction of evolutionary dynamics SO BIOINFORMATICS LA English DT Article ID PHYLOGEOGRAPHY AB SPREAD is a user-friendly, cross-platform application to analyze and visualize Bayesian phylogeographic reconstructions incorporating spatial-temporal diffusion. The software maps phylogenies annotated with both discrete and continuous spatial information and can export high-dimensional posterior summaries to keyhole markup language (KML) for animation of the spatial diffusion through time in virtual globe software. In addition, SPREAD implements Bayes factor calculation to evaluate the support for hypotheses of historical diffusion among pairs of discrete locations based on Bayesian stochastic search variable selection estimates. SPREAD takes advantage of multicore architectures to process large joint posterior distributions of phylogenies and their spatial diffusion and produces visualizations as compelling and interpretable statistical summaries for the different spatial projections. C1 [Bielejec, Filip; Lemey, Philippe] Katholieke Univ Leuven, Rega Inst Med Res, Clin & Epidemiol Virol Sect, Louvain, Belgium. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. RP Bielejec, F (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Clin & Epidemiol Virol Sect, Louvain, Belgium. EM filip.bielejec@rega.kuleuven.be OI Rambaut, Andrew/0000-0003-4337-3707 FU European Research Council under the European Community [(FP7/2007-2013)/ERC, 260864]; National Institutes of Health [R01 GM086887]; National Evolutionary Synthesis Center (NESCent) [NSF EF-0423641] FX European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 260864; National Institutes of Health (R01 GM086887); The National Evolutionary Synthesis Center (NESCent) catalysed this collaboration through a working group (NSF EF-0423641). NR 10 TC 183 Z9 184 U1 4 U2 36 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD OCT 15 PY 2011 VL 27 IS 20 BP 2910 EP 2912 DI 10.1093/bioinformatics/btr481 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 830TR UT WOS:000295680600021 PM 21911333 ER PT J AU Hayn, MH Orom, H Shavers, VL Sanda, MG Glasgow, M Mohler, JL Underwood, W AF Hayn, Matthew H. Orom, Heather Shavers, Vickie L. Sanda, Martin G. Glasgow, Mark Mohler, James L. Underwood, Willie, III TI Racial/Ethnic Differences in Receipt of Pelvic Lymph Node Dissection Among Men With Localized/Regional Prostate Cancer SO CANCER LA English DT Article DE prostate; prostatic cancer; lymph node excision; African Americans; Hispanic Americans; European Continental Ancestry Group; Surveillance; Epidemiology, and End Results ID RADICAL PROSTATECTOMY; RACIAL-DIFFERENCES; ANATOMICAL EXTENT; AMERICAN MEN; SURVIVAL; LYMPHADENECTOMY; IMPLICIT; QUALITY; ANTIGEN; RACE AB BACKGROUND: Black and Hispanic men have a lower prostate cancer (PCa) survival rate than white men. This racial/ethnic survival gap has been explained in part by differences in tumor characteristics, stage at diagnosis, and disparities in receipt of definitive treatment. Another potential contributing factor is racial/ethnic differences in the timely and accurate detection of lymph node metastases. The current study was conducted to examine the association between race/ethnicity and the receipt of pelvic lymph node dissection (PLND) among men with localized/regional PCa. METHODS: Logistic regression was used to estimate the adjusted odds of undergoing PLND among men who were diagnosed during 2000 to 2002 with PCa, who underwent radical prostatectomy or PLND without radical prostatectomy, and who were diagnosed in regions covered by the Surveillance, Epidemiology, and End Results database (n = 40,848). RESULTS: Black men were less likely to undergo PLND than white men (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.84-0.98). When the analysis was stratified by PCa grade, black men with well differentiated PCa (OR, 0.48; 95% CI, 0.27-0.84) and poorly differentiated PCa (OR, 0.73; 95% CI, 0.60-0.89) were less likely to undergo PLND than their white counterparts, but racial differences were not observed among men with moderately differentiated PCa (OR, 0.96; 95% CI, 0.88-1.05). CONCLUSIONS: Among men with poorly differentiated PCa, failure to undergo PLND was associated with worse survival. Racial disparities in the receipt of PLND, especially among men with poorly differentiated PCa, may contribute to racial differences in prostate cancer survival. Cancer 2011;117:4651-8. (C) 2011 American Cancer Society. C1 [Hayn, Matthew H.; Mohler, James L.; Underwood, Willie, III] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA. [Orom, Heather; Underwood, Willie, III] SUNY Buffalo, Dept Community Hlth & Hlth Behav, Buffalo, NY 14260 USA. [Shavers, Vickie L.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02215 USA. [Sanda, Martin G.] Harvard Univ, Sch Med, Boston, MA USA. [Glasgow, Mark] SUNY Buffalo, Dept Social & Preventat Med, Buffalo, NY 14260 USA. [Underwood, Willie, III] Roswell Pk Canc Inst, Div Canc Prevent & Populat Sci, Off Canc Hlth Dispar Res, Buffalo, NY 14263 USA. RP Underwood, W (reprint author), Roswell Pk Canc Inst, Dept Urol, Elm & Carlton St, Buffalo, NY 14263 USA. EM willie.underwood@roswellpark.org RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015 FU Robert Wood Johnson Harold Amos Career Development Award; Astellas/American Urology Association Foundation; National Institutes of Health [1RC1EB011001-01]; Department of Defense [PC021005] FX This work was supported by a Robert Wood Johnson Harold Amos Career Development Award and an Astellas/American Urology Association Foundation Rising Star in Urology Award (to W.U., III), Grant 1RC1EB011001-01 from the National Institutes of Health (to M.G.S.), and Department of Defense Grant PC021005 (to J.L.M.) NR 44 TC 13 Z9 13 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2011 VL 117 IS 20 BP 4651 EP 4658 DI 10.1002/cncr.26103 PG 8 WC Oncology SC Oncology GA 832IG UT WOS:000295797400012 PM 21456009 ER PT J AU Vire, B David, A Wiestner, A AF Vire, Berengere David, Alexandre Wiestner, Adrian TI TOSO, the Fc mu Receptor, Is Highly Expressed on Chronic Lymphocytic Leukemia B Cells, Internalizes upon IgM Binding, Shuttles to the Lysosome, and Is Downregulated in Response to TLR Activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID O-GLYCOSYLATION SITES; TRANS-GOLGI NETWORK; PROLINE-RICH DOMAIN; TOLL-LIKE RECEPTORS; TRANSFERRIN RECEPTOR; PHENYLARSINE OXIDE; INDUCED APOPTOSIS; IMMUNE-RESPONSES; INHIBITION; ENDOCYTOSIS AB TOSO/FAIM3 recently has been identified as the long-sought-after FcR for IgM (Fc mu R). Fc mu R is expressed on human CD19(+) B cells, CD4(+)/CD8(+) T cells, and CD56(+)/CD3(-) NK cells and has been shown to be overexpressed in chronic lymphocytic leukemia (CLL) cells. CLL is a malignancy of mature IgM(+) B lymphocytes that display features of polyreactive, partially anergized B cells related to memory B cells. In this article, we report that Fc mu R is O-glycosylated in its extracellular domain and identify the major sites of O-glycosylation. By using immunofluorescence confocal microscopy, we found that Fc mu R localized to the cell membrane but also found that large pools of Fc mu R accumulate in the trans-Golgi network. Aggregation of Fc mu R on CLL cells by IgM prompted rapid internalization of both IgM and Fc mu R, reaching half-maximal internalization of cell-bound IgM within 1 min. Upon internalization, Fc mu R transported IgM through the endocytic pathway to the lysosome, where it was degraded. Using a series of Fc mu R deletion mutants, we identified a proline-rich domain essential for cell surface expression of Fc mu R and a second domain, containing a YXX Phi motif, that controls internalization. Although it has been reported that BCR activation increases Fc mu R expression, we found that activation of TLRs strongly downregulated Fc mu R at both the mRNA and protein levels. Through internalization of IgM bound immune complexes, Fc mu R may play a role in immune surveillance and contribute to B cell activation. In addition, Fc mu R deserves study as a potential pathway for the delivery of therapeutic Ab-drug conjugates into CLL cells. The Journal of Immunology, 2011, 187: 4040-4050. C1 [Vire, Berengere; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [David, Alexandre] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov RI David, Alexandre/B-2447-2013 OI David, Alexandre/0000-0003-3365-1339 FU National, Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National, Heart, Lung, and Blood Institute, National Institutes of Health. NR 48 TC 31 Z9 32 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2011 VL 187 IS 8 BP 4040 EP 4050 DI 10.4049/jimmunol.1100532 PG 11 WC Immunology SC Immunology GA 829YN UT WOS:000295623100016 PM 21908732 ER PT J AU Zhou, R Horai, R Mattapallil, MJ Caspi, RR AF Zhou, Ru Horai, Reiko Mattapallil, Mary J. Caspi, Rachel R. TI A New Look at Immune Privilege of the Eye: Dual Role for the Vision-Related Molecule Retinoic Acid SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; GROWTH-FACTOR-BETA; AQUEOUS-HUMOR; IMMUNOSUPPRESSIVE FACTOR; DENDRITIC CELLS; DIFFERENTIATION; FOXP3; INDUCTION; INFLAMMATION AB The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-gamma production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-beta as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-beta and RA were both needed and synergized for Treg conversion by AH, with TGF-beta-enhancing T cell expression of RA receptor alpha. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-za-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment. The Journal of Immunology, 2011, 187: 4170-4177. C1 [Zhou, Ru; Horai, Reiko; Mattapallil, Mary J.; Caspi, Rachel R.] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Room 10N222,10 Ctr Dr,MSC 1857, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU National Eye Institute, National Institutes of Health FX This work was supported by the intramural research grant of National Eye Institute, National Institutes of Health. NR 41 TC 19 Z9 19 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2011 VL 187 IS 8 BP 4170 EP 4177 DI 10.4049/jimmunol.1101634 PG 8 WC Immunology SC Immunology GA 829YN UT WOS:000295623100029 PM 21918194 ER PT J AU Hasko, G Csoka, B Koscso, B Chandra, R Pacher, P Thompson, LF Deitch, EA Spolarics, Z Virag, L Gergely, P Rolandelli, RH Nemeth, ZH AF Hasko, Gyoergy Csoka, Balazs Koscso, Balazs Chandra, Rachna Pacher, Pal Thompson, Linda F. Deitch, Edwin A. Spolarics, Zoltan Virag, Laszlo Gergely, Pal Rolandelli, Rolando H. Nemeth, Zoltan H. TI Ecto-5 '-Nucleotidase (CD73) Decreases Mortality and Organ Injury in Sepsis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID A(2B) ADENOSINE RECEPTORS; NF-KAPPA-B; ISCHEMIA-REPERFUSION INJURY; INDUCED THYMOCYTE APOPTOSIS; MURINE SEPTIC PERITONITIS; ACUTE LUNG INJURY; POLYMICROBIAL SEPSIS; RENAL ISCHEMIA; DEFICIENT MICE; NUCLEOTIDE PHOSPHOHYDROLYSIS AB The extracellular concentrations of adenosine are increased during sepsis, and adenosine receptors regulate the host's response to sepsis. In this study, we investigated the role of the adenosine-generating ectoenzyme, ecto-5'-nucleotidase (CD73), in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury, as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased cleavage of caspase-3 and poly(ADP-ribose) polymerase and increased activation of NF-kappa B. Septic CD73 KO mice had higher blood urea nitrogen levels and increased cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using alpha, beta-methylene ADP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis. The Journal of Immunology, 2011, 187: 4256-4267. C1 [Rolandelli, Rolando H.; Nemeth, Zoltan H.] Morristown Med Ctr, Dept Surg, Morristown, NJ 07960 USA. [Hasko, Gyoergy; Csoka, Balazs; Koscso, Balazs; Chandra, Rachna; Deitch, Edwin A.; Spolarics, Zoltan; Nemeth, Zoltan H.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Hasko, Gyoergy; Virag, Laszlo; Gergely, Pal] Univ Debrecen, Dept Med Chem, Med & Hlth Sci Ctr, H-4032 Debrecen, Hungary. [Pacher, Pal] NIAAA, Bethesda, MD 20892 USA. [Thompson, Linda F.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. RP Nemeth, ZH (reprint author), Morristown Med Ctr, Dept Surg, 100 Madison Ave, Morristown, NJ 07960 USA. EM haskoge@umdnj.edu; zoltan.nemeth@atlantichealth.org RI Virag, Laszlo/E-6124-2010; Gergely, Pal/A-5547-2008; Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health [GM66189, AI18220, GM084932]; National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; Hungarian Research Fund (OTKA) [CK 78275] FX This work was supported by National Institutes of Health Grants GM66189 (G. H.), AI18220 (L. F. T.), and GM084932 (Z.S.), the Intramural Research Program of National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, and the Hungarian Research Fund (OTKA) (CK 78275). NR 78 TC 40 Z9 40 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2011 VL 187 IS 8 BP 4256 EP 4267 DI 10.4049/jimmunol.1003379 PG 12 WC Immunology SC Immunology GA 829YN UT WOS:000295623100038 PM 21918191 ER PT J AU Carregaro, V Sa-Nunes, A Cunha, TM Grespan, R Oliveira, CJF Lima-Junior, DS Costa, DL Verri, WA Milanezi, CM Pham, V Brand, DD Valenzuela, JG Silva, JS Ribeiro, JMC Cunha, FQ AF Carregaro, Vanessa Sa-Nunes, Anderson Cunha, Thiago M. Grespan, Renata Oliveira, Carlo J. F. Lima-Junior, Djalma S. Costa, Diego L. Verri, Waldiceu A., Jr. Milanezi, Cristiane M. Van My Pham Brand, David D. Valenzuela, Jesus G. Silva, Joao S. Ribeiro, Jose M. C. Cunha, Fernando Q. TI Nucleosides from Phlebotomus papatasi Salivary Gland Ameliorate Murine Collagen-Induced Arthritis by Impairing Dendritic Cell Functions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN PHOSPHATASE-ACTIVITY; ADENOSINE RECEPTORS; RHEUMATOID-ARTHRITIS; LEISHMANIA-MAJOR; T-CELLS; CUTANEOUS LEISHMANIASIS; 5'-ADENOSINE MONOPHOSPHATE; IMMUNE SUPPRESSION; ARTHROPOD SALIVA; IXODES-DAMMINI AB Among several pharmacological compounds, Phlebotomine saliva contains substances with anti-inflammatory properties. In this article, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Phlebotomus papatasi in an experimental model of arthritis (collagen-induced arthritis [CIA]) and identified the constituents responsible for such activity. Daily administration of SGE, initiated at disease onset, attenuated the severity of CIA, reducing the joint lesion and proinflammatory cytokine release. In vitro incubation of dendritic cells (DCs) with SGE limited specific CD4(+) Th17 cell response. We identified adenosine (ADO) and 5'AMP as the major salivary molecules responsible for anti-inflammatory activities. Pharmacologic inhibition of ADO A2(A) receptor or enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect. Importantly, CD73 (ecto-5'-nucleotidase enzyme) is expressed on DC surface during stage of activation, suggesting that ADO is also generated by 5'AMP metabolism. Moreover, both nucleosides mimicked SGE-induced anti-inflammatory activity upon DC function in vitro and attenuated establishment of CIA in vivo. We reveal that ADO and 5'AMP are present in pharmacological amounts in P. papatasi saliva and act preferentially on DC function, consequently reducing Th17 subset activation and suppressing the autoimmune response. Thus, it is plausible that these constituents might be promising therapeutic molecules to target immune inflammatory diseases. The Journal of Immunology, 2011, 187: 4347-4359. C1 [Cunha, Thiago M.; Cunha, Fernando Q.] Univ Sao Paulo, Dept Pharmacol, Sch Med Ribeirao Preto, BR-14049900 Sao Paulo, Brazil. [Carregaro, Vanessa; Lima-Junior, Djalma S.; Costa, Diego L.; Milanezi, Cristiane M.; Van My Pham; Silva, Joao S.; Cunha, Fernando Q.] Univ Sao Paulo, Dept Biochem & Immunol, Sch Med Ribeirao Preto, BR-14049900 Sao Paulo, Brazil. [Sa-Nunes, Anderson] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, BR-14049900 Sao Paulo, Brazil. [Grespan, Renata; Verri, Waldiceu A., Jr.] Univ Estadual Londrina, Dept Pathol, Londrina, Parana, Brazil. [Oliveira, Carlo J. F.] Univ Fed Triangulo Mineiro, Inst Biol & Nat Sci, BR-38025180 Uberaba, MG, Brazil. [Van My Pham; Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Brand, David D.] Vet Affairs Med Ctr, Res Serv, Memphis, TN 38163 USA. [Brand, David D.] Univ Tennessee, Hlth Sci Ctr, Dept Med, Memphis, TN 38163 USA. [Brand, David D.] Univ Tennessee, Hlth Sci Ctr, Dept Mol Sci, Memphis, TN 38163 USA. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Cunha, FQ (reprint author), Univ Sao Paulo, Dept Pharmacol, Sch Med Ribeirao Preto, Ave Bandeirantes 3900, BR-14049900 Sao Paulo, Brazil. EM jribeiro@niaid.nih.gov; fdqcunha@fmrp.usp.br RI Cunha, Thiago/B-7729-2012; Silva, Joao/A-4484-2008; Carregaro, Vanessa/D-2913-2012; Sa-Nunes, Anderson/D-8667-2012; Verri, Waldiceu/I-1330-2013; Lima-Junior, Djalma/H-4833-2013; Cunha, Fernando/M-3090-2014; OI Costa, Diego/0000-0002-9440-2814; Cunha, Fernando Queiroz/0000-0003-4755-1670; Cunha, Thiago/0000-0003-1084-0065; Sa-Nunes, Anderson/0000-0002-1859-4973; Verri, Waldiceu/0000-0003-2756-9283; Lima-Junior, Djalma/0000-0002-2092-8047; Ribeiro, Jose/0000-0002-9107-0818 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo; Comissao de Aperfeicoamento de Pessoal de Nival Superior; Conselho Nacional de Pesquisas; Fundacao de Apoio ao Ensino; Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto; Instituto Nacional de Ciencia e Tecnologia em Vacinas; Department of Veterans Affairs; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Comissao de Aperfeicoamento de Pessoal de Nival Superior, Conselho Nacional de Pesquisas, Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, and Instituto Nacional de Ciencia e Tecnologia em Vacinas. D. D. B. was supported by a grant from the Department of Veterans Affairs. J.G.V. and J.M.C.R. were supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 62 TC 16 Z9 17 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2011 VL 187 IS 8 BP 4347 EP 4359 DI 10.4049/jimmunol.1003404 PG 13 WC Immunology SC Immunology GA 829YN UT WOS:000295623100047 PM 21930966 ER PT J AU Spornick, N Guptill, V Koziol, D Wesley, R Finkel, J Quezado, ZMN AF Spornick, Nicholas Guptill, Virginia Koziol, Deloris Wesley, Robert Finkel, Julia Quezado, Zenaide M. N. TI Mouse current vocalization threshold measured with a neurospecific nociception assay: The effect of sex, morphine, and isoflurane SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Nociception; Sine-wave; Sex; Opioid; Anesthesia; Morphine ID CURRENT PERCEPTION THRESHOLD; WAVE ELECTRICAL-STIMULATION; PERIPHERAL NEUROPATHY; THERMAL NOCICEPTION; GENDER-DIFFERENCES; LOW RATES; PAIN; ANALGESIA; MICE; RESPONSES AB Sine-wave electrical stimulation at frequencies 2000, 250, and 5 Hz to respectively evaluate A beta, A delta, and C sensory neurons has recently been added to the armamentarium used to evaluate sensory neurons. We developed an automated nociception assay using sine-wave stimulation methodology to determine current vocalization threshold in response to 2000, 250, and 5 Hz and examine the effects of sex, analgesics, and anesthetics in mice. At baseline, males had significantly higher mean current vocalization thresholds compared with female mice at 2000, 250, and 5 Hz (p <= 0.019). By 1 h after intrathecal injections of morphine there were significant increases in current vocalization threshold percent changes from baseline that varied with doses (p = 0.0001) and frequency used (p < 0.0001). Specifically, with increasing doses of morphine, there were significantly greater increases in current vocalization threshold percent changes from baseline in response to 5 Hz compared with 250 and 2000 Hz stimulation in a significantly ordered pattern: 5 Hz > 250 Hz (p < 0.0001) and 250 Hz > 2000 Hz (p = 0.0002). Forty-five minutes after exposure, there were no effects of isoflurane on current vocalization thresholds at any frequency. Therefore, our findings suggest that this automated nociception assay using sine-wave stimulation in mice, can be valuable for measurements of the effects of sex, opioids, and anesthetics on the response to electrical stimuli that preferentially stimulate A beta, A delta, and C-sensory fibers in vivo. This investigation suggests the validation of this assay and supports its use to examine mechanisms of nociception in mice. (C) 2011 Elsevier B.V. All rights reserved. C1 [Quezado, Zenaide M. N.] George Washington Univ, Sheikh Zayed Inst Pediat Surg Innovat, Childrens Natl Med Ctr, Sch Med & Hlth Sci, Washington, DC 20010 USA. [Guptill, Virginia; Quezado, Zenaide M. N.] NIH, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. [Koziol, Deloris; Wesley, Robert] NIH, Biostat & Clin Epidemiol Serv, Off Director, Ctr Clin, Bethesda, MD 20892 USA. RP Quezado, ZMN (reprint author), George Washington Univ, Sheikh Zayed Inst Pediat Surg Innovat, Childrens Natl Med Ctr, Sch Med & Hlth Sci, 111 Michigan Ave, Washington, DC 20010 USA. EM zquezado@cnmc.org RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU NIH Clinical Center, National Institutes of Health, Bethesda, MD; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC FX This research was supported by the Intramural Research Program of the NIH Clinical Center, National Institutes of Health, Bethesda, MD, and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC. NR 41 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2011 VL 201 IS 2 BP 390 EP 398 DI 10.1016/j.jneumeth.2011.08.011 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 834XX UT WOS:000295998900017 PM 21864576 ER PT J AU Wang, SS Hartge, P Yeager, M Carreon, T Ruder, AM Linet, M Inskip, PD Black, A Hsing, AW Alavanja, M Beane-Freeman, L Safaiean, M Chanock, SJ Rajaraman, P AF Wang, Sophia S. Hartge, Patricia Yeager, Meredith Carreon, Tania Ruder, Avima M. Linet, Martha Inskip, Peter D. Black, Amanda Hsing, Ann W. Alavanja, Michael Beane-Freeman, Laura Safaiean, Mahboobeh Chanock, Stephen J. Rajaraman, Preetha TI Joint Associations Between Genetic Variants and Reproductive Factors in Glioma Risk Among Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE genes; glioma; menstrual cycle; polymorphism; single nucleotide; reproduction; women ID GENOME-WIDE ASSOCIATION; EXOGENOUS HORMONE USE; BRAIN-TUMORS; ADULT GLIOMA; SUSCEPTIBILITY; GLIOBLASTOMA; COHORT; MENINGIOMA; ALLELES; HISTORY AB In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (< 12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women. C1 [Wang, Sophia S.] Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Hartge, Patricia; Linet, Martha; Inskip, Peter D.; Black, Amanda; Hsing, Ann W.; Alavanja, Michael; Beane-Freeman, Laura; Safaiean, Mahboobeh; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Yeager, Meredith; Chanock, Stephen J.] NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. [Carreon, Tania; Ruder, Avima M.] Ctr Dis Control & Prevent, Div Surveillance Hazard Evaluat & Field Studies, NIOSH, Cincinnati, OH USA. RP Wang, SS (reprint author), Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sowang@coh.org RI Ruder, Avima/I-4155-2012; Beane Freeman, Laura/C-4468-2015 OI Ruder, Avima/0000-0003-0419-6664; Beane Freeman, Laura/0000-0003-1294-4124 FU National Cancer Institute [N01-CO-12400]; National Institute for Occupational Safety and Health FX This research was supported by intramural funds from the National Cancer Institute and the National Institute for Occupational Safety and Health. It was been funded in whole or in part with federal funds from the National Cancer Institute under contract N01-CO-12400. NR 26 TC 17 Z9 17 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2011 VL 174 IS 8 BP 901 EP 908 DI 10.1093/aje/kwr184 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830TI UT WOS:000295679700004 PM 21920947 ER PT J AU Torner, A Dickman, P Duberg, AS Kristinsson, S Landgren, O Bjorkholm, M Svensson, A AF Torner, Anna Dickman, Paul Duberg, Ann-Sofi Kristinsson, Sigurdur Landgren, Ola Bjorkholm, Magnus Svensson, Ake TI A Method to Visualize and Adjust for Selection Bias in Prevalent Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; cubic spline; epidemiologic methods; hepatitis C; monoclonal gammopathy of undetermined significance; selection bias ID HEPATITIS-C; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; SURVIVAL; INFECTION; MODELS AB Selection bias and confounding are concerns in cohort studies where the reason for inclusion of subjects in the cohort may be related to the outcome of interest. Selection bias in prevalent cohorts is often corrected by excluding observation time and events during the first time period after inclusion in the cohort. This time period must be chosen carefully-long enough to minimize selection bias but not too long so as to unnecessarily discard observation time and events. A novel method visualizing and estimating selection bias is described and exemplified by using 2 real cohort study examples: a study of hepatitis C virus infection and a study of monoclonal gammopathy of undetermined significance. The method is based on modeling the hazard for the outcome of interest as a function of time since inclusion in the cohort. The events studied were "hospitalizations for kidney-related disease" in the hepatitis C virus cohort and "death" in the monoclonal gammopathy of undetermined significance cohort. Both cohorts show signs of considerable selection bias as evidenced by increased hazard in the time period after inclusion in the cohort. The method was very useful in visualizing selection bias and in determining the initial time period to be excluded from the analyses. C1 [Torner, Anna] Swedish Inst Infect Dis Control, Dept Epidemiol, S-17182 Solna, Sweden. [Dickman, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden. [Duberg, Ann-Sofi] Orebro Univ Hosp, Dept Infect Dis, Orebro, Sweden. [Kristinsson, Sigurdur; Bjorkholm, Magnus] Karolinska Univ Hosp, Div Hematol, Dept Med, Solna, Sweden. [Landgren, Ola] NCI, Bethesda, MD 20892 USA. [Svensson, Ake] Stockholm Univ, Dept Math Stat, S-10691 Stockholm, Sweden. RP Torner, A (reprint author), Swedish Inst Infect Dis Control, Dept Epidemiol, Tomtebodavagen 19A, S-17182 Solna, Sweden. EM anna.torner@smi.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015; OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476; Svensson, Ake/0000-0001-7974-4077 FU Swedish Institute for Infectious Disease Control FX This work was financially supported by the Swedish Institute for Infectious Disease Control. NR 18 TC 8 Z9 8 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 OCT 15 PY 2011 VL 174 IS 8 BP 969 EP 976 DI 10.1093/aje/kwr211 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830TI UT WOS:000295679700012 PM 21920949 ER PT J AU Tin, A Woodward, OM Kao, WHL Liu, CT Lu, XN Nalls, MA Shriner, D Semmo, M Akylbekova, EL Wyatt, SB Hwang, SJ Yang, Q Zonderman, AB Adeyemo, AA Palmer, C Meng, Y Reilly, M Shlipak, MG Siscovick, D Evans, MK Rotimi, CN Flessner, MF Kottgen, M Cupples, LA Fox, CS Kottgen, A AF Tin, Adrienne Woodward, Owen M. Kao, Wen Hong Linda Liu, Ching-Ti Lu, Xiaoning Nalls, Michael A. Shriner, Daniel Semmo, Mariam Akylbekova, Ermeg L. Wyatt, Sharon B. Hwang, Shih-Jen Yang, Qiong Zonderman, Alan B. Adeyemo, Adebowale A. Palmer, Cameron Meng, Yan Reilly, Muredach Shlipak, Michael G. Siscovick, David Evans, Michele K. Rotimi, Charles N. Flessner, Michael F. Koettgen, Michael Cupples, L. Adrienne Fox, Caroline S. Koettgen, Anna CA CARe & CHARGE Consortia TI Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele SO HUMAN MOLECULAR GENETICS LA English DT Article ID URIC-ACID; CARDIOVASCULAR-DISEASE; GENETIC-LOCI; POPULATION; DESIGN; TRANSPORTER; FRAMINGHAM; GLUCOSE; SLC2A9; HEART AB Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P < 5.0 x 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P = 1.0 x 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P = 3.8 x 10(-32)) and SLC22A12 (P = 2.1 x 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P = 2.7 x 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants. C1 [Koettgen, Anna] Freiburg Univ Hosp, Dept Med 4, Div Renal, D-79110 Freiburg, Germany. [Tin, Adrienne; Kao, Wen Hong Linda; Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Woodward, Owen M.] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Shriner, Daniel; Adeyemo, Adebowale A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Shriner, Daniel; Koettgen, Michael] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Akylbekova, Ermeg L.] Jackson State Univ, Jackson, MS 39213 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Hwang, Shih-Jen; Cupples, L. Adrienne; Fox, Caroline S.] NHLBI Framingham Heart Study, Framingham, MA 01702 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Reilly, Muredach] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Palmer, Cameron] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Palmer, Cameron] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Palmer, Cameron; Meng, Yan] Broad Inst Harvard & MIT, Metab Dis Initiat, Cambridge, MA USA. [Flessner, Michael F.] NIDDK, KUH, NIH, Bethesda, MD 20892 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Kottgen, A (reprint author), Freiburg Univ Hosp, Dept Med 4, Div Renal, Berliner Allee 29, D-79110 Freiburg, Germany. EM akottgen@jhsph.edu RI Kottgen, Anna/D-2920-2012; Yang, Qiong/G-5438-2014; OI Adeyemo, Adebowale/0000-0002-3105-3231; Zonderman, Alan B/0000-0002-6523-4778; Cupples, L. Adrienne/0000-0003-0273-7965 FU National Heart, Lung and Blood Institute; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; NIDDK [DK032753-25A1]; German Research Foundation FX The authors wish to acknowledge the support of the National Heart, Lung and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. We would like to thank Dr Yohannes Hagos who kindly provided the URAT1 plasmid, Dr H. Endou for the permission to use it, as well as Dr William B. Guggino for contributing experimental resources.; Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS): this research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (intramural project # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov).; Howard University Family Study (HUFS): The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. We thank the participants of the Howard University Family Study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health.; Individual support: O.M.W. was supported by NIDDK: DK032753-25A1, A.K. was supported by the Emmy Noether Programme of the German Research Foundation. NR 53 TC 36 Z9 42 U1 0 U2 9 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 OCT 15 PY 2011 VL 20 IS 20 BP 4056 EP 4068 DI 10.1093/hmg/ddr307 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 824AN UT WOS:000295171200015 PM 21768215 ER PT J AU Wood, AR Hernandez, DG Nalls, MA Yaghootkar, H Gibbs, JR Harries, LW Chong, S Moore, M Weedon, MN Guralnik, JM Bandinelli, S Murray, A Ferrucci, L Singleton, AB Melzer, D Frayling, TM AF Wood, Andrew R. Hernandez, Dena G. Nalls, Michael A. Yaghootkar, Hanieh Gibbs, J. Raphael Harries, Lorna W. Chong, Sean Moore, Matthew Weedon, Michael N. Guralnik, Jack M. Bandinelli, Stefania Murray, Anna Ferrucci, Luigi Singleton, Andrew B. Melzer, David Frayling, Timothy M. TI Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENE-EXPRESSION; GENOTYPE DATA; HAPLOTYPES; VARIANTS AB The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism(SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P < 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work. C1 [Wood, Andrew R.; Yaghootkar, Hanieh; Weedon, Michael N.; Murray, Anna; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England. [Hernandez, Dena G.; Nalls, Michael A.; Yaghootkar, Hanieh; Harries, Lorna W.; Chong, Sean; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Reta Lila Labs, Inst Neurol, London WC1N 3BG, England. [Harries, Lorna W.] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Guralnik, Jack M.] Univ Maryland, Dept Epidemiol & Publ Hlth, Sch Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. NIA, Clin Res Branch, ASTRA Unit, Harbor Hosp, Baltimore, MD USA. RP Frayling, TM (reprint author), Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England. EM tim.frayling@pms.ac.uk RI Singleton, Andrew/C-3010-2009; Harries, Lorna/D-2241-2014; OI Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838 FU Wellcome Trust [083270/Z/07/Z]; U.S. National Institute on Aging (NIA); NIA; National Institute of Health (NIH); Peninsula NIHR Clinical Research Facility FX This work was supported by the Wellcome Trust 083270/Z/07/Z. The InCHIANTI study was supported by contract funding from the U.S. National Institute on Aging (NIA), and the research was supported in part by the Intramural Research Program, NIA, and National Institute of Health (NIH). A.R.W. supported by the Peninsula NIHR Clinical Research Facility. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 18 TC 33 Z9 33 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2011 VL 20 IS 20 BP 4082 EP 4092 DI 10.1093/hmg/ddr328 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 824AN UT WOS:000295171200018 PM 21798870 ER PT J AU Troyer, JL Roelke, ME Jespersen, JM Baggett, N Buckley-Beason, V MacNulty, D Craft, M Packer, C Pecon-Slattery, J O'Brien, SJ AF Troyer, Jennifer L. Roelke, Melody E. Jespersen, Jillian M. Baggett, Natalie Buckley-Beason, Valerie MacNulty, Dan Craft, Meggan Packer, Craig Pecon-Slattery, Jill O'Brien, Stephen J. TI FIV diversity: FIVPle subtype composition may influence disease outcome in African lions SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 10th International Feline Retrovirus Research Symposium (IFRRS) CY MAY 23-26, 2010 CL Charleston, SC SP Amer Phys Therapy Assoc DE FIVPle; Lions; CDV; Babesia ID FELINE IMMUNODEFICIENCY VIRUS; CROSS-SPECIES TRANSMISSION; CANINE-DISTEMPER VIRUS; LENTIVIRUS INFECTION; PANTHERA-LEO; PHYLOGENETIC ASPECTS; SERENGETI LIONS; MOLECULAR CLONE; DOMESTIC CAT; WILD AB Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIVFca) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIVPle) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIVPle subtypes, the data suggest that FIVPle subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations. (C) 2011 Elsevier B.V. All rights reserved. C1 [Troyer, Jennifer L.; Roelke, Melody E.] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21701 USA. NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21701 USA. [MacNulty, Dan; Craft, Meggan; Packer, Craig] Univ Minnesota, Dept Ecol Evolut & Behav, St Paul, MN 55108 USA. RP Troyer, JL (reprint author), NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21701 USA. EM troyerj@mail.nih.gov RI Craft, Meggan/A-9393-2012; Troyer, Jennifer/B-8415-2012; MacNulty, Dan/L-3965-2016 OI Craft, Meggan/0000-0001-5333-8513; FU Intramural NIH HHS [Z99 CA999999] NR 56 TC 9 Z9 9 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD OCT 15 PY 2011 VL 143 IS 3-4 SI SI BP 338 EP 346 DI 10.1016/j.vetimm.2011.06.013 PG 9 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 828FI UT WOS:000295486500021 PM 21723622 ER PT J AU Kawakami, Y Marti, M Kawakami, H Itou, J Quach, T Johnson, A Sahara, S O'Leary, DDM Nakagawa, Y Lewandoski, M Pfaff, S Evans, SM Belmonte, JCI AF Kawakami, Yasuhiko Marti, Merce Kawakami, Hiroko Itou, Junji Quach, Thu Johnson, Austin Sahara, Setsuko O'Leary, Dennis D. M. Nakagawa, Yasushi Lewandoski, Mark Pfaff, Samuel Evans, Sylvia M. Izpisua Belmonte, Juan Carlos TI Islet1-mediated activation of the beta-catenin pathway is necessary for hindlimb initiation in mice SO DEVELOPMENT LA English DT Article DE Islet1; beta-catenin; Mouse limb initiation; Fgf10 ID VERTEBRATE LIMB DEVELOPMENT; MOUSE DEVELOPMENT; MOTOR-NEURON; WNT SIGNALS; OUTGROWTH; IDENTITY; BUD; TBX5; FGF8; GENE AB The transcriptional basis of vertebrate limb initiation, which is a well-studied system for the initiation of organogenesis, remains elusive. Specifically, involvement of the beta-catenin pathway in limb initiation, as well as its role in hindlimb-specific transcriptional regulation, are under debate. Here, we show that the beta-catenin pathway is active in the limb-forming area in mouse embryos. Furthermore, conditional inactivation of beta-catenin as well as Islet1, a hindlimb-specific factor, in the lateral plate mesoderm results in a failure to induce hindlimb outgrowth. We further show that Islet1 is required for the nuclear accumulation of. catenin and hence for activation of the beta-catenin pathway, and that the beta-catenin pathway maintains Islet1 expression. These two factors influence each other and function upstream of active proliferation of hindlimb progenitors in the lateral plate mesoderm and the expression of a common factor, Fgf10. Our data demonstrate that Islet1 and beta-catenin regulate outgrowth and Fgf10-Fgf8 feedback loop formation during vertebrate hindlimb initiation. Our study identifies Islet1 as a hindlimb-specific transcriptional regulator of initiation, and clarifies the controversy regarding the requirement of beta-catenin for limb initiation. C1 [Kawakami, Yasuhiko; Kawakami, Hiroko; Pfaff, Samuel; Izpisua Belmonte, Juan Carlos] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. [Kawakami, Yasuhiko; Kawakami, Hiroko; Itou, Junji; Quach, Thu; Johnson, Austin] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Kawakami, Yasuhiko; Kawakami, Hiroko; Itou, Junji; Nakagawa, Yasushi] Univ Minnesota, Stem Cell Inst, Minneapolis, MN 55455 USA. [Kawakami, Yasuhiko; Nakagawa, Yasushi] Univ Minnesota, Ctr Dev Biol, Minneapolis, MN 55455 USA. [Kawakami, Yasuhiko] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Marti, Merce; Izpisua Belmonte, Juan Carlos] Ctr Regenerat Med Barcelona, Barcelona 08003, Spain. [Sahara, Setsuko; O'Leary, Dennis D. M.] Salk Inst Biol Studies, Molecular Neurosci Lab, La Jolla, CA 92037 USA. [Nakagawa, Yasushi] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. [Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Evans, Sylvia M.] Univ Calif San Diego, Skaggs Sch Pharm, La Jolla, CA 92093 USA. [Evans, Sylvia M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Kawakami, Y (reprint author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM kawak005@umn.edu; belmonte@salk.edu RI Evans, Sylvia/G-1980-2015 FU Minnesota Medical Foundation [3962-9211-09]; American Cancer Society [IRG-58-001-52-IRG04]; NINDS [5R37NS037116]; HHMI; National Institutes of Health [R01 NS049357]; CIBER; MICINN; Fundacion Cellex; G. Harold and Leila Y. Mathers Charitable Foundation; Leona M. and Harry B. Helmsley Charitable Trust; Sanofi-Aventis FX This work was supported by the Minnesota Medical Foundation (3962-9211-09) and American Cancer Society Institutional Research Grant (IRG-58-001-52-IRG04) to Y.K., NINDS (5R37NS037116) and HHMI to S. P., the National Institutes of Health (R01 NS049357) to Y.N., and CIBER, MICINN, Fundacion Cellex, the G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi-Aventis to J.C.I.B. Deposited in PMC for release after 6 months. NR 46 TC 23 Z9 24 U1 0 U2 1 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 OCT 15 PY 2011 VL 138 IS 20 BP 4465 EP 4473 DI 10.1242/dev.065359 PG 9 WC Developmental Biology SC Developmental Biology GA 822YD UT WOS:000295085600014 PM 21937598 ER PT J AU Bloom-Feshbach, K Simonsen, L Viboud, C Molbak, K Miller, MA Gottfredsson, M Andreasen, V AF Bloom-Feshbach, Kimberly Simonsen, Lone Viboud, Cecile Molbak, Kare Miller, Mark A. Gottfredsson, Magnus Andreasen, Viggo TI Natality Decline and Miscarriages Associated With the 1918 Influenza Pandemic: The Scandinavian and United States Experiences SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID NEW-YORK-CITY; PREGNANT-WOMEN; EMERGING INFECTIONS; ASIAN INFLUENZA; A(H1N1) VIRUS; SPANISH FLU; MORTALITY; INFANTS; EPIDEMICS; ICELAND AB Background. Although pregnancy is a recognized risk factor for severe influenza infection, the effect of influenza on miscarriages and births remains unclear. We examined the relationship between influenza and birth rates during the 1918 pandemic in the United States, Denmark, Sweden, and Norway. Methods. We compiled monthly birth rates from 1911 through 1930 in 3 Scandinavian countries and the United States, identified periods of unusually low or high birth rates, and quantified births as "missing" or "in excess" of the normal expectation. Using monthly influenza data, we correlated the timing of peak pandemic exposure and depressions in birth rates, and identified pregnancy stages at risk of influenza-related miscarriage. Results. Birth rates declined in all study populations in spring 1919 by a mean of 2.2 births per 1000 persons, representing a 5%-15% drop below baseline levels (P < .05). The 1919 natality depression reached its trough 6.1-6.8 months after the autumn pandemic peak, suggesting that missing births were attributable to excess first trimester miscarriages in similar to 1 in 10 women who were pregnant during the peak of the pandemic. Pandemic-related mortality was insufficient to explain observed patterns. Conclusions. The observed birth depressions were consistent with pandemic influenza causing first trimester miscarriages in similar to 1 in 10 pregnant women. Causality is suggested by temporal synchrony across geographical areas. C1 [Bloom-Feshbach, Kimberly; Simonsen, Lone; Viboud, Cecile; Miller, Mark A.; Gottfredsson, Magnus; Andreasen, Viggo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bloom-Feshbach, Kimberly] Mt Sinai Sch Med, New York, NY USA. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC USA. [Molbak, Kare] Statens Serum Inst, Dept Epidemiol, DK-2300 Copenhagen, Denmark. [Andreasen, Viggo] Roskilde Univ Ctr, Dept Sci Syst & Models, Reykjavik, Iceland. [Gottfredsson, Magnus] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Bloom-Feshbach, K (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 16,Stone House,MSC 6705, Bethesda, MD 20892 USA. EM kimberlybf@gmail.com OI Molbak, Kare/0000-0002-3100-4990; Gottfredsson, Magnus/0000-0003-2465-0422; Simonsen, Lone/0000-0003-1535-8526 FU Danish Medical Research Council [271-07-0555]; Fogarty International Center; Department of Homeland Security; Fogarty International Center, National Institutes of Health; International Influenza Unit, Office of Global Affairs, Department of Health and Human Services FX This work was supported by the Danish Medical Research Council (271-07-0555 to V. A.); and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Fogarty International Center and Department of Homeland Security (funding support to L. S. and V. A.) This study was funded in part by the Intramural Influenza Research Program of the Fogarty International Center, National Institutes of Health, which is supported by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services. NR 40 TC 24 Z9 24 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2011 VL 204 IS 8 BP 1157 EP 1164 DI 10.1093/infdis/jir510 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821JB UT WOS:000294970100003 PM 21917887 ER PT J AU Katsounas, A Trippler, M Kottilil, S Lempicki, RA Gerken, G Schlaak, JF AF Katsounas, Antonios Trippler, Martin Kottilil, Shyam Lempicki, Richard A. Gerken, Guido Schlaak, Joerg F. TI Altered Expression of SHIP, a Toll-like Receptor Pathway Inhibitor, Is Associated With the Severity of Liver Fibrosis in Chronic Hepatitis C Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ENDOTOXIN TOLERANCE; INVOLVEMENT; ACTIVATION AB Hepatitis C-related fibrogenesis has been shown to involve complex interactions between peripheral and hepatic immune responses. Peripheral whole blood (PB) samples from patients with chronic hepatitis C (n = 36) were subjected to microarray analysis in order to identify gene expression patterns associated with immune pathways in PB and hepatic fibrosis. Distinct regulation of gene expression of inositol polyphosphate-5-phosphatase/145kDa (INPP5D or SHIP), a TLR2/TLR4-inhibitor, and heat shock protein 8/22kDa (HSPB8), an endogenous TLR4-ligand, during fibrogenesis was identified and could be confirmed by quantitative reverse-transcription polymerase chain reaction. These results suggest a potential link between peripheral activity of the TLR4-pathway, peripheral SHIP-dependent immune regulation, and liver fibrosis. C1 [Katsounas, Antonios; Trippler, Martin; Gerken, Guido; Schlaak, Joerg F.] Univ Hosp Essen, Dept Gastroenterol & Hepatol, D-45147 Essen, Germany. [Katsounas, Antonios; Lempicki, Richard A.] NCI Frederick, SAIC Frederick Inc, Lab Immunopathogenesis & Bioinformat, Frederick, MD USA. [Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Schlaak, JF (reprint author), Univ Hosp Essen, Dept Gastroenterol & Hepatol, Hufelandstr 55, D-45122 Essen, Germany. EM joerg.schlaak@uni-due.de RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Gerken, Guido/0000-0001-6734-5001; Schlaak, Joerg/0000-0002-9499-1014 FU Association for the Promotion of Scientific Research and Science of the Clinic for Gastroenterology and Hepatology at the University Hospital Essen (Essen, NRW, Germany); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by funds from the Association for the Promotion of Scientific Research and Science of the Clinic for Gastroenterology and Hepatology at the University Hospital Essen (Essen, NRW, Germany); and in part by federal funds from the National Cancer Institute, National Institutes of Health (contract no. HHSN261200800001E). NR 15 TC 1 Z9 2 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 OCT 15 PY 2011 VL 204 IS 8 BP 1181 EP 1185 DI 10.1093/infdis/jir500 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821JB UT WOS:000294970100006 PM 21917890 ER PT J AU Meunier, JC Gottwein, JM Houghton, M Russell, RS Emerson, SU Bukh, J Purcell, RH AF Meunier, Jean-Christophe Gottwein, Judith M. Houghton, Michael Russell, Rodney S. Emerson, Suzanne U. Bukh, Jens Purcell, Robert H. TI Vaccine-Induced Cross-Genotype Reactive Neutralizing Antibodies Against Hepatitis C Virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHIMPANZEES; INFECTION; EFFICACY AB We detected cross-reactive neutralizing antibodies (NtAb) against hepatitis C virus (HCV) in chimpanzees vaccinated with HCV-1 (genotype 1a) recombinant E1/E2 envelope glycoproteins. Five vaccinated chimpanzees, protected following HCV-1 challenge, were initially studied using the heterologous H77 (genotype 1a) HCVpp assay. All animals had developed NtAb after the second vaccination; 4 animals had reciprocal titers of >= 200 at the time of challenge. Using genotypes 1a-6a HCV pseudoparticles (HCVpp) and cell culture-derived HCV (HCVcc) assays, cross-reactive NtAb were detected against 1a, 4a, 5a, and 6a, with limited reactivity against 2a and 3a. Our study provides encouragement for the development of a recombinant envelope-based vaccine against hepatitis C. C1 [Gottwein, Judith M.; Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis Program CO HEP C, DK-2650 Hvidovre, Denmark. [Gottwein, Judith M.; Bukh, Jens] Copenhagen Univ Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Meunier, Jean-Christophe; Russell, Rodney S.; Emerson, Suzanne U.; Bukh, Jens; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Gottwein, Judith M.; Bukh, Jens] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-1168 Copenhagen, Denmark. [Houghton, Michael] Univ Alberta, Dept Med Microbiol & Immunol, Li Ka Shing Inst Virol, Edmonton, AB, Canada. RP Bukh, J (reprint author), Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis Program CO HEP C, DK-2650 Hvidovre, Denmark. EM jbukh@sund.ku.dk FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Lundbeck Foundation FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). J. B. was the recipient of a professorship at the University of Copenhagen with external funding from the Lundbeck Foundation. NR 15 TC 50 Z9 50 U1 1 U2 3 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 OCT 15 PY 2011 VL 204 IS 8 BP 1186 EP 1190 DI 10.1093/infdis/jir511 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821JB UT WOS:000294970100007 PM 21917891 ER PT J AU Sax, PE Tierney, C Collier, AC Daar, ES Mollan, K Budhathoki, C Godfrey, C Jahed, NC Myers, L Katzenstein, D Farajallah, A Rooney, JF Ha, B Woodward, WC Feinberg, J Tashima, K Murphy, RL Fischl, MA AF Sax, Paul E. Tierney, Camlin Collier, Ann C. Daar, Eric S. Mollan, Katie Budhathoki, Chakra Godfrey, Catherine Jahed, Nasreen C. Myers, Laurie Katzenstein, David Farajallah, Awny Rooney, James F. Ha, Belinda Woodward, William C. Feinberg, Judith Tashima, Karen Murphy, Robert L. Fischl, Margaret A. CA AIDS Clinical Trials Grp Study TI Abacavir/Lamivudine Versus Tenofovir DF/Emtricitabine as Part of Combination Regimens for Initial Treatment of HIV: Final Results SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ANTIRETROVIRAL-NAIVE; INFECTED PATIENTS; LAMIVUDINE; EMTRICITABINE; EFAVIRENZ; ABACAVIR; TENOFOVIR/EMTRICITABINE; LOPINAVIR/RITONAVIR; ZIDOVUDINE; EFFICACY AB Background. AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or >= 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. Methods. Primary endpoints were times to virologic failure, regimen modification, and safety event. Results. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). Conclusions. In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r. C1 [Sax, Paul E.] Harvard Univ, Div Infect Dis, Dept Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA. [Tierney, Camlin; Mollan, Katie; Budhathoki, Chakra] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Collier, Ann C.] Univ Washington, Harborview Med Ctr, Sch Med, Seattle, WA 98104 USA. [Daar, Eric S.] Univ Calif Los Angeles, Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Godfrey, Catherine] NIAID, Div Aids, Bethesda, MD 20892 USA. [Jahed, Nasreen C.] Social & Sci Syst Inc, Silver Spring, MD USA. [Myers, Laurie] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Katzenstein, David] Stanford Univ, Palo Alto, CA 94304 USA. [Farajallah, Awny] Bristol Myers Squibb Co, Plainsboro, NJ USA. [Rooney, James F.] Gilead Sci Inc, Foster City, CA 94404 USA. [Ha, Belinda] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. [Woodward, William C.] Abbott Labs, Abbott Pk, IL 60064 USA. [Feinberg, Judith] Univ Cincinnati, Cincinnati, OH USA. [Tashima, Karen] Brown Univ, Providence, RI 02912 USA. [Murphy, Robert L.] Northwestern Univ, Chicago, IL 60611 USA. [Fischl, Margaret A.] Univ Miami, Sch Med, Coral Gables, FL 33124 USA. RP Sax, PE (reprint author), Harvard Univ, Div Infect Dis, Dept Med, Brigham & Womens Hosp,Med Sch, 75 Francis St, Boston, MA 02115 USA. EM psax@partners.org OI Murphy, Robert/0000-0003-3936-2052 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [U01AI068636]; Statistical and Data Management Center (SDMC) [AI68634]; General Clinical Research Center Units; National Center for Research Resources; University of Miami [AI069477]; ACTG [AI27675]; CFAR [AI073961]; Ohio State University [AI069474]; CTU [AI69432]; University of North Carolina [AI69423]; GCRC [RR00046]; University of Alabama [U01 AI069452-03]; CCTS [1UL1 RR025777-01]; University of Colorado Health Sciences Center [RR025780]; University of Southern California [5U01 AI069428]; Vanderbilt Therapeutics CRS [AI069439]; subunit of Children's Hospital of Philadelphia [U01 AI069467-03]; Washington University [AI069495]; University of Puerto Rico [5U01 AI069415-03]; Duke University Medical Center [5U01 AI06948402]; Harbor-UCLA Medical Center [AI069424]; Case Western Reserve University [AI69501]; University of Rochester [U01 AI069511]; [AI38858]; [RR025747] FX This work was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), along with the previous grant number for the AIDS Clinical Trials Group (ACTG) Central Group, AI38858, and the Statistical and Data Management Center (SDMC) grant, AI68634. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the NIH. Also supported in part by the General Clinical Research Center Units funded by the National Center for Research Resources. Abbott Pharmaceuticals, Bristol Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided the study medications.; Other investigators and contributors included the following: Sandra Navarro, MD, and Lillian Colon, RN, BSN, University of Miami (Site 901) CTU Grant #AI069477, ACTG Grant #AI27675, CFAR Grant #AI073961; Susan L. Koletar, MD, and Diane Gochnour, RN, The Ohio State University (Site 2301) CTU Grant #AI069474; Julie Hoffman, RN, and Edward Seefried, RN, UCSD (Site 701) CTU Grant #AI69432; Carl Fichtenbaum, MD, and Michelle Saemann, RN, University of Cincinnati (Site 2401) CTU Grant #AI069513; Donna Pittard, RN, and David Ragan, RN, MSN, University of North Carolina (Site 3201) CTU Grant #AI69423, CFAR Grant #AI50410, GCRC Grant #RR00046 and Grant #RR025747; Elizabeth Lindsey, RN, and Tamara James, BS, University of Alabama (Site 5801) CTU Grant #U01 AI069452-03, CCTS Grant #1UL1 RR025777-01; Graham Ray, RN, MSN, and Steven Johnson, MD, University of Colorado Health Sciences Center (Site 6101) CTU Grant #RR025780; P. Jan Geiseler, MD, and Connie A. Funk, RN, MPH, University of Southern California (Site 1201) CTU Grant #5U01 AI069428; Michael Morgan, FNP, and Brenda Jackson, RN, Vanderbilt Therapeutics CRS (Site 3652) CTU Grant #AI069439; Pablo Tebas, MD, and Aleshia Thomas, RN, University of PA, subunit of Children's Hospital of Philadelphia (Site 6201) CTU Grant #U01 AI069467-03, CFAR Grant #5P30 AI045008-10; Ge-Youl Kim, RN, BSN, and Mark Rodriguez, RN, BSN, Washington University (Site 2101) CTU Grant #AI069495; Jorge L. Santana, MD, and Santiago Marrero, MD, University of Puerto Rico (Site 5401) CTU Grant #5U01 AI069415-03; Jane Norris, PA-C, and Sandra Valle, PA-C, Stanford University (Site 501) CTU Grant #AI69556; Gary Matthew Cox, MD, and Martha Silberman, RN, Duke University Medical Center (Site 1601) CTU Grant #5U01 AI06948402; Sadia Shaik, MD, and Ruben Lopez, MD, Harbor-UCLA Medical Center (Site 603) CTU Grant #AI069424, GCRC Grant #M01-RR00425; Margie Vasquez, RN, and Demetre Daskalakis, MD, New York University/ NYC HHC at Bellevue Hospital Center (Site 401) CTU Grant #AI069532; Valery Hughes, NP, and Christina Megill, PA, Cornell Chelsea (Site 7804) CTU Grant #AI69419, CSTC Grant #RR024996; Jessica Shore, BSN, and BabafemiTaiwo, MBBS, Northwestern University CRS (Site 2701) CTU Grant #AI069471; Mitchell Goldman, MD, and Molly Boston, RN, Indiana University (Site 2601) CTU Grant #UO1 AI025859; Jeffrey Lennox, MD, and Carlos del Rio, MD, The Ponce de Leon Center (A5802) CTU Grant #5U01 AI069418, CFAR Grant #P30 AI050409; Timothy W. Lane, MD, and Kim Epperson, RN, Moses H. Cone Memorial Hospital (Site 3203) CTU Grant #1U01 A1069423-01; Annie Luetkemeyer, MD, and Mary Payne, RN, UCSF (Site 801) CTU Grant #1U01 AI069502-01; Barbara Gripshover, MD, and Dawn Antosh, RN, Case Western Reserve University (Site 2501) CTU Grant #AI69501; Jane Reid RN, MS, APN-BC, and Mary Adams, RN, MPh, University of Rochester (Site 1101) CTU Grant #U01 AI069511, GCRC Grant #UL1 RR024160; Sheryl S. Storey, PA-C, and Shelia B. Dunaway, MD, University of Washington (Site 1401) CTU Grant #AI069434; Ilene Wiggins, RN, and Eric Zimmerman, RN, Johns Hopkins University (Site 201) CTU Grant #AI69465, CTSA Grant #U54 RR023561; Kimberly Y. Smith, MD, MPH, and Joan A.; Swiatek, RN, APN, Rush University Medical Center (Site 2702) CTU Grant #5U01 AI069471; Joseph Timpone, MD, and Princy Kumar, MD, Georgetown University (Site 1008) CTU Grant #1U01 AI069494-01; Ardis Moe, MD, and Maria Palmer PA-C, UCLA Care Center (Site 601) CTU Grant #AI069424; Jon Gothing, RN, BSN, ACRN, and Joanne Delaney, RN, BSN, Brigham and Women's Hospital, Boston, MA (Site 107) CTU Grant #AI06972; Kim Whitely, RN, and Robert Kalayjian, MD, Metro Health Center (Site 2503) CTU Grant #AI069501; Scott M. Hammer and Michael T. Yin, HIV Prevention & Treatment (Columbia University; Site 30329) CTU Grant #5U01 AI069470, Grant #1UL1 RR024156; Mamta Jain, MD, and Tianna Petersen, MS, UT Southwestern Medical Center at Dallas (Site 3751) CTU Grant #3U01 AI046376 05S4; Roberto Corales, DO, and Christine Hurley, RN, AIDS Community Health Center (Site 1108) CTU Grant #U01 AI069511, GCRC Grant #UL1 RR024160; Keith Henry, MD, and Bette Bordenave, RN, Hennepin County Medical Center (Site 1502) Grant #N01 AI72626; Amanda Youmans, NP, and Mary Albrecht, MD, Beth Israel Deaconess (Partners/Harvard) CRS (Site 103) CTU Grant #UOI A106947203; Richard B. Pollard, MD, and Abimbola Olusanya, NP, University of California, Davis Medical Center (Site 3851) Grant #AI38858; Paul R. Skolnik, MD, and Betsy Adams, RN, Boston Medical Center CRS (Site 104) CTU Grant #AI069472; Helen Patterson, LPN, The Miriam Hospital-Brown University (Partners/Harvard; Site 2951) CTU Grant #1U01 AI069472-01; Michelle Ukwu and Lauren Rogers, Peabody Health Center (Site 31443) CTU Grant #AI069471; Henry H. Balfour Jr., MD, and Kathy A. Fox, RN, MBA, University of Minnesota (Site 1501) CTU Grant #AI27661; Susan Swindells, MBBS, and Frances Van Meter, APRN, University of NebraskaMedical Center (Site 1505) CTU Grant #AI27661; University of Hawaii (Site 5201) CTU Grant #AI34853; Gregory Robbins, MD, and Nicole Burgett-Yandow, RN, BSN, Massachusetts General Hospital from the Partners/Harvard/BMC ACTU (Site 101) CTU Grant #1U01 AI069472-01; Charles E. Davis Jr., MD, and Colleen Boyce, RN, IHV Baltimore Treatment CRS (Site 4651) CTU Grant #5U01 AI069447 03; William A. O'Brien, MD, and Gerianne Casey, RN, University of Texas Medical Branch (Site 6301) CTU Grant #AI032782; Gene D. Morse, PharmD, and Chiu-Bin Hsaio, MD, SUNY-Buffalo (Site 1102) CTU Grant #5U01 A1027658; San Mateo County AIDS Program (Site 505) CTU Grant #AI27666; Jeffrey L. Meier, MD, and Jack T. Stapleton, MD, University of Iowa Healthcare (Site 1504) NIAID Grant #AI27661 and Grant #AI58740; DonnaMildvan, MD, andManuel Revuelta, MD, Beth IsraelMedical Center ACTU (Site 2851) CTU Grant #AI46370; David Currin, RN, Wake County HHS (Site 30076) CTU Grant #AI25868; Wafaa El Sadr, MD, MPH, MPA, and Avelino Loquere, RN, Harlem ACTG CRS (Site 31483) CTU Grant #5U01 AI069470-03; Nyef El-Daher, MD, and Tina Johnson, RN, McCree McCuller Wellness Center (Site 1107) CTU Grant #U01 AI069511, GCRC Grant #UL1 RR024160; Robert Gross, MD, MSCE, and Kathyrn Maffei, RN, BSN, University of Pennsylvania Health (Site 6206) CTU Grant #1U01 AI69467-01; Deborah McMahon, MD, and Barbara Rutecki, CRNP, MPH, University of Pittsburgh (Site 1001) CTU Grant #1UO1 AI069494-01; Michael Wulfsohn, MD, PhD, Andrew Cheng, MD, PhD, Michael Miller, PhD, and Norbert Bischofberger PhD, Gilead Sciences; Sara Hughes, PhD, GlaxoSmithKline, Inc. NR 17 TC 107 Z9 107 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2011 VL 204 IS 8 BP 1191 EP 1201 DI 10.1093/infdis/jir505 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821JB UT WOS:000294970100008 PM 21917892 ER PT J AU Brown, A Machan, JT Hayes, L Zervas, M AF Brown, Ashly Machan, Jason T. Hayes, Lindsay Zervas, Mark TI Molecular Organization and Timing of Wnt1 Expression Define Cohorts of Midbrain Dopamine Neuron Progenitors In Vivo SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE genetic inducible fate mapping; VTA; SNc; cell fate ID EMBRYONIC STEM-CELLS; PARKINSONS-DISEASE; NEUROTRANSMITTER SYSTEMS; CAENORHABDITIS-ELEGANS; VENTRAL MESENCEPHALON; BASAL GANGLIA; RAT-BRAIN; MOUSE; DIFFERENTIATION; PATHWAY AB Midbrain dopamine (MbDA) neurons are functionally heterogeneous and modulate complex functions through precisely organized anatomical groups. MbDA neurons are generated from Wnt1-expressing progenitors located in the ventral mesencephalon (vMes) during embryogenesis. However, it is unclear whether the progenitor pool is partitioned into distinct cohorts based on molecular identity and whether the timing of gene expression uniquely identifies subtypes of MbDA neurons. In this study we show that Wnt1-expressing MbDA progenitors from embryonic day (E)8.5-12.5 have dynamic molecular identities that correlate with specific spatial locations in the vMes. We also tested the hypothesis that the timing of Wnt1 expression in progenitors is related to the distribution of anatomically distinct cohorts of adult MbDA neurons using genetic inducible fate mapping (GIFM). We demonstrate that the Wnt1 lineage contributes to specific cohorts of MbDA neurons during a 7-day epoch and that the contribution to MbDA neurons predominates over other ventral Mb domains. In addition, we show that calbindin-, GIRK2-, and calretinin-expressing MbDA neuron subtypes are derived from Wnt1-expressing progenitors marked over a broad temporal window. Through GIFM and quantitative analysis we demonstrate that the Wnt1 lineage does not undergo progressive lineage restriction, which eliminates a restricted competence model of generating MbDA diversity. Interestingly, we uncover that two significant peaks of Wnt1 lineage contribution to MbDA neurons occur at E9.5 and E11.5. Collectively, our findings delineate the temporal window of MbDA neuron generation and show that lineage and timing predicts the terminal distribution pattern of MbDA neurons. J. Comp. Neurol. 519:2978-3000, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Hayes, Lindsay] Brown Univ, Dept Neurosci, Brown NIH Grad Partnership Program, Providence, RI 02903 USA. [Machan, Jason T.] Rhode Isl Hosp, Dept Orthoped, Providence, RI 02903 USA. [Machan, Jason T.] Rhode Isl Hosp, Dept Surg, Providence, RI 02903 USA. [Machan, Jason T.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA. [Hayes, Lindsay] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Zervas, Mark] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02903 USA. RP Zervas, M (reprint author), 70 Ship St, Providence, RI 02903 USA. EM Mark_Zervas@brown.edu RI Machan, Jason/D-3897-2013 OI Machan, Jason/0000-0003-2048-4914 FU Startup Research Funds; RI Hospital Center for Stem Cell Biology [701-1960]; Brown University, NIH [NS062443-02]; Brown Institute for Brain Science FX Grant sponsor: Startup Research Funds (to M.Z.); Grant sponsor: RI Hospital Center for Stem Cell Biology; Grant number: 701-1960 (to M.Z.); Grant sponsor: Brown University Neuroscience Graduate Program NIH Advanced Predoctoral Training Grant; Grant number: NS062443-02; Grant sponsor: Brown Institute for Brain Science Kaplan Summer Graduate Award (to A.B.). NR 66 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD OCT 15 PY 2011 VL 519 IS 15 BP 2978 EP 3000 DI 10.1002/cne.22710 PG 23 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 818XP UT WOS:000294790300004 PM 21713770 ER PT J AU Hayes, L Zhang, ZW Albert, P Zervas, M Ahn, S AF Hayes, Lindsay Zhang, Zhiwei Albert, Paul Zervas, Mark Ahn, Sohyun TI Timing of Sonic Hedgehog and Gli1 Expression Segregates Midbrain Dopamine Neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE fate mapping; VTA; SNc ID GENETIC LINEAGES; NERVOUS-SYSTEM; SPECIFICATION; IDENTITY; FATE; ACTIVATION; PATHWAY; SIGNALS; ORIGIN; MOUSE AB The ventral midbrain (vMb) is organized into distinct anatomical domains and contains cohorts of functionally distinct subtypes of midbrain dopamine (mDA) neurons. We tested the hypothesis that genetic history and timing of gene expression within mDA neuron progenitors impart spatial diversity. Using genetic inducible fate mapping to mark the Sonic hedgehog (Shh) and Gli1 lineages at varying embryonic stages, we performed a quantitative and qualitative comparison of the two lineages' contribution to the mDA neuron domains. Dynamic changes in Shh and Gli1 expression in the vMb primordia delineated their spatial contribution to the embryonic day 12.5 vMb: Both lineages first contributed to the medial domain, but subsequently the Gli1 lineage exclusively contributed to the lateral vMb while the Shh lineage expanded more broadly across the vMb. The contribution of both lineages to the differentiated mDA neuron domain was initially biased anteriorly and became more uniform across the anterior/posterior vMb throughout development. Our findings demonstrate that the early Shh and Gli1 lineages specify mDA neurons of the substantia nigra pars compacta while the late Shh and Gli1 lineages maintain their progenitor state longer in the posterior vMb to extend the production of mDA neurons in the ventral tegmental area. Together, our study demonstrates that the timing of gene expression along with the genetic lineage (Shh or Gli1) within the neural progenitors segregate mDA neurons into distinct spatial domains. J. Comp. Neurol. 519:3001-3018, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Hayes, Lindsay; Ahn, Sohyun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Hayes, Lindsay] Brown Univ, Dept Neurosci, Brown NIH Grad Partnership Program, Providence, RI 02906 USA. [Zhang, Zhiwei; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Zervas, Mark] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02906 USA. RP Ahn, S (reprint author), 9000 Rockville Pike,6B-2B220, Bethesda, MD 20892 USA. EM Mark_Zervas@brown.edu; ahnsohyun@mail.nih.gov FU National Institutes of Health [1ZIAHD008781] FX Grant sponsor: Intramural Research Program of the National Institutes of Health; Grant number: 1ZIAHD008781. NR 40 TC 26 Z9 27 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD OCT 15 PY 2011 VL 519 IS 15 BP 3001 EP 3018 DI 10.1002/cne.22711 PG 18 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 818XP UT WOS:000294790300005 PM 21713771 ER PT J AU Pandya, A Yakel, JL AF Pandya, Anshul Yakel, Jerrel L. TI Allosteric modulators of the alpha 4 beta 2 subtype of neuronal nicotinic acetylcholine receptors SO BIOCHEMICAL PHARMACOLOGY LA English DT Review DE Nicotinic acetylcholine receptor; Allosteric modulation; Positive allosteric modulators; Negative allosteric modulators ID BRYOZOAN FLUSTRA-FOLIACEA; GABA(A) RECEPTORS; BINDING-SITE; POTENTIATING LIGANDS; ALZHEIMERS-DISEASE; TREATMENT STRATEGY; XENOPUS OOCYTES; IN-VITRO; SUBUNIT; BRAIN AB Nicotinic acetylcholine receptors are ligand-gated ion conducting transmembrane channels from the Cys-loop receptor super-family. The alpha 4 beta 2 subtype is the predominant heteromeric subtype of nicotinic receptors found in the brain. Allosteric modulators for alpha 4 beta 2 receptors interact at a site other than the orthosteric site where acetylcholine binds. Many compounds which act as allosteric modulators of the alpha 4 beta 2 receptors have been identified, with both positive and negative effects. Such allosteric modulators either increase or decrease the response induced by agonist on the alpha 4 beta 2 receptors. Here we discuss the concept of allosterism as it pertains to the alpha 4 beta 2 receptors and summarize the important features of allosteric modulators for this nicotinic receptor subtype. Published by Elsevier Inc. C1 [Pandya, Anshul; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, MD F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM pandyaaa@niehs.nih.gov; yakel@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX We would like to thank and acknowledge the contributions of Patricia Lamb for her input in the preparation of this manuscript. We would also like to extend our appreciation to Dr. Christian Erxleben and Dr. Nikhil. A. Gokhale for their help in the review of the manuscript. Participants in this research review are funded and supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 72 TC 20 Z9 20 U1 1 U2 10 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 OCT 15 PY 2011 VL 82 IS 8 SI SI BP 952 EP 958 DI 10.1016/j.bcp.2011.04.020 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 815GD UT WOS:000294513200017 PM 21596025 ER PT J AU Murphy, MA Wentzensen, N AF Murphy, Megan A. Wentzensen, Nicolas TI Frequency of mismatch repair deficiency in ovarian cancer: a systematic review SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE ovarian cancer; mismatch repair deficiency; microsatellite instability; immunohistochemical staining; MLH1 methylation ID MICROSATELLITE-INSTABILITY STATUS; POORLY DIFFERENTIATED TYPE; CLEAR-CELL CARCINOMA; REPLICATION ERRORS; INTERNATIONAL CRITERIA; ENDOMETRIAL CARCINOMAS; PROMOTER METHYLATION; COLORECTAL-CANCER; EXPRESSION; GENE AB Loss of mismatch repair (MMR) capacity may represent an important tumor initiating mechanism in ovarian cancer. We conducted a systematic review to analyze the frequency of microsatellite instability (MSI), immunohistochemical (IHC) staining for MMR proteins, and hypermethylation of the MLH1 promoter region in ovarian cancers. Studies examining MSI, loss of MMR gene expression by IHC staining and MLH1 promoter hypermethylation in ovarian cancer were identified by a systematic literature search of the PubMed electronic database through August 31, 2009. Pertinent data was extracted from eligible studies and estimates for pooled proportions were computed using random effects models. The pooled proportion of MSI detection was 0.10 (95% CI, 0.0620.14) among 1,234 cases in 22 studies. Dinonucleotide markers had a higher frequency of instability than mononucleotide markers. The pooled proportion of MLH1 or MSH2 staining loss was 0.06 (95% CI, 0.0120.17) among 474 cases in three studies, with a higher frequency of loss in MLH1. The pooled proportion of MLH1 methylation was 0.10 (95% CI, 0.0620.15) among 672 cases in seven studies. Data reporting MSI and loss of MMR staining in the same cases was limited. Although MMR deficiency was found in all histologic subtypes, endometrioid cancers had the highest proportion. Approximately 10% of unselected ovarian cancers are related to MMR deficiency. While MMR deficiency is associated with improved survival in other MMR-deficiency related cancer sites, epidemiological and clinical factors related to the MMR-deficient phenotype have not been adequately studied in ovarian cancer to date. C1 [Murphy, Megan A.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU National Cancer Institute, National Institutes of Health; NIH [5 T32 CA09001-35] FX Grant sponsor: The Intramural Research Program of the National Cancer Institute, National Institutes of Health; Grant sponsor: NIH; Grant number: 5 T32 CA09001-35 NR 50 TC 23 Z9 23 U1 1 U2 2 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 OCT 15 PY 2011 VL 129 IS 8 BP 1914 EP 1922 DI 10.1002/ijc.25835 PG 9 WC Oncology SC Oncology GA 811PI UT WOS:000294224300013 PM 21140452 ER PT J AU O'Boyle, NM Guha, R Willighagen, EL Adams, SE Alvarsson, J Bradley, JC Filippov, IV Hanson, RM Hanwell, MD Hutchison, GR James, CA Jeliazkova, N Lang, ASID Langner, KM Lonie, DC Lowe, DM Pansanel, J Pavlov, D Spjuth, O Steinbeck, C Tenderholt, AL Theisen, KJ Murray-Rust, P AF O'Boyle, Noel M. Guha, Rajarshi Willighagen, Egon L. Adams, Samuel E. Alvarsson, Jonathan Bradley, Jean-Claude Filippov, Igor V. Hanson, Robert M. Hanwell, Marcus D. Hutchison, Geoffrey R. James, Craig A. Jeliazkova, Nina Lang, Andrew S. I. D. Langner, Karol M. Lonie, David C. Lowe, Daniel M. Pansanel, Jerome Pavlov, Dmitry Spjuth, Ola Steinbeck, Christoph Tenderholt, Adam L. Theisen, Kevin J. Murray-Rust, Peter TI Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk five years on SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID OPEN-SOURCE SOFTWARE; DEVELOPMENT KIT CDK; SOURCE JAVA LIBRARY; DRUG DISCOVERY; WEB; CHEMINFORMATICS; BIOINFORMATICS; PREDICTION; FRAMEWORK; SERVICES AB Background: The Blue Obelisk movement was established in 2005 as a response to the lack of Open Data, Open Standards and Open Source (ODOSOS) in chemistry. It aims to make it easier to carry out chemistry research by promoting interoperability between chemistry software, encouraging cooperation between Open Source developers, and developing community resources and Open Standards. Results: This contribution looks back on the work carried out by the Blue Obelisk in the past 5 years and surveys progress and remaining challenges in the areas of Open Data, Open Standards, and Open Source in chemistry. Conclusions: We show that the Blue Obelisk has been very successful in bringing together researchers and developers with common interests in ODOSOS, leading to development of many useful resources freely available to the chemistry community. C1 [O'Boyle, Noel M.] Natl Univ Ireland Univ Coll Cork, Analyt & Biol Chem Res Facil, Cork, Ireland. [Guha, Rajarshi] NIH, Ctr Translat Therapeut, Rockville, MD 20878 USA. [Willighagen, Egon L.] Karolinska Inst, Inst Environm Med, Div Mol Toxicol, S-17177 Stockholm, Sweden. [Adams, Samuel E.; Lowe, Daniel M.; Murray-Rust, Peter] Univ Cambridge, Dept Chem, Unilever Ctr Mol Sci Informat, Cambridge CB2 1EW, England. [Alvarsson, Jonathan; Spjuth, Ola] Uppsala Univ, Dept Pharmaceut Biosci, S-75124 Uppsala, Sweden. [Bradley, Jean-Claude] Drexel Univ, Dept Chem, Philadelphia, PA 19104 USA. [Filippov, Igor V.] NCI, Biol Chem Lab, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hanson, Robert M.] St Olaf Coll, Northfield, MN 55057 USA. [Hanwell, Marcus D.] Kitware Inc, Clifton Pk, NY 12065 USA. [Hutchison, Geoffrey R.] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [James, Craig A.] eMolecules Inc, Solana Beach, CA 92075 USA. [Jeliazkova, Nina] Ideaconsult Ltd, Sofia 1000, Bulgaria. [Lang, Andrew S. I. D.] Oral Roberts Univ, Dept Engn Comp Sci Phys & Math, Tulsa, OK 74171 USA. [Langner, Karol M.] Leiden Univ, Leiden Inst Chem, NL-2333 CC Leiden, Netherlands. [Lonie, David C.] SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA. [Pansanel, Jerome] Univ Strasbourg, IPHC, CNRS, UMR7178, F-67037 Strasbourg, France. [Pavlov, Dmitry] GGA Software Serv LLC, St Petersburg 194342, Russia. [Steinbeck, Christoph] EBI, Cheminformat & Metab Team, Cambridge, England. [Tenderholt, Adam L.] Univ Washington, Dept Chem, Seattle, WA 98195 USA. [Theisen, Kevin J.] iChemLabs, Piscataway, NJ 08854 USA. RP O'Boyle, NM (reprint author), Natl Univ Ireland Univ Coll Cork, Analyt & Biol Chem Res Facil, Cavanagh Pharm Bldg,Coll Rd, Cork, Ireland. EM baoilleach@gmail.com RI Steinbeck, Christoph/B-4131-2008; Willighagen, Egon/C-6136-2008; Langner, Karol/F-2119-2010; Hutchison, Geoffrey/B-3109-2009; Trivedi, Kruti/E-7558-2015; Adams, Sam/D-6257-2011; OI Willighagen, Egon/0000-0001-7542-0286; Langner, Karol/0000-0003-2826-5652; Hanwell, Marcus/0000-0002-5851-5272; Hutchison, Geoffrey/0000-0002-1757-1980; O'Boyle, Noel/0000-0003-4879-2003; Spjuth, Ola/0000-0002-8083-2864; Bradley, Jean-Claude/0000-0001-7144-4846; Lang, Andrew/0000-0002-9922-1414; Murray-Rust, Peter/0000-0003-3386-3972; Adams, Sam/0000-0001-7141-0400; Jeliazkova, Nina/0000-0002-4322-6179; Steinbeck, Christoph/0000-0001-6966-0814 FU Health Research Board [PD/2009/13]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX NMOB is supported by a Health Research Board Career Development Fellowship (PD/2009/13). The OSRA project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government. NR 81 TC 27 Z9 28 U1 2 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD OCT 14 PY 2011 VL 3 AR 37 DI 10.1186/1758-2946-3-37 PG 16 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891QQ UT WOS:000300232100004 PM 21999342 ER PT J AU Zaharevitz, DW AF Zaharevitz, Dan W. TI Adventures in public data SO JOURNAL OF CHEMINFORMATICS LA English DT Article AB This article contains the slides and transcript of a talk given by Dan Zaharevitz at the "Visions of a Semantic Molecular Future" symposium held at the University of Cambridge Department of Chemistry on 2011-01-19. A recording of the talk is available on the University Computing Service's Streaming Media Service archive at http://sms.cam.ac.uk/media/1095515 (unfortunately the first part of the recording was corrupted, so the talk appears to begin at slide 6, 'At a critical time'). We believe that Dan's message comes over extremely well in the textual transcript and that it would be poorer for serious editing. In addition we have added some explanations and references of some of the concepts in the slides and text. (Charlotte Bolton; Peter Murray-Rust, University of Cambridge) Editorial preface: The following paper is part of a series of publications which arose from a Symposium held at the Unilever Centre for Molecular Informatics at the University of Cambridge to celebrate the lifetime achievements of Peter Murray-Rust. One of the motives of Peter's work was and is a better transport and preservation of data and information in scientific publications. In both respects the following publication is relevant: it is about public data and their representation, and the publication represents a non-standard experiment of transporting the content of the scientific presentation. As you will see, it consists of the original slides used by Dan Zaharevitz in his talk "Adventures in Public Data" at the Unilever Centre together with a diligent transcript of his speech. The transcribers have gone through great effort to preserve the original spirit of the talk by preserving colloquial language as it is used at such occasions. For reasons known to us, the original speaker was unable to submit the manuscript in a more conventional form. We, the Editors, have discussed in depth whether such a format is suitable for a scientific journal. We have eventually decided to publish this "as is". We did this mostly because it was Peter's wish that this talk was published in this form and because we agreed with his notion that this format transmits the message just as well as a formal article as defined by our instructions for authors. We, the Editors, wish to make clear however that this is an exception that we made because we would like to preserve the temporal unity and message of this set of publications. Insisting on a formal publication would have meant losing this historical account as part of the thematic series of papers or disrupting the series. We hope that this will find the consent of our readership. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Zaharevitz, DW (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM zaharevd@mail.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD OCT 14 PY 2011 VL 3 AR 34 DI 10.1186/1758-2946-3-34 PG 18 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891QQ UT WOS:000300232100001 PM 22017861 ER PT J AU Lichten, M de Massy, B AF Lichten, Michael de Massy, Bernard TI The Impressionistic Landscape of Meiotic Recombination SO CELL LA English DT Review ID INITIATION; HOTSPOTS; MEIOSIS; YEAST; PRDM9; CONSERVATION; FEATURES; SITES; MOUSE AB Two high-resolution maps of meiotic recombination initiation sites across the genomes of budding yeast and mice illuminate broad similarities in the control of meiotic recombination in these diverse species but also highlight key differences. These studies offer new insights into the relationships between recombination, chromosome structure, and genome evolution. C1 [de Massy, Bernard] CNRS, Inst Human Genet, UPR1142, F-34396 Montpellier, France. [Lichten, Michael] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP de Massy, B (reprint author), CNRS, Inst Human Genet, UPR1142, F-34396 Montpellier, France. EM bernard.de-massy@igh.cnrs.fr RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU Center for Cancer Research, National Cancer Institute, NIH; Centre National de la Recherche Scientifique; Agence Nationale de la Recherche [09-BLAN-0269-01]; Association pour la Recherche contre le Cancer; Fondation pour la Recherche Medicale FX We thank Dan Camerini-Otero, Galina Pethukova, Scott Keeney, and members of their groups for data used in Figure 1. We apologize to many colleagues whose work was not cited here due to space limits. M.L. is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; B.d.M. is supported by the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (09-BLAN-0269-01), the Association pour la Recherche contre le Cancer, and the Fondation pour la Recherche Medicale. NR 23 TC 42 Z9 42 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 14 PY 2011 VL 147 IS 2 BP 267 EP 270 DI 10.1016/j.cell.2011.09.038 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837KD UT WOS:000296199300006 PM 22000007 ER PT J AU Guo, CY Gerasimova, T Hao, HP Ivanova, I Chakraborty, T Selimyan, R Oltz, EM Sen, RJ AF Guo, Changying Gerasimova, Tatiana Hao, Haiping Ivanova, Irina Chakraborty, Tirtha Selimyan, Roza Oltz, Eugene M. Sen, Ranjan TI Two Forms of Loops Generate the Chromatin Conformation of the Immunoglobulin Heavy-Chain Gene Locus SO CELL LA English DT Article ID B-CELL DEVELOPMENT; INTRONIC ENHANCER; IGH LOCUS; LYMPHOCYTE DEVELOPMENT; SWITCH RECOMBINATION; REGULATORY ELEMENTS; V(D)J RECOMBINATION; VARIABLE REGION; CTCF SITES; INSULATORS AB The immunoglobulin heavy-chain (IgH) gene locus undergoes radial repositioning within the nucleus and locus contraction in preparation for gene recombination. We demonstrate that IgH locus conformation involves two levels of chromosomal compaction. At the first level, the locus folds into several multi-looped domains. One such domain at the 30 end of the locus requires an enhancer, Em; two other domains at the 50 end are Em independent. At the second level, these domains are brought into spatial proximity by Em-dependent interactions with specific sites within the V-H region. Em is also required for radial repositioning of IgH alleles, indicating its essential role in large-scale chromosomal movements in developing lymphocytes. Our observations provide a comprehensive view of the conformation of IgH alleles in pro-B cells and the mechanisms by which it is established. C1 [Guo, Changying; Gerasimova, Tatiana; Ivanova, Irina; Chakraborty, Tirtha; Selimyan, Roza; Sen, Ranjan] NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Hao, Haiping] Johns Hopkins Univ, Sch Med, JHMI Deep Sequencing & Microarray Core, Baltimore, MD 21231 USA. [Oltz, Eugene M.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. RP Sen, RJ (reprint author), NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rs465z@nih.gov OI Hao, Haiping/0000-0002-8826-1568 FU National Institute on Aging (Baltimore, MD); NIH [P01 HL68744, CA100905] FX We are indebted to Cornelis Murre and Suchit Jhunjhunwala for sharing and troubleshooting the procedures for small probe FISH. We thank Drs. Dinah Singer, Amy Kenter, Cornelis Murre, Fred Alt, and Sebastian Fugmann for discussions throughout the work and critical appraisal of the manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging (Baltimore, MD) and by NIH grant (P01 HL68744 and CA100905) to E.M.O. NR 44 TC 77 Z9 79 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 14 PY 2011 VL 147 IS 2 BP 332 EP 343 DI 10.1016/j.cell.2011.08.049 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837KD UT WOS:000296199300012 PM 21982154 ER PT J AU Herkenham, M Rathore, P Brown, P Listwak, SJ AF Herkenham, Miles Rathore, Priyanka Brown, Pierre Listwak, Samuel J. TI Cautionary notes on the use of NF-kappa B p65 and p50 antibodies for CNS studies SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE NF-kappa?kappa?B; transcription factor; immunohistochemistry; antibody specificity ID FOCAL CEREBRAL-ISCHEMIA; TRAUMATIC BRAIN-INJURY; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; RAT-BRAIN; PROINFLAMMATORY CYTOKINES; TRANSCRIPTIONAL ACTIVITY; TRYPANOSOMA-BRUCEI; DEFICIENT MOUSE; MESSENGER-RNA AB Background: The characterization and cellular localization of transcription factors like NF-kappa B requires the use of antibodies for western blots and immunohistochemistry. However, if target protein levels are low and the antibodies not well characterized, false positive data can result. In studies of NF-kappa B activity in the CNS, antibodies detecting NF-kappa B proteins have been used to support the finding that NF-kappa B is constitutively active in neurons, and activity levels are further increased by neurotoxic treatments, glutamate stimulation, or elevated synaptic activity. The specificity of the antibodies used was analyzed in this study. Methods: Selectivity and nonselectivity of commonly used commercial and non-commercial p50 and p65 antibodies were demonstrated in western blot assays conducted in tissues from mutant gene knockout mice lacking the target proteins. Results: A few antibodies for p50 and p65 each mark a single band at the appropriate molecular weight in gels containing proteins from wildtype tissue, and this band is absent in proteins from knockout tissues. Several antibodies mark proteins that are present in knockout tissues, indicating that they are nonspecific. These include antibodies raised against the peptide sequence containing the nuclear localization signals of p65 (MAB3026; Chemicon) and p50 (sc-114; Santa Cruz). Some antibodies that recognize target proteins at the correct molecular weight still fail in western blot analysis because they also mark additional proteins and inconsistently so. We show that the criterion for validation by use of blocking peptides can still fail the test of specificity, as demonstrated for several antibodies raised against p65 phosphorylated at serine 276. Finally, even antibodies that show specificity in western blots produce nonspecific neuronal staining by immunohistochemistry. Conclusions: We note that many of the findings in the literature about neuronal NF-kappa B are based on data garnered with antibodies that are not selective for the NF-kappa B subunit proteins p65 and p50. The data urge caution in interpreting studies of neuronal NF-kappa B activity in the brain. C1 [Herkenham, Miles; Rathore, Priyanka; Brown, Pierre; Listwak, Samuel J.] NIMH, Funct Neuroanat Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Lab Cellular & Mol Regulat, NIH, 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 work was supported by the Intramural Research Program, National Institute of Mental Health, NIH. NR 63 TC 19 Z9 19 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD OCT 14 PY 2011 VL 8 AR 141 DI 10.1186/1742-2094-8-141 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 843VM UT WOS:000296703100001 PM 21999414 ER PT J AU Beca, S Helli, PB Simpson, JA Zhao, DL Farman, GP Jones, PP Tian, XX Wilson, LS Ahmad, F Chen, SRW Movsesian, MA Manganiello, V Maurice, DH Conti, M Backx, PH AF Beca, Sanja Helli, Peter B. Simpson, Jeremy A. Zhao, Dongling Farman, Gerrie P. Jones, Peter P. Tian, Xixi Wilson, Lindsay S. Ahmad, Faiyaz Chen, S. R. Wayne Movsesian, Matthew A. Manganiello, Vincent Maurice, Donald H. Conti, Marco Backx, Peter H. TI Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca2+ Release and Cardiac Contractility, Independently of L-Type Ca2+ Current SO CIRCULATION RESEARCH LA English DT Article DE PDE4D; cAMP; cardiac function; excitation-contraction coupling; PLN ID OBSTRUCTIVE PULMONARY-DISEASE; HEART-RATE-VARIABILITY; SIGNALING CROSS-TALK; OUTWARD K+ CURRENT; VENTRICULAR MYOCYTES; MOUSE; MICE; CAMP; ARRHYTHMIAS; INHIBITORS AB Rationale: Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-gamma-dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a). Objective: The goal of this study was to determine whether PDE4D regulates basal cardiac contractility. Methods and Results: At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D(-/-)) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D(-/-) cardiomyocytes showed increased whole-cell Ca2+ transient amplitudes and SR Ca2+ content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor R-p-adenosine-3',5' cyclic monophosphorothioate (R-p-cAMP) lowered whole-cell Ca2+ transient amplitudes and SR Ca2+ content in PDE4D(-/-) cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca2+ transients, or SR Ca2+ content in PDE4D(-/-) preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D(-/-). The functional changes in PDE4D(-/-) myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D(-/-) cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. Conclusions: PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca2+ channels or ryanodine receptor. Because whole-cell Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure. (Circ Res. 2011;109:1024-1030.) C1 [Beca, Sanja; Helli, Peter B.; Simpson, Jeremy A.; Zhao, Dongling; Farman, Gerrie P.; Backx, Peter H.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Backx, Peter H.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Backx, Peter H.] Univ Toronto, Div Cardiol, Toronto, ON, Canada. [Beca, Sanja; Helli, Peter B.; Simpson, Jeremy A.; Zhao, Dongling; Farman, Gerrie P.; Backx, Peter H.] Univ Toronto, Univ Hlth Network, Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada. [Jones, Peter P.; Tian, Xixi; Chen, S. R. Wayne] Univ Calgary, Dept Physiol & Biophys, Calgary, AB, Canada. [Wilson, Lindsay S.; Maurice, Donald H.] Queens Univ, Dept Pathol & Mol Med, Kingston, ON, Canada. [Maurice, Donald H.] Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. [Ahmad, Faiyaz; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Movsesian, Matthew A.] Univ Utah, Vet Affairs Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. [Movsesian, Matthew A.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Movsesian, Matthew A.] Univ Utah, Dept Pharmacol, Salt Lake City, UT USA. [Conti, Marco] Univ Calif San Francisco, Dept Obstet & Gynaecol, San Francisco, CA 94143 USA. RP Backx, PH (reprint author), 150 Coll St, Toronto, ON M5S 3E2, Canada. EM p.backx@utoronto.ca RI Jones, Peter/G-2618-2013 FU Canadian Institutes of Health Research; Heart and Stroke Foundation (HSF) of Ontario; Heart and Stroke Richard Lewar Centre of Excellence (HSRLCE), University of Toronto; HSRLCE; HSF of Canada; Foundation Leducq [06CVD02 cycAMP]; National Institutes of Health [HL0927088]; United States Department of Veterans Affairs FX This work was supported by a Canadian Institutes of Health Research grant to Dr Backx, who is a Career Investigator with the Heart and Stroke Foundation (HSF) of Ontario. Dr Beca holds a postdoctoral fellowship from the Heart and Stroke Richard Lewar Centre of Excellence (HSRLCE), University of Toronto. Dr Helli held postdoctoral fellowships from HSRLCE and HSF of Canada. Support was also provided by Foundation Leducq Grant 06CVD02 cycAMP (to M.C. and M.A.M.), National Institutes of Health Grant HL0927088 (to M.C.), and grants from the United States Department of Veterans Affairs Medical Research Funds (to M.A.M.). NR 41 TC 32 Z9 33 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 14 PY 2011 VL 109 IS 9 BP 1024 EP U119 DI 10.1161/CIRCRESAHA.111.250464 PG 29 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 837KC UT WOS:000296199100008 PM 21903937 ER PT J AU Kitagaki, J Yang, YL AF Kitagaki, Jirouta Yang, Yili TI DNA intercalator korkormicin A preferentially kills tumor cells expressing wild type p53 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Korkormicin A; DNA intercalation; p53; Apoptosis; Antitumor agent ID BIOLOGICAL-ACTIVITIES; ANTICANCER AGENTS; CANCER-THERAPY; DEPSIPEPTIDE; ECHINOMYCIN; INHIBITORS; BINDING; MDM2; PHOSPHORYLATION; MICROMONOSPORA AB Korkormicin A belongs to a family of nature-produced cyclic depsipeptides. It has potent antitumor activity against both leukemia cell P388 and carcinoma cell M109. To further explore its potential as a cancer therapeutic, the mechanism of its antitumor activity was investigated. We found that korkormicin A can bind to DNA through intercalation. It also induces p53 phosphorylation, which leads to inhibition of p53 degradation and activation of p53-dependent transcription. Furthermore, korkormicin A preferentially induces apoptosis in transformed cells retaining wild type p53. As it has been shown that p53 usually induces apoptosis in transformed cells, but only growth arrest in untransformed cells, these results indicate that korkormicin A is a potential antitumor agent for cancers with wild type p53. Published by Elsevier Inc. C1 [Kitagaki, Jirouta; Yang, Yili] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. RP Yang, YL (reprint author), NCI, Canc & Dev Biol Lab, NIH, Bldg 538,Rm 224,1050 Boyles St, Frederick, MD 21702 USA. EM Yili.Yang@nih.gov FU Center for Cancer Research, National Cancer Institute; Japanese Society for the Promotion of Science FX We thank Dr. AO. Perantoni (Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health) for helpful encourage and support, Dr. J. Leet (Bristol-Myers Squibb) and R. Lam (Nereus Pharmaceuticals) for the sample of korkormicin A, Dr. H. Saneyoshi (Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health) for helpful discussion, and the NIH Fellows Editorial Board for editorial assistance with this article. This work was supported by the Center for Cancer Research, National Cancer Institute and the Japanese Society for the Promotion of Science (J. Kitagaki). NR 33 TC 4 Z9 4 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 14 PY 2011 VL 414 IS 1 BP 186 EP 191 DI 10.1016/j.bbrc.2011.09.054 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 837PH UT WOS:000296215200034 PM 21946062 ER PT J AU Osabe, M Negishi, M AF Osabe, Makoto Negishi, Masahiko TI Active ERK1/2 Protein Interacts with the Phosphorylated Nuclear Constitutive Active/Androstane Receptor (CAR; NR1I3), Repressing Dephosphorylation and Sequestering CAR in the Cytoplasm SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOUSE-LIVER; CYP2B GENE; INDUCTION; KINASE; TRANSLOCATION; ACTIVATION; ENZYMES; PXR AB The nuclear constitutive active/androstane receptor (CAR) is inactivated and sequestered in the cytoplasm when Thr-38 is phosphorylated. Here, we have demonstrated that activated ERK1/2 interacts with phosphorylated CAR to repress dephosphorylation of Thr-38. The phosphorylation-dependent interaction between CAR and ERK1/2 was examined by co-immunoprecipitation experiments of ectopically expressed FLAG-tagged CAR T38A and CAR T38D mutants with endogenous phospho-ERK1/2 in Huh-7 cells. Phospho-ERK1/2 coprecipitated only the phosphorylation-mimicking CAR T38D mutant; this coprecipitation was mediated by the interaction with the xenochemical response signal peptide near the C terminus of CAR. This interaction increased after EGF treatment and decreased after treatment with the MEK inhibitor U0126 as well as after knockdown of MEK1/2 by shRNA in Huh-7 cells. The phosphorylation levels of Thr-38 of CAR decreased in U0126-treated Huh-7 cells. Thus, activated ERK1/2 interacts with CAR and represses dephosphorylation of Thr-38, providing a cell signal-regulated mechanism for CAR activation. C1 [Osabe, Makoto; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health; National Institutes of Health, NIEHS [Z01ES1005-01] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program and National Institutes of Health Grant Z01ES1005-01 from NIEHS. NR 19 TC 27 Z9 29 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2011 VL 286 IS 41 BP 35763 EP 35769 DI 10.1074/jbc.M111.284596 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834AG UT WOS:000295927100049 PM 21873423 ER PT J AU Yang, JH Nahm, MH Bush, CA Cisar, JO AF Yang, Jinghua Nahm, Moon H. Bush, C. Allen Cisar, John O. TI Comparative Structural and Molecular Characterization of Streptococcus pneumoniae Capsular Polysaccharide Serogroup 10 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PNEUMOCOCCUS-GROUP; BIOSYNTHETIC LOCI; COMPETENCE; VARIANTS; SEROLOGY; ORALIS AB Streptococcus pneumoniae serogroup 10 includes four cross-reactive capsular polysaccharide (CPS) serotypes (10F, 10A, 10B, and 10C). In the present study, the structures of CPS10B and CPS10C were determined by chemical and high resolution NMR methods to define the features of each serotype. Both CPS10C and CPS10F had beta 1-6-linked Galf branches formed from the termini of linear repeating units by wzy-dependent polymerization through the 4-OH of subterminal GalNAc. The only difference between these polysaccharides was the wcrC-dependent alpha 1-2 or wcrF-dependent alpha 1-4 linkages between Gal and ribitol-5-phosphate. The presence of one linkage or the other also distinguished the repeating units of CPS10B and CPS10A. However, whereas these polysaccharides both had beta 1-3-linked Galf branches linked to GalNAc, only CPS10A had additional beta 1-6-linked Galp branches. These Galp branches and the reaction of a CPS10A-specific monoclonal antibody were eliminated by deletion of wcrG from the cps10A locus. In contrast, deletion of this gene from the cps10B locus had no effect on the structure of CPS10B, thereby identifying wcrG as a pseudogene in this serotype. The beta 1-3-linked Galf branches of CPS10A and CPS10B were eliminated by deletion of wcrD from each corresponding cps locus. Deletion of this gene also eliminated wcrG-dependent beta 1-6-linked Galp branches from CPS10A, thereby identifying WcrG as a branching enzyme that acts on the product of WcrD. These findings provide a complete view of the molecular, structural, and antigenic features of CPS serogroup 10, as well as insight into the possible emergence of new serotypes. C1 [Yang, Jinghua; Cisar, John O.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Nahm, Moon H.] Univ Alabama, Dept Pathol, Birmingham, AL 35249 USA. [Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Cisar, JO (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 3A-301,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov OI Nahm, Moon/0000-0002-6922-1042 FU National Institutes of Health [AI-31473]; NIDCR FX This work was supported, in whole or in part, by National Institutes of Health Grant AI-31473 (to M. H. N.). This work was also supported by the Intramural Research Program of the NIDCR. NR 19 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2011 VL 286 IS 41 BP 35813 EP 35822 DI 10.1074/jbc.M111.255422 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834AG UT WOS:000295927100054 PM 21859716 ER PT J AU Yang, X Guo, ZY Sun, F Li, W Alfano, A Shimelis, H Chen, MY Brodie, AMH Chen, HG Xiao, Z Veenstra, TD Qiu, Y AF Yang, Xi Guo, Zhiyong Sun, Feng Li, Wei Alfano, Alan Shimelis, Hermela Chen, Mingyuan Brodie, Angela M. H. Chen, Hegang Xiao, Zhen Veenstra, Timothy D. Qiu, Yun TI Novel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; RESISTANT GROWTH; PALMITOYLATION; PROGRESSION; THERAPY AB Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors. C1 [Yang, Xi; Guo, Zhiyong; Sun, Feng; Li, Wei; Alfano, Alan; Shimelis, Hermela; Chen, Mingyuan; Brodie, Angela M. H.; Qiu, Yun] Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. [Chen, Hegang] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Xiao, Zhen; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick, NIH, Frederick, MD 21702 USA. RP Qiu, Y (reprint author), Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, 655 W Baltimore St,BRB Rm 4-002, Baltimore, MD 21202 USA. EM yqiu@som.umaryland.edu OI Shimelis, Hermela/0000-0003-1284-8909 FU National Institutes of Health [CA106504]; NCI [HHSN261200800001E]; Department of Defense [W81XWH-08-1-0174] FX This work was supported, in whole or in part, by National Institutes of Health Grant CA106504 (to Y. Q.) and Grant HHSN261200800001E through the NCI. This work was also supported by Department of Defense Grant W81XWH-08-1-0174 (to Y. Q.). NR 22 TC 37 Z9 38 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2011 VL 286 IS 41 BP 36152 EP 36160 DI 10.1074/jbc.M111.265124 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834AG UT WOS:000295927100087 PM 21878636 ER PT J AU Francis, R Xu, X Park, H Wei, CJ Chang, S Chatterjee, B Lo, C AF Francis, Richard Xu, Xin Park, Hyunsoo Wei, Chin-Jen Chang, Stephen Chatterjee, Bishwanath Lo, Cecilia TI Connexin43 Modulates Cell Polarity and Directional Cell Migration by Regulating Microtubule Dynamics SO PLOS ONE LA English DT Article ID GAP JUNCTIONAL COMMUNICATION; NEURAL CREST CELLS; N-CADHERIN; FIBROBLAST MIGRATION; NEURONAL MIGRATION; EPITHELIAL-CELLS; PLASMA-MEMBRANE; TGF-BETA; MICE; EXPRESSION AB Knockout mice deficient in the gap junction gene connexin43 exhibit developmental anomalies associated with abnormal neural crest, primordial germ cell, and proepicardial cell migration. These migration defects are due to a loss of directional cell movement, and are associated with abnormal actin stress fiber organization and a loss of polarized cell morphology. To elucidate the mechanism by which Cx43 regulates cell polarity, we used a wound closure assays with mouse embryonic fibroblasts (MEFs) to examine polarized cell morphology and directional cell movement. Studies using embryonic fibroblasts from Cx43 knockout (Cx43KO) mice showed Cx43 deficiency caused cell polarity defects as characterized by a failure of the Golgi apparatus and the microtubule organizing center to reorient with the direction of wound closure. Actin stress fibers at the wound edge also failed to appropriately align, and stabilized microtubule (Glu-tubulin) levels were markedly reduced. Forced expression of Cx43 with deletion of its tubulin-binding domain (Cx43dT) in both wildtype MEFs and neural crest cell explants recapitulated the cell migration defects seen in Cx43KO cells. However, forced expression of Cx43 with point mutation causing gap junction channel closure had no effect on cell motility. TIRF imaging revealed increased microtubule instability in Cx43KO cells, and microtubule targeting of membrane localized Cx43 was reduced with expression of Cx43dT construct in wildtype cells. Together, these findings suggest the essential role of Cx43 gap junctions in development is mediated by regulation of the tubulin cytoskeleton and cell polarity by Cx43 via a nonchannel function. C1 [Francis, Richard; Lo, Cecilia] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15260 USA. [Xu, Xin; Park, Hyunsoo; Wei, Chin-Jen; Chang, Stephen; Chatterjee, Bishwanath] NHLBI, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. RP Francis, R (reprint author), Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15260 USA. EM cel36@pitt.edu RI Francis, Richard/P-2524-2015 FU NHLBI [ZO1-HL005701] FX This work was supported by NHLBI grant ZO1-HL005701. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 48 Z9 50 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2011 VL 6 IS 10 AR e26379 DI 10.1371/journal.pone.0026379 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834RQ UT WOS:000295981600056 PM 22022608 ER PT J AU Silverman, RH Das Gupta, J Lombardi, VC Ruscetti, FW Pfost, MA Hagen, KS Peterson, DL Ruscetti, SK Bagni, RK Petrow-Sadowski, C Gold, B Dean, M Mikovits, JA AF Silverman, Robert H. Das Gupta, Jaydip Lombardi, Vincent C. Ruscetti, Francis W. Pfost, Max A. Hagen, Kathryn S. Peterson, Daniel L. Ruscetti, Sandra K. Bagni, Rachel K. Petrow-Sadowski, Cari Gold, Bert Dean, Michael Mikovits, Judy A. TI Partial Retraction SO SCIENCE LA English DT Correction C1 [Silverman, Robert H.; Das Gupta, Jaydip] Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. [Lombardi, Vincent C.; Pfost, Max A.; Hagen, Kathryn S.; Peterson, Daniel L.; Mikovits, Judy A.] Whittemore Peterson Inst, Reno, NV 89557 USA. [Ruscetti, Francis W.; Gold, Bert; Dean, Michael] NCI, Expt Immunol Lab, Frederick, MD 21701 USA. [Ruscetti, Sandra K.] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Bagni, Rachel K.] NCI, Adv Technol Program, Frederick, MD 21701 USA. [Petrow-Sadowski, Cari] NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Silverman, RH (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM silverr@ccf.org NR 1 TC 28 Z9 28 U1 0 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 14 PY 2011 VL 334 IS 6053 BP 176 EP 176 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832UI UT WOS:000295833600021 PM 21998366 ER PT J AU Martin, WJ Glass, RI Balbus, JM Collins, FS AF Martin, William J., II Glass, Roger I. Balbus, John M. Collins, Francis S. TI A Major Environmental Cause of Death SO SCIENCE LA English DT Editorial Material ID INDOOR AIR-POLLUTION; SMOKE C1 [Martin, William J., II; Glass, Roger I.; Balbus, John M.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Martin, WJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjmartin@mail.nih.gov; glassr@mail.nih.gov NR 12 TC 57 Z9 59 U1 3 U2 37 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 14 PY 2011 VL 334 IS 6053 BP 180 EP 181 DI 10.1126/science.1213088 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832UI UT WOS:000295833600029 PM 21998373 ER PT J AU Rambold, AS Lippincott-Schwartz, J AF Rambold, Angelika S. Lippincott-Schwartz, Jennifer TI SevERing Mitochondria SO SCIENCE LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM; FISSION C1 [Rambold, Angelika S.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Rambold, AS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov FU Intramural NIH HHS [Z01 HD001609-14, ZIA HD001609-16] NR 17 TC 5 Z9 6 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 14 PY 2011 VL 334 IS 6053 BP 186 EP 187 DI 10.1126/science.1214059 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832UI UT WOS:000295833600033 PM 21998377 ER PT J AU Lau, CY Swann, EM Singh, S Kafaar, Z Meissner, HI Stansbury, JP AF Lau, Chuen-Yen Swann, Edith M. Singh, Sagri Kafaar, Zuhayr Meissner, Helen I. Stansbury, James P. TI Conceptual framework for behavioral and social science in HIV vaccine clinical research SO VACCINE LA English DT Article DE HIV vaccine; Behavioral social science; Conceptual framework; Clinical trial ID RANDOMIZED-CONTROLLED-TRIAL; DZIVE SHIRI PROJECT; SOUTH-AFRICA; STRUCTURAL INTERVENTIONS; PREVENTION INTERVENTION; EDUCATIONAL-ATTAINMENT; ECONOMIC COOPERATION; HEALTH INTERVENTION; REPRODUCTIVE HEALTH; TREATMENT ADHERENCE AB HIV vaccine clinical research occurs within a context where biomedical science and social issues are inter-linked. Previous HIV vaccine research has considered behavioral and social issues, but often treated them as independent of clinical research processes. Systematic attention to the intersection of behavioral and social issues within a defined clinical research framework is needed to address gaps, such as those related to participation in trials, completion of trials, and the overall research experience. Rigorous attention to these issues at project inception can inform trial design and conduct by matching research approaches to the context in which trials are to be conducted. Conducting behavioral and social sciences research concurrent with vaccine clinical research is important because it can help identify potential barriers to trial implementation, as well as ultimate acceptance and dissemination of trial results. We therefore propose a conceptual framework for behavioral and social science in HIV vaccine clinical research and use examples from the behavioral and social science literature to demonstrate how the model can facilitate identification of significant areas meriting additional exploration. Standardized use of the conceptual framework could improve HIV vaccine clinical research efficiency and relevance. Published by Elsevier Ltd. C1 [Lau, Chuen-Yen] NIAID, Collaborat Clin Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Swann, Edith M.] VRP DAIDS NIAID NIH DHHS, Vaccine Clin Res Branch, Bethesda, MD 20892 USA. [Singh, Sagri] Int AIDS Vaccine Initiat, Country Programme, New York, NY 10038 USA. [Singh, Sagri] Int AIDS Vaccine Initiat, Reg Programme, New York, NY 10038 USA. [Kafaar, Zuhayr] Univ Stellenbosch, Dept Psychol, ZA-7602 Matieland, South Africa. [Meissner, Helen I.] NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. [Stansbury, James P.] FDA CDER OND SEALD, Silver Spring, MD 20993 USA. RP Lau, CY (reprint author), NIAID, Collaborat Clin Res Branch, Div Clin Res, NIH, 6700B Rockledge Dr,Rm 1112, Bethesda, MD 20892 USA. EM lauc@mail.nih.gov; swanne@niaid.nih.gov; ssingh@iavi.org; zkafaar@sun.ac.za; meissneh@od.nih.gov; james.p.stansbury@fda.hhs.gov FU Intramural NIH HHS [Z99 AI999999] NR 82 TC 6 Z9 6 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD OCT 13 PY 2011 VL 29 IS 44 BP 7794 EP 7800 DI 10.1016/j.vaccine.2011.07.108 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841WW UT WOS:000296546900036 PM 21821083 ER PT J AU Mailankody, S Pfeiffer, RM Kristinsson, SY Korde, N Bjorkholm, M Goldin, LR Turesson, I Landgren, O AF Mailankody, Sham Pfeiffer, Ruth M. Kristinsson, Sigurdur Y. Korde, Neha Bjorkholm, Magnus Goldin, Lynn R. Turesson, Ingemar Landgren, Ola TI Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS) SO BLOOD LA English DT Article ID HIGH-DOSE THERAPY; UNDETERMINED SIGNIFICANCE MGUS; STEM-CELL TRANSPLANTATION; MONOCLONAL GAMMOPATHY; LONG-TERM; STANDARD CHEMOTHERAPY; RANDOMIZED-TRIAL; POPULATION; MELPHALAN; SURVIVAL AB Using population-based data from Sweden, we identified all multiple myeloma (MM) patients (n = 8740) and 5652 monoclonal gammopathy of undetermined significance (MGUS) patients diagnosed between 1986 and 2005. We calculated standardized incidence rates (SIRs) for all subsequent hematologic and nonhematologic malignancies for MM patients diagnosed before/after 1995 (introduction of high-dose melphalan/autologous stem cell transplantation [HDM-ASCT]) and 2000 (introduction of immunomodulatory drugs [IMiDs]), respectively. MM patients had an 11.51-fold (95% confidence interval: 8.19-15.74) increased risk of acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS); risk was very similar before/after 1995 and 2000, respectively. MGUS patients had an 8.01-fold (5.40-11.43) increased risk of AML/MDS. Risk was confined to IgG/IgA, while no IgM MGUS patients developed AML/MDS; patients with monoclonal-protein (M-protein) concentrations > 1.5 g/dL (SIR = 11.12; 3.61-25.96) had higher risk than those < 1.5 g/dL (SIR = 4.67; 1.71-10.16). An excess risk of nonmelanoma skin cancer was observed subsequent to both MM (SIR = 2.22; 1.74-2.80) and MGUS (SIR = 3.30; 2.76-3.90). Our novel observations of an excess risk for AML/MDS following IgG/IgA (but not IgM) MGUS, and the highest risk associated with M-protein concentrations > 1.5 g/dL, support a role for nontreatment-related factors in plasma cell dyscrasias. AML/MDS risk following MM was the same before/after the introduction of HDM-ASCT. Longer follow-up is needed to characterize second tumor risks in the IMiD era. (Blood. 2011; 118(15):4086-4092) C1 [Landgren, Ola] NCI, Multiple Myeloma Sect, Ctr Canc Res, Med Oncol Branch,NIH, Bethesda, MD 20892 USA. [Mailankody, Sham] Washington Hosp Ctr, Washington, DC 20010 USA. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Univ Hosp & Inst, Hematol Ctr, Dept Med, Stockholm, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Dept Med, Hematol Sect, Malmo, Sweden. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Ctr Canc Res, Med Oncol Branch,NIH, 9000 Rockville Pike,Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Intramural NIH HHS NR 41 TC 75 Z9 76 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 13 PY 2011 VL 118 IS 15 BP 4086 EP 4092 DI 10.1182/blood-2011-05-355743 PG 7 WC Hematology SC Hematology GA 838IT UT WOS:000296282200015 PM 21795746 ER PT J AU Donahue, RE Tuschong, L Bauer, TR Yau, YY Leitman, SF Hickstein, DD AF Donahue, Robert E. Tuschong, Laura Bauer, Thomas R., Jr. Yau, Yu Ying Leitman, Susan F. Hickstein, Dennis D. TI Leukocyte integrin activation mediates transient neutropenia after G-CSF administration SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; BLOOD PROGENITOR CELLS; ADHESION DEFICIENCY; DISEASE PHENOTYPE; GRANULOCYTE; TRANSPLANTATION; CHEMOTHERAPY; NEUTROPHILS; KINETICS; DONORS AB After administration of granulocyte colony-stimulating factor (G-CSF), there is a marked, albeit transient, drop in circulating neutrophils. To determine the role of leukocyte integrins in this disappearance, a dog having canine leukocyte adhesion deficiency (CLAD) or CLAD dogs who had undergone gene correction either by matched littermate allogeneic transplant or autologous gene therapy were evaluated. Shortly after G-CSF administration, a dramatic, yet transient, neutropenia was observed in the control littermates. This neutropenia was not as marked in the CLAD dogs. In all instances, it was CD18(+) neutrophils that preferentially egressed from the circulation. The association of CD18 with this rapid loss suggested leukocyte integrin activation after G-CSF administration. To determine the activation status of the integrin, a monoclonal antibody recognizing the activated alpha-subunit cation binding domain (mAb24) was used to evaluate human leukocytes after G-CSF administration. Mirroring the dramatic decrease in circulating neutrophil numbers, there was a dramatic and specific increase in the activation of the alpha-subunit after G-CSF expression on polymorphonuclear leukocytes. This activation, like the drop in neutrophil count, was transient. These results demonstrate that the leukocyte integrin on circulating neutrophils is transiently activated after G-CSF administration and mediates the transient neutropenia observed after G-CSF administration. (Blood. 2011;118(15):4209-4214) C1 [Donahue, Robert E.] NHLBI, Hematol Branch, Rockville, MD 20850 USA. [Tuschong, Laura; Bauer, Thomas R., Jr.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yau, Yu Ying; Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Donahue, RE (reprint author), NHLBI, VMD Hematol Branch, 5 Res Ct, Rockville, MD 20850 USA. EM donahuer@nhlbi.nih.gov FU Hematology Branch, National Heart, Lung, and Blood Institute; Department of Transfusion Medicine, Clinical Center, National Institutes of Health; Experimental Transplantation and Immunology Center for Cancer Research, National Cancer Institute FX This work was supported by the Hematology Branch, National Heart, Lung, and Blood Institute, Experimental Transplantation and Immunology Center for Cancer Research, National Cancer Institute, and the Department of Transfusion Medicine, Clinical Center, National Institutes of Health. NR 32 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 13 PY 2011 VL 118 IS 15 BP 4209 EP 4214 DI 10.1182/blood-2011-06-360461 PG 6 WC Hematology SC Hematology GA 838IT UT WOS:000296282200030 PM 21844566 ER PT J AU Arai, S Jagasia, M Storer, B Chai, XY Pidala, J Cutler, C Arora, M Weisdorf, DJ Flowers, MED Martin, PJ Palmer, J Jacobsohn, D Pavletic, SZ Vogelsang, GB Lee, SJ AF Arai, Sally Jagasia, Madan Storer, Barry Chai, Xiaoyu Pidala, Joseph Cutler, Corey Arora, Mukta Weisdorf, Daniel J. Flowers, Mary E. D. Martin, Paul J. Palmer, Jeanne Jacobsohn, David Pavletic, Steven Z. Vogelsang, Georgia B. Lee, Stephanie J. TI Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria SO BLOOD LA English DT Article ID WORKING GROUP-REPORT; BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; DEVELOPMENT PROJECT; CLINICAL-TRIALS; CHRONIC GVHD; CLASSIFICATION; DURATION AB In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689. (Blood. 2011;118(15):4242-4249) C1 [Storer, Barry; Chai, Xiaoyu; Flowers, Mary E. D.; Martin, Paul J.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Arai, Sally] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Palmer, Jeanne] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Jacobsohn, David] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ Hosp, Dept Oncol, Baltimore, MD 21287 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org FU National Institutes of Health/National Cancer Institute [CA 118953] FX This work was supported by National Institutes of Health/National Cancer Institute grant CA 118953. NR 22 TC 83 Z9 86 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 13 PY 2011 VL 118 IS 15 BP 4242 EP 4249 DI 10.1182/blood-2011-03-344390 PG 8 WC Hematology SC Hematology GA 838IT UT WOS:000296282200035 PM 21791424 ER PT J AU Martires, KJ Baird, K Steinberg, SM Grkovic, L Joe, GO Williams, KM Mitchell, SA Datiles, M Hakim, FT Pavletic, SZ Cowen, EW AF Martires, Kathryn J. Baird, Kristin Steinberg, Seth M. Grkovic, Lana Joe, Galen O. Williams, Kirsten M. Mitchell, Sandra A. Datiles, Manuel Hakim, Fran T. Pavletic, Steven Z. Cowen, Edward W. TI Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; CIRCULATING IMMUNE-COMPLEXES; WORKING GROUP-REPORT; CHRONIC GRAFT; SYSTEMIC-SCLEROSIS; HUMAN SCLERODERMA; LOCALIZATION AB Chronic GVHD is one of the most severe complications of allogeneic HSCT. The sclerotic skin manifestations of cGVHD (ScGVHD) result from inflammation and fibrosis of the dermis, subcutaneous tissue, or fascia, leading to significant functional disability. Risk factors and clinical markers associated with ScGVHD remain largely unexamined. By using a single-visit, cross-sectional design, we evaluated 206 patients with cGVHD at the National Institutes of Health. Most patients manifested severe (ie, 63% National Institutes of Health score "severe"), refractory disease (median treatments = 4). ScGVHD was detected in 109 (52.9%) patients. ScGVHD was associated with greater platelet count (P < .001) and C3 (P < .001), and decreased forced vital capacity (P = .013). Total body irradiation (TBI) was associated with development of ScGVHD (P = .002). TBI administered in reduced-intensity conditioning was most strongly associated with ScGVHD (14/15 patients, P <. 0001). Patients with ScGVHD had significant impairments of joint range of motion and grip strength (P < .001). Greater body surface area involvement was associated with poorer survival (P = .015). We conclude that TBI, particularly in reduced-intensity regimens, may be an important risk factor for ScGVHD. Widespread skin involvement is associated with significant functional impairment, distressing symptoms, and diminished survival. This trial is registered at http://www.clinicaltrials.gov as NCT00331968. (Blood. 2011;118(15):4250-4257) C1 [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Grkovic, Lana; Williams, Kirsten M.; Hakim, Fran T.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Joe, Galen O.] Natl Inst Hlth Clin Ctr, Dept Rehabil Med, Bethesda, MD USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Datiles, Manuel] NEI, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov OI Datiles, Manuel III B./0000-0003-4660-1664 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; National Institutes of Health; Pfizer Inc FX This study was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. K.J.M. was 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 Inc). NR 50 TC 30 Z9 31 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 13 PY 2011 VL 118 IS 15 BP 4250 EP 4257 DI 10.1182/blood-2011-04-350249 PG 8 WC Hematology SC Hematology GA 838IT UT WOS:000296282200036 PM 21791415 ER PT J AU Ashktorab, H Nguza, B Fatemi, M Nouraie, M Smoot, DT Schaffer, AA Kupfer, SS Camargo, CA Brim, H AF Ashktorab, Hassan Nguza, Bijou Fatemi, Mehrnaz Nouraie, Mehdi Smoot, Duane T. Schaeffer, Alejandro A. Kupfer, Sonia S. Camargo, Carlos A., Jr. Brim, Hassan TI Case-Control Study of Vitamin D, dickkopf homolog 1 (DKK1) Gene Methylation, VDR Gene Polymorphism and the Risk of Colon Adenoma in African Americans SO PLOS ONE LA English DT Article ID D-RECEPTOR GENE; BREAST-CANCER RISK; COLORECTAL-CANCER; RECTAL-CANCER; CIRCULATING 25-HYDROXYVITAMIN-D; D DEFICIENCY; PREVENTION; POPULATION; ASSOCIATIONS; METAANALYSIS AB Background: There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population. Methods: The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard University Hospital. Serum levels of 25(OH)D (including D3, D2, and total) were measured by liquid chromatography-mass spectrometry. DNA analysis focused on 49 single nucleotide polymorphisms (SNPs) in the VDR gene. Promoter methylation analysis of DKK1 was also performed. The resulting data were processed in unadjusted and multivariable logistic regression analyses. Results: Cases and controls differed in vitamin D status (D-3 < 50 nmol/L: Median of 35.5 in cases vs. 36.8 in controls nmol/L; P = 0.05). Low levels of 25(OH)D-3 (< 50 nmol/L) were observed in 86% of cases and 68% of controls and it was associated with higher risks of colon polyp (odds ratio of 2.7, 95% confidence interval 1.3-3.4). The SNP analysis showed no association between 46 VDR polymorphisms and colon polyp. The promoter of the DKK1 gene was unmethylated in 96% of the samples. Conclusion: We found an inverse association between serum 25(OH)D-3 and colon polyp in AAs. VDR SNPs and DKK1 methylation were not associated with colon polyp. Vitamin D levels may in part explain the higher incidence of polyp in AAs. C1 [Ashktorab, Hassan; Nguza, Bijou; Fatemi, Mehrnaz; Smoot, Duane T.] Howard Univ, Coll Med, Dept Med, Washington, DC 20059 USA. [Ashktorab, Hassan; Nguza, Bijou; Fatemi, Mehrnaz; Smoot, Duane T.] Howard Univ, Ctr Canc, Coll Med, Washington, DC 20059 USA. [Nouraie, Mehdi] Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC USA. [Brim, Hassan] Howard Univ, Coll Med, Dept Pathol, Washington, DC USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kupfer, Sonia S.] Univ Chicago, Dept Med, Gastroenterol Sect, Chicago, IL 60637 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Dept Med, Washington, DC 20059 USA. EM hashktorab@howard.edu RI Schaffer, Alejandro/F-2902-2012 FU National Institutes of Health [CA102681]; Massachusetts General Hospital Center for D-receptor Activation Research; NIH, NLM FX This work was supported in part by a PHS grant from the National Institutes of Health CA102681, (H.A) and by the Massachusetts General Hospital Center for D-receptor Activation Research (C.A.C). The Cancer Research Foundation (S.S.K.) and the Digestive Disease Research Core Center (P30 DK42086). This work was also supported by the Intramural Research Program of the NIH, NLM (A.A.S.). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 9 Z9 9 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2011 VL 6 IS 10 AR e25314 DI 10.1371/journal.pone.0025314 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834QT UT WOS:000295978600012 PM 22022386 ER PT J AU Sheldon, KL Maldonado, EN Lemasters, JJ Rostovtseva, TK Bezrukov, SM AF Sheldon, Kely L. Maldonado, Eduardo N. Lemasters, John J. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Phosphorylation of Voltage-Dependent Anion Channel by Serine/Threonine Kinases Governs Its Interaction with Tubulin SO PLOS ONE LA English DT Article ID OUTER MITOCHONDRIAL-MEMBRANE; PROTEIN-KINASE; CYCLIC-AMP; CELL-DEATH; PERMEABILITY TRANSITION; VDAC; APOPTOSIS; CAMP; INHIBITION; GRAMICIDIN AB Tubulin was recently found to be a uniquely potent regulator of the voltage-dependent anion channel (VDAC), the most abundant channel of the mitochondrial outer membrane, which constitutes a major pathway for ATP/ADP and other metabolites across this membrane. Dimeric tubulin induces reversible blockage of VDAC reconstituted into a planar lipid membrane and dramatically reduces respiration of isolated mitochondria. Here we show that VDAC phosphorylation is an important determinant of its interaction with dimeric tubulin. We demonstrate that in vitro phosphorylation of VDAC by either glycogen synthase kinase-3 beta (GSK3 beta) or cAMP-dependent protein kinase A (PKA), increases the on-rate of tubulin binding to the reconstituted channel by orders of magnitude, but only for tubulin at the cis side of the membrane. This and the fact the basic properties of VDAC, such as single-channel conductance and selectivity, remained unaltered by phosphorylation allowed us to suggest the phosphorylation regions positioned on the cytosolic loops of VDAC and establish channel orientation in our reconstitution experiments. Experiments on human hepatoma cells HepG2 support our conjecture that VDAC permeability for the mitochondrial respiratory substrates is regulated by dimeric tubulin and channel phosphorylation. Treatment of HepG2 cells with colchicine prevents microtubule polymerization, thus increasing dimeric tubulin availability in the cytosol. Accordingly, this leads to a decrease of mitochondrial potential measured by assessing mitochondrial tetramethylrhodamine methyester uptake with confocal microscopy. Inhibition of PKA activity blocks and reverses mitochondrial depolarization induced by colchicine. Our findings suggest a novel functional link between serine/threonine kinase signaling pathways, mitochondrial respiration, and the highly dynamic microtubule network which is characteristic of cancerogenesis and cell proliferation. C1 [Sheldon, Kely L.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Sheldon, Kely L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Maldonado, Eduardo N.; Lemasters, John J.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Sheldon, KL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX These studies were supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (for K.L.S., T.K.R., and S.M.B). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 39 Z9 39 U1 1 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 OCT 13 PY 2011 VL 6 IS 10 AR e25539 DI 10.1371/journal.pone.0025539 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834QT UT WOS:000295978600021 PM 22022409 ER PT J AU King, AM Salome, C Salome-Grosjean, E De Ryck, M Kaminski, R Valade, A Stables, JP Kohn, H AF King, Amber M. Salome, Christophe Salome-Grosjean, Elise De Ryck, Marc Kaminski, Rafal Valade, Anne Stables, James P. Kohn, Harold TI Primary Amino Acid Derivatives: Substitution of the 4 '-N '-Benzylamide Site in (R)-N '-Benzyl 2-Amino-3-methylbutanamide, (R)-N '-Benzyl 2-Amino-3,3-dimethylbutanamide, and (R)-N '-Benzyl 2-Amino-3-methoxypropionamide Provides Potent Anticonvulsants with Pain-Attenuating Properties SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID N-BENZYLACETAMIDE DERIVATIVES; GATED SODIUM-CHANNELS; NEUROPATHIC PAIN; BIOLOGICAL EVALUATION; RODENT MODELS; FORMALIN TEST; EPILEPSY; DRUG; AGENTS; DISCOVERY AB Recently, we reported that select N'-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N'-benzyl 2-amino acetamides (MES ED50 = 13-21 mg/kg) exceeded those of phenobarbital (ED50 = 22 mg/kg). Two additional studies defining the structure activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N'-benzyl 2-amino-3-methylbutanamide and (R)-N'-benzyl 2-amino-3,3-dimethyl-butanamide were sensitive to substituents at the 4'-N'-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4'-N'-benzylamide site of (R)-N'-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (similar to 4-fold) increase in activity (ED50 = 8.9 mg/kg), a value that surpassed phenytoin (ED50 = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants. C1 [King, Amber M.; Salome, Christophe; Salome-Grosjean, Elise; Kohn, Harold] Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [De Ryck, Marc; Kaminski, Rafal; Valade, Anne] UCB Pharma SA, CNS Res, B-1420 Braine Lalleud, Belgium. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, Anticonvulsant Screening Program, NIH, Bethesda, MD 20892 USA. [Kohn, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kohn, H (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM hkohn@email.unc.edu FU UCB Pharma (Braine-l'Alleud, Belgium) FX The project was supported by UCB Pharma (Braine-l'Alleud, Belgium) with the assistance of Dr. Robert Kramer. The authors thank the NINDS and the ASP at the National Institutes of Health with Drs. Tracy Chen and Jeffrey Jiang, for kindly performing the pharmacological studies via the ASP's contract site at the University of Utah with Drs. H. Wolfe, H.S. White, and K. Wilcox. Harold Kohn has a royalty-stake position in (R)-3. NR 51 TC 11 Z9 11 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 13 PY 2011 VL 54 IS 19 BP 6417 EP 6431 DI 10.1021/jm200759t PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 829AG UT WOS:000295546200002 PM 21861463 ER PT J AU King, AM De Ryck, M Kaminski, R Valade, A Stables, JP Kohn, H AF King, Amber M. De Ryck, Marc Kaminski, Rafal Valade, Anne Stables, James P. Kohn, Harold TI Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N '-Benzyl 2-Amino-3-methylbutanamide SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AMINO-ACID-DERIVATIVES; WEINREB AMIDES; CARBOXYLIC-ACIDS; EPILEPSY; ESTERS; BENZYLAMIDES; ALDEHYDES; AFFINITY; DESIGN; POTENT AB Primary amino acid derivatives (PAADs) (N'-benzyl 2-substituted 2-amino acetamides) are structurally related to functionalized amino acids (FAAs) (N'-benzyl 2-substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model, and the reported structure-activity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4'-N'-benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogues of (R)-N'-benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s). C1 [King, Amber M.; Kohn, Harold] Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [De Ryck, Marc; Kaminski, Rafal; Valade, Anne] UCB Pharma SA, CNS Res, B-1420 Braine Lalleud, Belgium. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, Anticonvulsant Screening Program, NIH, Rockville, MD 20892 USA. [Kohn, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kohn, H (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM hkohn@email.unc.edu FU UCB Pharma (Braine-l'Alleud, Belgium) FX The project was supported by UCB Pharma (Braine-l'Alleud, Belgium) with the assistance of Dr. Robert Kramer. We thank Dr. Christophe Salome for preparing (R)-23. The authors thank the NINDS and the ASP at the National Institutes of Health with Drs. Tracy Chen and Jeffrey Jiang, for kindly performing the pharmacological studies via the ASP's contract site at the University of Utah with Drs. H. Wolfe, H. S. White, and K. Wilcox. Harold Kohn has a royalty-stake position in (R)-26. NR 48 TC 7 Z9 7 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 13 PY 2011 VL 54 IS 19 BP 6432 EP 6442 DI 10.1021/jm200760a PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 829AG UT WOS:000295546200003 PM 21861466 ER PT J AU Seif, T Makriyannis, A Kunos, G Bonci, A Hopf, FW AF Seif, T. Makriyannis, A. Kunos, G. Bonci, A. Hopf, F. W. TI THE ENDOCANNABINOID 2-ARACHIDONOYLGLYCEROL MEDIATES D1 AND D2 RECEPTOR COOPERATIVE ENHANCEMENT OF RAT NUCLEUS ACCUMBENS CORE NEURON FIRING SO NEUROSCIENCE LA English DT Article DE endocannabinoid; cannabinoid receptors; nucleus accumbens; dopamine receptors; drug addiction ID METABOTROPIC GLUTAMATE-RECEPTOR; MEDIUM SPINY NEURONS; LONG-TERM DEPRESSION; CONDITIONED PLACE PREFERENCE; ACID AMIDE HYDROLASE; DOPAMINE-RECEPTORS; CANNABINOID RECEPTORS; SEEKING BEHAVIOR; COCAINE-SEEKING; CB1 RECEPTOR AB Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CBI receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Seif, T.; Bonci, A.; Hopf, F. W.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, Emeryville, CA 94608 USA. [Makriyannis, A.] Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. [Kunos, G.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Hopf, FW (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, 5858 Horton St,Suite 200, Emeryville, CA 94608 USA. EM woody@gallo.ucsf.edu FU NIDA [F32DA028065]; State of California for medical research for alcohol and substance abuse through the University of California, San Francisco; [RO1AA015358] FX This work was supported by the RO1AA015358 (F.W.H.), NIDA F32DA028065 (T.S.), and funds provided by the State of California for medical research for alcohol and substance abuse through the University of California, San Francisco (A.B.). NR 114 TC 17 Z9 17 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 13 PY 2011 VL 193 BP 21 EP 33 DI 10.1016/j.neuroscience.2011.07.055 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 824GA UT WOS:000295189200003 PM 21821098 ER PT J AU Kiselycznyk, C Svenningsson, P Delpire, E Holmes, A AF Kiselycznyk, C. Svenningsson, P. Delpire, E. Holmes, A. TI GENETIC, PHARMACOLOGICAL AND LESION ANALYSES REVEAL A SELECTIVE ROLE FOR CORTICOHIPPOCAMPAL GLUN2B IN A NOVEL REPEATED SWIM STRESS PARADIGM SO NEUROSCIENCE LA English DT Article DE glutamate; prefrontal cortex; amygdala; NMDA; anxiety; depression ID D-ASPARTATE ANTAGONIST; LONG-TERM DEPRESSION; TAIL SUSPENSION TEST; ELEVATED-PLUS-MAZE; NMDA RECEPTOR; PREFRONTAL CORTEX; STRAIN DIFFERENCES; MAJOR DEPRESSION; ACID RECEPTORS; WORKING-MEMORY AB Glutamate and N-methyl-D-aspartate receptor (NMDAR) dysfunction is strongly implicated in the pathophysiology of mood and anxiety disorders. Treatment with NMDAR antagonists has antidepressant efficacy in treatment-resistant depressives. In preclinical rodent models, NMDAR antagonist administration reduces anxiety- and stress-related behaviors in concert with increases in prefrontal cortical (PFC) dendritic spinogenesis and synaptic proteins. While these effects have been attributed to actions at the NMDAR GluN2B subunit, the precise role of cortical GluN2B in mediating emotional behaviors and stress-responsivity is not fully understood. Here, we employed a novel mutant model in which the GluN2B subunit is postnatally deleted in principal neurons in the cortex and the dorsal CA1 subregion of the hippocampus. GluN2BKO mice were phenotyped on a battery of tests for anxiety-related (light/dark exploration, stress-induced hyperthermia) and antidepressant-sensitive (sucrose preference, novelty-induced hypophagia, single-trial forced swim) behaviors. A novel repeated inescapable forced swim paradigm (riFS) was developed to assess behavioral responses to repeated stress in the GluN2BKO mice. For comparison, non-mutant C57BL/6J mice were tested for single-trial forced swim behavior after systemic Ro 25-6981 treatment and for riFS behavior after lesions of the ventromedial prefrontal cortex. riFS-induced alterations in corticolimbic GluN2B expression were also examined in C57BL/6J mice. We found that GluN2BKO mice reduced "despair-like" behavior in the riFS procedure, as compared to GluN2BFLOX controls. By contrast, GluN2BKO mice showed minimal alterations on anxiety-like or antidepressant-sensitive assays, including the single-trial forced swim test. In C57BL/6J mice, induction of "despair-like" responses in the riFS test was attenuated by vmPFC lesions, and was associated with changes in limbic GluN2B expression. Collectively, these data suggest that cortical GluN2B plays a major role in modulating adaptive responses to stress. Current findings provide further support for GluN2B as a key mechanism underlying stress responsivity, and a novel pharmacotherapeutic target for stress-related neuropsychiatric disorders. Published by Elsevier Ltd on behalf of IBRO. C1 [Kiselycznyk, C.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, Rockville, MD 20852 USA. [Kiselycznyk, C.; Svenningsson, P.] Karolinska Inst, Dept Clin Neurosci, Lab Translat Neuropharmacol, Stockholm, Sweden. [Delpire, E.] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. RP Kiselycznyk, C (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM kiselycznykc@mail.nih.gov FU National Institute of Alcohol Abuse; Alcoholism Intramural Research Program [Z01-AA000411] FX We are very grateful to Lee Chedester for construction of the riFS apparatus, to Guoxiang Luo for genotyping and Kazu Nakazawa for valuable comments. Research supported by the National Institute of Alcohol Abuse and Alcoholism Intramural Research Program (Z01-AA000411). NR 63 TC 14 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 13 PY 2011 VL 193 BP 259 EP 268 DI 10.1016/j.neuroscience.2011.06.015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 824GA UT WOS:000295189200026 PM 21704131 ER PT J AU Spivey, TL Uccellini, L Ascierto, ML Zoppoli, G De Giorgi, V Delogu, LG Engle, AM Thomas, JM Wang, E Marincola, FM Bedognetti, D AF Spivey, Tara L. Uccellini, Lorenzo Ascierto, Maria Libera Zoppoli, Gabriele De Giorgi, Valeria Delogu, Lucia Gemma Engle, Alyson M. Thomas, Jaime M. Wang, Ena Marincola, Francesco M. Bedognetti, Davide TI Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID ACUTE CELLULAR REJECTION; NF-KAPPA-B; CHEMOKINE RECEPTOR CXCR3; ANTIBODY-MEDIATED REJECTION; KIDNEY-TRANSPLANT BIOPSIES; ADAPTIVE IMMUNE-RESPONSES; NATURAL-KILLER-CELLS; TRANSCRIPTION FACTOR IRF-1; HUMAN RENAL-ALLOGRAFTS; ACUTE LUNG REJECTION AB In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-gamma, CXCR3/CCR5 ligand, IEF genes, TNF-alpha, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed. C1 [Spivey, Tara L.; Uccellini, Lorenzo; Ascierto, Maria Libera; De Giorgi, Valeria; Engle, Alyson M.; Thomas, Jaime M.; Wang, Ena; Marincola, Francesco M.; Bedognetti, Davide] Ctr Clin, Infect Dis & Immunogenet Sect IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. [Spivey, Tara L.; Uccellini, Lorenzo; Ascierto, Maria Libera; De Giorgi, Valeria; Engle, Alyson M.; Thomas, Jaime M.; Wang, Ena; Marincola, Francesco M.; Bedognetti, Davide] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Spivey, Tara L.] NIH, Clin Res Training Program CRTP, Bethesda, MD 20892 USA. [Spivey, Tara L.] Rush Univ, Med Ctr, Rush Med Coll, Chicago, IL 60612 USA. [Uccellini, Lorenzo] Luigi Sacco Hosp, I-20157 Milan, Italy. [Ascierto, Maria Libera; Zoppoli, Gabriele; Bedognetti, Davide] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Ascierto, Maria Libera] Univ Genoa, Ctr Excellence Biomed Res CEBR, I-16132 Genoa, Italy. [Zoppoli, Gabriele] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Delogu, Lucia Gemma] Univ Sassari, Dept Drug Sci, I-07100 Sassari, Italy. [Bedognetti, Davide] Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Bedognetti, Davide] Natl Inst Canc Res, I-16132 Genoa, Italy. RP Marincola, FM (reprint author), Ctr Clin, Infect Dis & Immunogenet Sect IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov; Davide.Bedognetti@nih.gov RI Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012; Zoppoli, Gabriele/B-6935-2016; De Giorgi, Valeria/D-4582-2017; OI Zoppoli, Gabriele/0000-0003-3890-5588; Bedognetti, Davide/0000-0002-5857-773X FU Clinical Research Training Program; Pfizer Inc.; Conquer Cancer Foundation of the American Society of Clinical Oncology FX Tara Spivey's research fellowship was made possible through 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 Inc.). Davide Bedognetti is a participant in the NIH Graduate Partnership Program and a graduate student at University of Genoa. Davide Bedognetti's fellowship is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology (2011 Young Investigator Award). Davide Bedognetti thanks Dr. Pietro Blandini (U.C. Sampdoria, Genoa, Italy) for his useful suggestion on multidimensional data analysis. NR 198 TC 39 Z9 39 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 12 PY 2011 VL 9 AR 174 DI 10.1186/1479-5876-9-174 PG 22 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 845UA UT WOS:000296847600001 PM 21992116 ER PT J AU Haspel, G O'Donovan, MJ AF Haspel, Gal O'Donovan, Michael J. TI A Perimotor Framework Reveals Functional Segmentation in the Motoneuronal Network Controlling Locomotion in Caenorhabditis elegans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NEURONAL NETWORK; CIRCUIT; BEHAVIOR; NEMATODES; DYNAMICS; ASCARIS; SYSTEMS; MOTIFS; MODEL; CORD AB The neuronal connectivity dataset of the nematode Caenorhabditis elegans attracts wide attention from computational neuroscientists and experimentalists. However, the dataset is incomplete. The ventral and dorsal nerve cords of a single nematode were reconstructed halfway along the body and the posterior data are missing, leaving 21 of 75 motoneurons of the locomotor network with partial or no connectivity data. Using a new framework for network analysis, the perimotor space, we identified rules of connectivity that allowed us to approximate the missing data by extrapolation. Motoneurons were mapped into perimotor space in which each motoneuron is located according to the muscle cells it innervates. In this framework, a pattern of iterative connections emerges which includes most (0.90) of the connections. We identified a repeating unit consisting of 12 motoneurons and 12 muscle cells. The cell bodies of the motoneurons of such a unit are not necessarily anatomical neighbors and there is no obvious anatomical segmentation. A connectivity model, composed of six repeating units, is a description of the network that is both simplified (modular and without noniterative connections) and more complete (includes the posterior part) than the original dataset. The perimotor framework of observed connectivity and the segmented connectivity model give insights and advance the study of the neuronal infrastructure underlying locomotion in C. elegans. Furthermore, we suggest that the tools used herein may be useful to interpret, simplify, and represent connectivity data of other motor systems. C1 [Haspel, Gal; O'Donovan, Michael J.] Natl Inst Neurol Disorders & Stroke, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Haspel, G (reprint author), Natl Inst Neurol Disorders & Stroke, Neural Control Lab, Sect Dev Neurobiol, NIH, 35 Convent Dr,MSC 3700, Bethesda, MD 20892 USA. EM haspelg@ninds.nih.gov RI o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Haspel, Gal/0000-0001-6701-697X FU National Institutes of Health-National Institute of Neurological Disorders and Stroke FX This work was supported in part by the intramural program of the National Institutes of Health-National Institute of Neurological Disorders and Stroke. We thank David Hall and Beth Chen for discussions of the connectivity database, Sinisa Pajevic for advice on statistics, and Daphne Soares, Kim Hoke, Larry Abbott, and Olaf Sporns for discussions of this manuscript. Some portions of MATLAB code were acquired from MATLAB Central. NR 44 TC 13 Z9 13 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 12 PY 2011 VL 31 IS 41 BP 14611 EP 14623 DI 10.1523/JNEUROSCI.2186-11.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 835FB UT WOS:000296019600018 PM 21994377 ER PT J AU Sivakumaran, TA Igo, RP Kidd, JM Itsara, A Kopplin, LJ Chen, W Hagstrom, SA Peachey, NS Francis, PJ Klein, ML Chew, EY Ramprasad, VL Tay, WT Mitchell, P Seielstad, M Stambolian, DE Edwards, AO Lee, KE Leontiev, DV Jun, G Wang, Y Tian, LP Qiu, FY Henning, AK LaFramboise, T Sen, P Aarthi, M George, R Raman, R Das, MK Vijaya, L Kumaramanickavel, G Wong, TY Swaroop, A Abecasis, GR Klein, R Klein, BEK Nickerson, DA Eichler, EE Iyengar, SK AF Sivakumaran, Theru A. Igo, Robert P., Jr. Kidd, Jeffrey M. Itsara, Andy Kopplin, Laura J. Chen, Wei Hagstrom, Stephanie A. Peachey, Neal S. Francis, Peter J. Klein, Michael L. Chew, Emily Y. Ramprasad, Vedam L. Tay, Wan-Ting Mitchell, Paul Seielstad, Mark Stambolian, Dwight E. Edwards, Albert O. Lee, Kristine E. Leontiev, Dmitry V. Jun, Gyungah Wang, Yang Tian, Liping Qiu, Feiyou Henning, Alice K. LaFramboise, Thomas Sen, Parveen Aarthi, Manoharan George, Ronnie Raman, Rajiv Das, Manmath Kumar Vijaya, Lingam Kumaramanickavel, Govindasamy Wong, Tien Y. Swaroop, Anand Abecasis, Goncalo R. Klein, Ronald Klein, Barbara E. K. Nickerson, Deborah A. Eichler, Evan E. Iyengar, Sudha K. TI A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID COMPLEMENT FACTOR-H; BEAVER DAM EYE; COPY NUMBER VARIATION; SEGMENTAL DUPLICATIONS; SUSCEPTIBILITY; GENOME; HAPLOTYPE; VARIANT; GENES; ASSOCIATION AB Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31 x 10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52 x 10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstreamof Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in Delta CNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number. C1 [Sivakumaran, Theru A.; Igo, Robert P., Jr.; Leontiev, Dmitry V.; Jun, Gyungah; Wang, Yang; Tian, Liping; Qiu, Feiyou] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Sivakumaran, Theru A.] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA. [Kopplin, Laura J.; LaFramboise, Thomas; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Ophthalmol, Cleveland, OH 44106 USA. [Kidd, Jeffrey M.; Itsara, Andy; Nickerson, Deborah A.; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Chen, Wei; Abecasis, Goncalo R.] Univ Michigan Sch Publ Hlth, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI USA. [Hagstrom, Stephanie A.; Peachey, Neal S.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Hagstrom, Stephanie A.; Peachey, Neal S.] Case Western Reserve Univ, Dept Ophthalmol, Cleveland Clin Lerner Coll Med, Cleveland, OH 44106 USA. [Peachey, Neal S.] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, Res Serv, Cleveland, OH USA. [Francis, Peter J.; Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Ramprasad, Vedam L.; Aarthi, Manoharan; Kumaramanickavel, Govindasamy] Sankara Nethralaya, Vis Res Fdn, SNONGC Dept Genet & Mol Biol, Chennai, Tamil Nadu, India. [Tay, Wan-Ting; Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore Eye Res Inst, Singapore 117595, Singapore. [Mitchell, Paul] Univ Sydney, Ctr Vis Res, Sydney, NSW 2006, Australia. [Seielstad, Mark] Genome Inst Singapore, Singapore, Singapore. [Stambolian, Dwight E.] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Stambolian, Dwight E.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Edwards, Albert O.] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Lee, Kristine E.; Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Jun, Gyungah] Boston Univ, Dept Med, Boston, MA 02215 USA. [Jun, Gyungah] Boston Univ, Dept Ophthalmol, Boston, MA 02215 USA. [Jun, Gyungah] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Henning, Alice K.] EMMES Corp, Rockville, MD USA. [Sen, Parveen; Raman, Rajiv; Das, Manmath Kumar; Vijaya, Lingam] Sankara Nethralaya, Vis Res Fdn, Dept Med Retina, Chennai, Tamil Nadu, India. [George, Ronnie] Sankara Nethralaya, Vis Res Fdn, Dept Glaucoma, Chennai, Tamil Nadu, India. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Australia. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Swaroop, Anand] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Sivakumaran, TA (reprint author), Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM ski@case.edu RI Mitchell, Paul/P-1498-2014; OI Jun, Gyungah/0000-0002-3230-8697; george, ronnie/0000-0001-7368-0252; Seielstad, Mark/0000-0001-5783-1401; Kidd, Jeffrey/0000-0002-9631-1465; Abecasis, Goncalo/0000-0003-1509-1825; Swaroop, Anand/0000-0002-1975-1141; Klein, Ronald/0000-0002-4428-6237 FU National Eye Institute [EY015810, U10EY06594, EY015286, EY13438, EY10605, T32 EY007157]; Retina Research Foundation; Department of Biotechnology, Government of India, New Delhi, India [DBT/PR7788/MED/12/299/2006]; National Heart, Lung, and Blood Institute [HL07567]; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK057292]; National Institutes of Health [T32 GM07250]; Singapore's National Medical Research Council [0796/2003, 0863/2004, CSI/0002/2005]; Biomedical Research Council [501/1/25-5]; Singapore Tissue Network; U.S. Public Health Service Resource from National Center for Research Resources [RR03655]; Gene Expression and Genotyping Facility of the Comprehensive Cancer Center at Case Western Reserve University; University Hospitals of Cleveland [P30CA43703] FX This study was supported, in part, by EY015810, U10EY06594, EY015286, EY13438, EY10605 and T32 EY007157 from the National Eye Institute; the Retina Research Foundation; the Department of Biotechnology (DBT/PR7788/MED/12/299/2006), Government of India, New Delhi, India (GK); training grant HL07567, from the National Heart, Lung, and Blood Institute; U01DK057292 from the National Institute of Diabetes and Digestive and Kidney Diseases; and the Medical Sciences Training Program T32 GM07250 (LJK), National Institutes of Health; grants from Singapore's National Medical Research Council Grant (0796/2003, 0863/2004 and CSI/0002/2005), Biomedical Research Council (501/1/25-5) and Singapore Tissue Network. Some of the analyses were carried out using the software package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. This research was also supported by the Gene Expression and Genotyping Facility of the Comprehensive Cancer Center at Case Western Reserve University and University Hospitals of Cleveland (P30CA43703). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 27 Z9 27 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 12 PY 2011 VL 6 IS 10 AR e25598 DI 10.1371/journal.pone.0025598 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PW UT WOS:000295976000025 PM 22022419 ER PT J AU Mayer, ML AF Mayer, Mark L. TI Emerging Models of Glutamate Receptor Ion Channel Structure and Function SO STRUCTURE LA English DT Review ID N-TERMINAL DOMAIN; LIGAND-BINDING DOMAIN; AMPA RECEPTOR; KAINATE RECEPTORS; NMDA RECEPTORS; CRYSTAL-STRUCTURE; CONFORMATIONAL-CHANGES; SUBUNIT ARRANGEMENT; ACTIVATION; MECHANISM AB Excitatory synaptic transmission in the brain is mediated by ligand-gated ion channels (iGluRs) activated by glutamate. Distinct from other neurotransmitter receptors, the extracellular domains of iGluRs are loosely packed assemblies with two clearly distinct layers, each of which has both local and global 2-fold axes of symmetry. By contrast, the iGluR transmembrane segments have 4-fold symmetry and share a conserved pore loop architecture found in tetrameric voltage-gated ion channels. The striking layered architecture of iGluRs revealed by the 3.6 angstrom resolution structure of an AMPA receptor homotetramer likely arose from gene fusion events that occurred early in evolution. Although this modular design has greatly facilitated biophysical and structural studies on individual iGluR domains, and suggested conserved mechanisms for iGluR gating, recent work is beginning to reveal unanticipated diversity in the structure, allosteric regulation, and assembly of iGluR subtypes. C1 NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov RI Mayer, Mark/H-5500-2013 FU NICHD, NIH FX The author thanks Eric Gouaux for the anomalous difference density maps and Sasha Sobolevsky for comments on the review. This work was supported by the intramural research program of NICHD, NIH. NR 56 TC 47 Z9 47 U1 2 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT 12 PY 2011 VL 19 IS 10 BP 1370 EP 1380 DI 10.1016/j.str.2011.08.009 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 836QB UT WOS:000296125100007 PM 22000510 ER PT J AU Sette, P Mu, RL Dussupt, V Jiang, JS Snyder, G Smith, P Xiao, TS Bouamr, F AF Sette, Paola Mu, Ruiling Dussupt, Vincent Jiang, Jiansheng Snyder, Greg Smith, Patrick Xiao, Tsan Sam Bouamr, Fadila TI The Phe105 Loop of Alix Bro1 Domain Plays a Key Role in HIV-1 Release SO STRUCTURE LA English DT Article ID ALG-2-INTERACTING PROTEIN ALIX; ESCRT-III; STRUCTURAL BASIS; BINDING PARTNER; SACCHAROMYCES-CEREVISIAE; PARTICLE-PRODUCTION; UBIQUITIN LIGASE; HD-PTP; VIRUS; ALG-2 AB Alix and cellular paralogs HD-PTP and Brox contain N-terminal Bro1 domains that bind ESCRT-III CHMP4. In contrast to HD-PTP and Brox, expression of the Bro1 domain of Alix alleviates HIV-1 release defects that result from interrupted access to ESCRT. In an attempt to elucidate this functional discrepancy, we solved the crystal structures of the Bro1 domains of HD-PTP and Brox. They revealed typical "boomerang" folds they share with the Bro1 Alix domain. However, they each contain unique structural features that may be relevant to their specific function(s). In particular, phenylalanine residue in position 105 (Phe105) of Alix belongs to a long loop that is unique to its Bro1 domain. Concurrently, mutation of Phe105 and surrounding residues at the tip of the loop compromise the function of Alix in HIV-1 budding without affecting its interactions with Gag or CHMP4. These studies identify a new functional determinant in the Bro1 domain of Alix. C1 [Mu, Ruiling; Jiang, Jiansheng; Snyder, Greg; Smith, Patrick; Xiao, Tsan Sam] NIAID, Immunol Lab, Struct Immunobiol Unit, NIH, Bethesda, MD 20892 USA. [Sette, Paola; Dussupt, Vincent; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Xiao, TS (reprint author), NIAID, Immunol Lab, Struct Immunobiol Unit, NIH, Bethesda, MD 20892 USA. EM xiaot@mail.nih.gov; bouamrf@mail.nih.gov RI MU, RUILING/H-3655-2012; Xiao, Tsan/A-8590-2010; Xiao, Tsan/I-7616-2013 OI Xiao, Tsan/0000-0001-9688-475X FU Division of Intramural Research, NIAID, NIH; Office of AIDS Research (OAR, NIH) FX We would like to thank the beamline staff at both Argonne National Laboratory (GM-CAT) and Brookhaven National Laboratory (X29) for facilitating X-ray diffraction data collection, and Alicia Buckler-White and her group at LMM for DNA sequencing. F.B. and T.S.X. are supported by the Division of Intramural Research, NIAID, NIH. This project was also supported by funds from the Office of AIDS Research (OAR, NIH) to F.B. and T.S.X. The authors declare no conflict of interest. NR 85 TC 15 Z9 17 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT 12 PY 2011 VL 19 IS 10 BP 1485 EP 1495 DI 10.1016/j.str.2011.07.016 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 836QB UT WOS:000296125100017 PM 21889351 ER PT J AU Black, A Buys, S Berg, CD AF Black, Amanda Buys, Saundra Berg, Christine D. TI Ovarian Cancer Screening and Mortality Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Black, Amanda] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Buys, Saundra] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Black, A (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM bergc@mail.nih.gov RI Berg , Christine/K-1047-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 12 PY 2011 VL 306 IS 14 BP 1544 EP 1545 DI 10.1001/jama.2011.1462 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 831FS UT WOS:000295714700013 ER PT J AU Shiels, MS AF Shiels, Meredith S. TI Errors in a Study of Proportions of Kaposi Sarcoma, Selected Non-Hodgkin Lymphomas, and Cervical Cancer in the United States Occurring in Persons With AIDS, 1980-2007 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM shielsms@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 12 PY 2011 VL 306 IS 14 BP 1548 EP 1548 DI 10.1001/jama.2011.1467 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 831FS UT WOS:000295714700018 ER PT J AU Nabel, GJ Kwong, PD Mascola, JR AF Nabel, Gary J. Kwong, Peter D. Mascola, John R. TI Progress in the rational design of an AIDS vaccine SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE HIV-1; vaccine design; informatics; structural biology; antibody response; computational techniques ID IMMUNODEFICIENCY-VIRUS TYPE-1; GP120 ENVELOPE GLYCOPROTEIN; HIV-1 GP120; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; POTENT NEUTRALIZATION; CD4-BINDING SITE; STRUCTURAL BASIS; BROAD; ARCHITECTURE AB Human immunodeficiency virus-1 (HIV-1) has a high degree of genetic and antigenic diversity that has impeded the development of an effective vaccine using traditional methods. We are attempting to develop an AIDS vaccine by employing strategies that include structural biology and computational modelling, in an effort to develop immunogens capable of eliciting neutralizing antibodies of the requisite breadth and potency against circulating strains of HIV-1. C1 [Nabel, Gary J.; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3005, Bethesda, MD 20892 USA. EM gnabel@mail.nih.gov NR 35 TC 28 Z9 28 U1 1 U2 6 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 12 PY 2011 VL 366 IS 1579 BP 2759 EP 2765 DI 10.1098/rstb.2011.0096 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 815TW UT WOS:000294553600005 PM 21893538 ER PT J AU Xu, HC Lu, AG Sharp, FR AF Xu, Huichun Lu, Aigang Sharp, Frank R. TI Regional genome transcriptional response of adult mouse brain to hypoxia SO BMC GENOMICS LA English DT Article ID INDUCED ISCHEMIC TOLERANCE; CENTRAL NEUROGENIC NEUROPROTECTION; HEPATOCYTE NUCLEAR FACTOR-4; FOCAL CEREBRAL-ISCHEMIA; NEONATAL-RAT BRAIN; INDUCIBLE FACTOR-I; GENE-EXPRESSION; ELECTRICAL-STIMULATION; GLUCOCORTICOID-RECEPTOR; INDUCED APOPTOSIS AB Background: Since normal brain function depends upon continuous oxygen delivery and short periods of hypoxia can precondition the brain against subsequent ischemia, this study examined the effects of brief hypoxia on the whole genome transcriptional response in adult mouse brain. Result: Pronounced changes of gene expression occurred after 3 hours of hypoxia (8% O-2) and after 1 hour of re-oxygenation in all brain regions. The hypoxia-responsive genes were predominantly up-regulated in hindbrain and predominantly down-regulated in forebrain - possibly to support hindbrain survival functions at the expense of forebrain cognitive functions. The up-regulated genes had a significant role in cell survival and involved both shared and unshared signaling pathways among different brain regions. Up-regulation of transcriptional signaling including hypoxia inducible factor, insulin growth factor (IGF), the vitamin D3 receptor/retinoid X nuclear receptor, and glucocorticoid signaling was common to many brain regions. However, many of the hypoxia-regulated target genes were specific for one or a few brain regions. Cerebellum, for example, had 1241 transcripts regulated by hypoxia only in cerebellum but not in hippocampus; and, 642 (54%) had at least one hepatic nuclear receptor 4A (HNF4A) binding site and 381 had at least two HNF4A binding sites in their promoters. The data point to HNF4A as a major hypoxia-responsive transcription factor in cerebellum in addition to its known role in regulating erythropoietin transcription. The genes unique to hindbrain may play critical roles in survival during hypoxia. Conclusion: Differences of forebrain and hindbrain hypoxia-responsive genes may relate to suppression of forebrain cognitive functions and activation of hindbrain survival functions, which may coordinately mediate the neuroprotection afforded by hypoxia preconditioning. C1 [Xu, Huichun] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Lu, Aigang] Univ Cincinnati, Dept Neurol, Vontz Ctr Mol Studies, Cincinnati, OH 45267 USA. RP Xu, HC (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr, Bethesda, MD 20892 USA. EM huichun.xu@nih.gov FU [NS42774]; [NS43252]; [MH67039]; [NS44283]; [NS28167]; [NS0546452] FX This work was supported by NS42774, NS43252, MH67039, NS44283, NS28167 and NS0546452. We thank Ryan Davis and Stephenie Liu in the UCD M.I.N.D. Institute Genomics Facility for their work on the microarrays. We are grateful to Drs. Bruce Lyeth, Robert Berman, Philip Schwartzkroin and Jeffrey Gregg for their help and constructive feedback regarding these studies. We also thank Dr. Arezou Sarabi for communicating details of their published work (Sarabi et al., 2008). NR 60 TC 7 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 11 PY 2011 VL 12 AR 499 DI 10.1186/1471-2164-12-499 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 848KK UT WOS:000297050300001 PM 21988864 ER PT J AU Abou-Kheir, W Hynes, PG Martin, P Yin, JJ Liu, YN Seng, V Lake, R Spurrier, J Kelly, K AF Abou-Kheir, Wassim Hynes, Paul G. Martin, Philip Yin, Juan Juan Liu, Yen-Nien Seng, Victoria Lake, Ross Spurrier, Joshua Kelly, Kathleen TI Self-Renewing Pten(-/-)TP53(-/-) Protospheres Produce Metastatic Adenocarcinoma Cell Lines with Multipotent Progenitor Activity SO PLOS ONE LA English DT Article ID TUMOR-INITIATING CELLS; PROSTATE-CANCER CELLS; STEM-CELLS; PTEN; BONE; TUMORIGENESIS; POPULATION; SURVIVAL; PATHWAY; ORIGIN AB Prostate cancers of luminal adenocarcinoma histology display a range of clinical behaviors. Although most prostate cancers are slow-growing and indolent, a proportion is aggressive, developing metastasis and resistance to androgen deprivation treatment. One hypothesis is that a portion of aggressive cancers initiate from stem-like, androgen-independent tumor-propagating cells. Here we demonstrate the in vitro creation of a mouse cell line, selected for growth as self-renewing stem/progenitor cells, which manifests many in vivo properties of aggressive prostate cancer. Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease. C1 [Abou-Kheir, Wassim; Hynes, Paul G.; Martin, Philip; Yin, Juan Juan; Liu, Yen-Nien; Seng, Victoria; Lake, Ross; Spurrier, Joshua; Kelly, Kathleen] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Abou-Kheir, Wassim] Amer Univ Beirut, Fac Med, Dept Anat Cell Biol & Physiol Sci, Beirut, Lebanon. RP Abou-Kheir, W (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, United States of America FX The authors acknowledge the support of the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 7 Z9 7 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 11 PY 2011 VL 6 IS 10 AR e26112 DI 10.1371/journal.pone.0026112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OZ UT WOS:000295973200037 PM 22022528 ER PT J AU Saleh, AD Savage, JE Cao, L Soule, BP Ly, D DeGraff, W Harris, CC Mitchell, JB Simone, NL AF Saleh, Anthony D. Savage, Jason E. Cao, Liu Soule, Benjamin P. Ly, David DeGraff, William Harris, Curtis C. Mitchell, James B. Simone, Nicole L. TI Cellular Stress Induced Alterations in MicroRNA let-7a and let-7b Expression Are Dependent on p53 SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR; MESSENGER-RNA; CANCER; CELLS; GROWTH; PROLIFERATION; MODULATION; RESISTANCE; PROFILES; THERAPY AB Genotoxic stressors, such as radiation, induce cellular damage that activates pre-programmed repair pathways, some of which involve microRNAs (miRNA) that alter gene expression. The let-7 family of miRNA regulates multiple cellular processes including cell division and DNA repair pathways. However, the role and mechanism underlying regulation of let-7 genes in response to stress have yet to be elucidated. In this study we demonstrate that let-7a and let-7b expression decreases significantly following exposure to agents that induce stress including ionizing radiation. This decrease in expression is dependent on p53 and ATM in vitro and is not observed in a p53(-/-) colon cancer cell line (HCT116) or ATM(-/-) human fibroblasts. Chromatin Immunoprecipitation (ChIP) analysis showed p53 binding to a region upstream of the let-7 gene following radiation exposure. Luciferase transient transfections demonstrated that this p53 binding site is necessary for radiation-induced decreases in let-7 expression. A radiation-induced decrease in let-7a and let-7b expression is also observed in radiation-sensitive tissues in vivo and correlates with altered expression of proteins in p53-regulated proapoptotic signaling pathways. In contrast, this decreased expression is not observed in p53 knock-out mice suggesting that p53 directly repress let-7 expression. Exogenous expression of let-7a and let-7b increased radiation-induced cytotoxicity in HCT116 p53(+/+) cells but not HCT116 p53(-/-) cells. These results are the first demonstration of a mechanistic connection between the radiation-induced stress response and the regulation of miRNA and radiation-induced cytotoxicity and suggest that this process may be a molecular target for anticancer agents. C1 [Saleh, Anthony D.; Savage, Jason E.; Ly, David; Simone, Nicole L.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Cao, Liu] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Soule, Benjamin P.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [DeGraff, William; Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Saleh, AD (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM simonen@mail.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 41 Z9 43 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 11 PY 2011 VL 6 IS 10 AR e24429 DI 10.1371/journal.pone.0024429 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OZ UT WOS:000295973200002 PM 22022355 ER PT J AU Daniels, SR Pratt, CA Hayman, LL AF Daniels, Stephen R. Pratt, Charlotte A. Hayman, Laura L. TI Reduction of Risk for Cardiovascular Disease in Children and Adolescents SO CIRCULATION LA English DT Article DE atherosclerosis; diet; hypertension; obesity ID AMERICAN-HEART-ASSOCIATION; INTIMA-MEDIA THICKNESS; HIGH BLOOD-PRESSURE; BODY-MASS INDEX; CHILDHOOD OBESITY PREVENTION; TYPE-2 DIABETES-MELLITUS; PHYSICAL-ACTIVITY; UNITED-STATES; YOUNG FINNS; SCIENTIFIC STATEMENT C1 [Daniels, Stephen R.] Univ Colorado, Sch Med, Childrens Hosp, Dept Pediat, Aurora, CO 80045 USA. [Pratt, Charlotte A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Hayman, Laura L.] Univ Massachusetts Boston, Coll Nursing & Hlth Sci, Boston, MA USA. RP Daniels, SR (reprint author), Univ Colorado, Sch Med, Childrens Hosp, Dept Pediat, 13123 E 16th Ave,B065, Aurora, CO 80045 USA. EM Daniels.stephen@tchden.org FU NCI NIH HHS [1U56CA118635-03, U56 CA118635]; NCRR NIH HHS [UL1RR 025758-02, UL1 RR025758] NR 113 TC 43 Z9 48 U1 3 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 11 PY 2011 VL 124 IS 15 BP 1673 EP U181 DI 10.1161/CIRCULATIONAHA.110.016170 PG 22 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 835PW UT WOS:000296049300017 PM 21986774 ER PT J AU Takeda, K Tonthat, NK Glover, T Xu, WJ Koonin, EV Yanagida, M Schumacher, MA AF Takeda, Kojiro Tonthat, Nam K. Glover, Tiffany Xu, Weijun Koonin, Eugene V. Yanagida, Mitsuhiro Schumacher, Maria A. TI Implications for proteasome nuclear localization revealed by the structure of the nuclear proteasome tether protein Cut8 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SISTER-CHROMATID SEPARATION; 26 S PROTEASE; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; SUBCELLULAR-LOCALIZATION; SUBUNIT; PROTEOLYSIS; ANAPHASE; MITOSIS; SYSTEM AB Degradation of nuclear proteins by the 26S proteasome is essential for cell viability. In yeast, the nuclear envelope protein Cut8 mediates nuclear proteasomal sequestration by an uncharacterized mechanism. Here we describe structures of Schizosaccharomyces pombe Cut8, which shows that it contains a unique, modular fold composed of an extended N-terminal, lysine-rich segment that when ubiquitinated binds the proteasome, a dimer domain followed by a six-helix bundle connected to a flexible C tail. The Cut8 six-helix bundle shows structural similarity to 14-3-3 phosphoprotein-binding domains, and binding assays show that this domain is necessary and sufficient for liposome and cholesterol binding. Moreover, specific mutations in the 14-3-3 regions corresponding to putative cholesterol recognition/interaction amino acid consensus motifs abrogate cholesterol binding. In vivo studies confirmed that the 14-3-3 region is necessary for Cut8 membrane localization and that dimerization is critical for its function. Thus, the data reveal the Cut8 organization at the nuclear envelope. Reconstruction of Cut8 evolution suggests that it was present in the last common ancestor of extant eukaryotes and accordingly that nuclear proteasomal sequestration is an ancestral eukaryotic feature. The importance of Cut8 for cell viability and its absence in humans suggests it as a possible target for the development of specific chemotherapeutics against invasive fungal infections. C1 [Tonthat, Nam K.; Schumacher, Maria A.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Takeda, Kojiro; Yanagida, Mitsuhiro] OIST, Cell Unit G0, Okinawa, Japan. [Glover, Tiffany; Xu, Weijun] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Unit 1000, Houston, TX 77030 USA. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Schumacher, MA (reprint author), Duke Univ, Med Ctr, Dept Biochem, Room 243A,Nanaline H Duke Bldg,Box 3711, Durham, NC 27710 USA. EM maria.schumacher@duke.edu FU M. D. Anderson Trust; National Institutes of Health [GM074815] FX This work was supported by an M. D. Anderson Trust Fellowship and National Institutes of Health Grant GM074815 (to M.A.S.). NR 43 TC 9 Z9 9 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2011 VL 108 IS 41 BP 16950 EP 16955 DI 10.1073/pnas.1103617108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800022 PM 21976488 ER PT J AU Kaczmarczyk, SJ Sitaraman, K Young, HA Hughes, SH Chatterjee, DK AF Kaczmarczyk, Stanislaw J. Sitaraman, Kalavathy Young, Howard A. Hughes, Stephen H. Chatterjee, Deb K. TI Protein delivery using engineered virus-like particles SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE surface display; TRAIL ID CELL-PENETRATING PEPTIDES; ROUS-SARCOMA-VIRUS; MAMMALIAN-CELLS; RETROVIRAL VECTORS; CRE RECOMBINASE; IN-VIVO; TRANSDUCTION; MICROINJECTION; MECHANISM; DEATH AB Over the years, researchers have developed several methods to deliver macromolecules into the cytosol and nucleus of living cells. However, there are limitations to all of these methods. The problems include (i) inefficient uptake, (ii) endosomal entrapment, (iii) delivery that is restricted to certain cell types, and (iv) damage to cells in the delivery process. Retroviral vectors are often used for gene delivery; however, integration of the genome of retroviral vector into the host genome can have serious consequences. Here we describe a safe alternative in which virus-like particles (VLPs), derived from an avian retrovirus, are used to deliver protein to cells. We show that these VLPs are a highly adaptable platform that can be used to deliver proteins either as part of Gag fusion proteins (intracellular delivery) or on the surface of VLPs. We generated VLPs that contain Gag-Cre recombinase, Gag-Fcy::Fur, and Gag-human caspase-8 as a proof-of-concept and demonstrated that the encapsidated proteins are active in recipient cells. In addition, we show that murine IFN-gamma and human TNF-related apoptosis-inducing ligand can be displayed on the surface of VLPs, and that these modified VLPs can cause the appropriate response in cells, as evidenced by phosphorylation of STAT1 and induction of cell death, respectively. C1 [Kaczmarczyk, Stanislaw J.; Sitaraman, Kalavathy; Chatterjee, Deb K.] NCI, Prot Express Lab, Adv Technol Program, Sci Applicat Int Corp SAIC Frederick Inc, Frederick, MD 21702 USA. [Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Chatterjee, DK (reprint author), NCI, Prot Express Lab, Adv Technol Program, Sci Applicat Int Corp SAIC Frederick Inc, Frederick, MD 21702 USA. EM dchatterjee@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN 261 2008 00001E] FX We thank Drs. James Hartley and Timothy Harris for support and encouragement throughout the work. We also thank Michael Sanford for the flow cytometry experiment, Marritta Grau for editing the manuscript, and Jiro Wada for preparation of the figures. Funding was received from National Cancer Institute, National Institutes of Health Grant HHSN 261 2008 00001E. NR 42 TC 60 Z9 61 U1 3 U2 25 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 OCT 11 PY 2011 VL 108 IS 41 BP 16998 EP 17003 DI 10.1073/pnas.1101874108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800030 PM 21949376 ER PT J AU Berendsen, AD Fisher, LW Kilts, TM Owens, RT Robey, PG Gutkind, JS Young, MF AF Berendsen, Agnes D. Fisher, Larry W. Kilts, Tina M. Owens, Rick T. Robey, Pamela G. Gutkind, J. Silvio Young, Marian F. TI Modulation of canonical Wnt signaling by the extracellular matrix component biglycan SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mineralization; regeneration; skeleton ID HEPARAN-SULFATE PROTEOGLYCANS; BONE-FORMATION; BETA-CATENIN; LRP6; MICE; EXPRESSION; RECEPTOR; DECORIN; DIFFERENTIATION; PROLIFERATION AB Although extracellular control of canonical Wnt signaling is crucial for tissue homeostasis, the role of the extracellular microenvironment in modulating this signaling pathway is largely unknown. In the present study, we show that a member of the small leucine-rich proteoglycan family, biglycan, enhances canonical Wnt signaling by mediating Wnt function via its core protein. Immunoprecipitation analysis revealed that biglycan interacts with both the canonical Wnt ligand Wnt3a and the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), possibly via the formation of a trimeric complex. Biglycan-deficient cells treated with exogenous Wnt3a had less Wnt3a retained in cell layers compared with WT cells. Furthermore, the Wnt-induced levels of LRP6 phosphorylation and expression of several Wnt target genes were blunted in biglycan-deficient cells. Both recombinant biglycan proteoglycan and biglycan core protein increased Wnt-induced beta-catenin/T cell-specific factor-mediated transcriptional activity, and this activity was completely inhibited by Dickkopf 1. Interestingly, recombinant biglycan was able to rescue impaired Wnt signaling caused by a previously described missense mutation in the extracellular domain of human LRP6 (R611C). Furthermore, biglycan's modulation of canonical Wnt signaling affected the functional activities of osteoprogenitor cells, including the RUNX2-mediated transcriptional activity and calcium deposition. Use of a transplant system and a fracture healing model revealed that expression of Wnt-induced secreted protein 1 was decreased in bone formed by biglycan-deficient cells, further suggesting reduced Wnt signaling in vivo. We propose that biglycan may serve as a reservoir for Wnt in the pericellular space and modulate Wnt availability for activation of the canonical Wnt pathway. C1 [Berendsen, Agnes D.; Fisher, Larry W.; Kilts, Tina M.; Robey, Pamela G.; Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Owens, Rick T.] LifeCell Corp, Branchburg, NJ 08876 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Young, MF (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. EM Myoung@dir.nidcr.nih.gov RI Gutkind, J. Silvio/A-1053-2009; Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Division of Intramural Research, National Institute for Dental and Craniofacial Research of the National Institutes of Health FX We thank Li Li, Azusa Maeda, Emily Pinnow, and Brian Sworder, Craniofacial and Skeletal Diseases Branch, National Institute for Dental and Craniofacial Research, for technical assistance. This research was supported in part by the Division of Intramural Research, National Institute for Dental and Craniofacial Research, of the Intramural Research Program of the National Institutes of Health. NR 38 TC 49 Z9 50 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2011 VL 108 IS 41 BP 17022 EP 17027 DI 10.1073/pnas.1110629108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800034 PM 21969569 ER PT J AU Li, GR Du, XL Vass, WC Papageorge, AG Lowy, DR Qian, XL AF Li, Guorong Du, Xiaoli Vass, William C. Papageorge, Alex G. Lowy, Douglas R. Qian, Xiaolan TI Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GTPASE-ACTIVATING PROTEIN; SH2 DOMAIN; METASTASIS; PAXILLIN; GROWTH; INVASION AB The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions. C1 [Li, Guorong; Du, Xiaoli; Vass, William C.; Papageorge, Alex G.; Lowy, Douglas R.; Qian, Xiaolan] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lowyd@mail.nih.gov; qianx@mail.nih.gov FU National Institutes of Health, National Cancer Institute, and Center for Cancer Research FX We thank Zhizhong Fei and Lyra Olson for technical assistance, Nicolae Popescu for providing yeast two-hybrid assay information, Curt Harris for NSCLC lines, and Kenneth Yamada for helpful discussions and reagents. This research was supported by the Intramural Research Program, National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 25 TC 35 Z9 37 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2011 VL 108 IS 41 BP 17129 EP 17134 DI 10.1073/pnas.1112122108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800052 PM 21969587 ER PT J AU Zheng, K An, JJ Yang, F Xu, WF Xu, ZQD Wu, JY Hokfelt, TGM Fisahn, A Xu, BJ Lu, B AF Zheng, Kang An, Juan Ji Yang, Feng Xu, Weifeng Xu, Zhi-Qing David Wu, Jianyoung Hoekfelt, Tomas G. M. Fisahn, Andre Xu, Baoji Lu, Bai TI TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gamma oscillations; synaptic transmission; Cre recombinase; dendrite; slice ID FAST-SPIKING CELLS; NEUROTROPHIC FACTOR; RAT HIPPOCAMPUS; RECEPTOR TRKB; SYNAPTIC MODULATION; VISUAL-CORTEX; IN-VITRO; OSCILLATIONS; SCHIZOPHRENIA; INHIBITION AB Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development and synaptic plasticity, its exact role in neuronal network activity remains elusive. Using mutant mice (TrkB-PV(-/-)) in which the gene for the BDNF receptor, tyrosine kinase B receptor (trkB), has been specifically deleted in parvalbumin-expressing, fast-spiking GABAergic (PV+) interneurons, we show that TrkB is structurally and functionally important for the integrity of the hippocampal network. The amplitude of glutamatergic inputs to PV+ interneurons and the frequency of GABAergic inputs to excitatory pyramidal cells were reduced in the TrkB-PV(-/-) mice. Functionally, rhythmic network activity in the gamma-frequency band (30-80 Hz) was significantly decreased in hippocampal area CA1. This decrease was caused by a desynchronization and overall reduction in frequency of action potentials generated in PV+ interneurons of TrkB-PV(-/-) mice. Our results show that the integration of PV+ interneurons into the hippocampal microcircuit is impaired in TrkB-PV(-/-) mice, resulting in decreased rhythmic network activity in the gamma-frequency band. C1 [Lu, Bai] GlaxoSmithKline Inc, R&D China, Shanghai 201203, Peoples R China. [Zheng, Kang; Yang, Feng] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Zheng, Kang; Xu, Zhi-Qing David; Hoekfelt, Tomas G. M.] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. [An, Juan Ji; Xu, Baoji] Georgetown Univ, Dept Pharmacol, Washington, DC 20057 USA. [Xu, Weifeng; Wu, Jianyoung] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Fisahn, Andre] Karolinska Inst, Kl Alzheimers Dis Res Ctr, Dept Neurobiol Care Sci & Soc, Neuronal Oscillat Lab, SE-14186 Stockholm, Sweden. RP Lu, B (reprint author), GlaxoSmithKline Inc, R&D China, Shanghai 201203, Peoples R China. EM tomas.hokfelt@ki.se; bai.b.lu@gsk.com RI Lu, Bai/A-4018-2012 FU National Institute of Mental Health; Swedish Research Council; National Institutes of Health/Karolinska Institutet; National Institutes of Health [NS050596] FX We thank Dr. Robert F. Bonner (Section on Medical Biophysics, National Institute of Child Health and Human Development); Dr. Jaime Rodriguez-Canales and Mr. Jeffrey Charles Hanson (Laboratory of Pathology, National Cancer Institute); and Dr. Wen-Jun Gao (Department of Neurobiology and Anatomy, Drexel University College of Medicine) for providing technical help with laser capture microdissection. This work was supported by the Intramural Research Programs of the National Institute of Mental Health (to B. L.), Swedish Research Council (to T. G. M. H.), National Institutes of Health/Karolinska Institutet Collaborative Doctoral Program in Neuroscience (to T. G. M. H.), and National Institutes of Health Grant NS050596 (to B.X.). NR 44 TC 21 Z9 21 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 OCT 11 PY 2011 VL 108 IS 41 BP 17201 EP 17206 DI 10.1073/pnas.1114241108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800064 PM 21949401 ER PT J AU Acosta, A Hurtado, MD Gorbatyuk, O La Sala, M Duncan, D Aslanidi, G Campbell-Thompson, M Zhang, L Herzog, H Voutetakis, A Baum, BJ Zolotukhin, S AF Acosta, Andres Hurtado, Maria D. Gorbatyuk, Oleg La Sala, Michael Duncan, David Aslanidi, George Campbell-Thompson, Martha Zhang, Lei Herzog, Herbert Voutetakis, Antonis Baum, Bruce J. Zolotukhin, Sergei TI Salivary PYY: A Putative Bypass to Satiety SO PLOS ONE LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; TASTE RECEPTOR-CELLS; GENE THERAPEUTICS; EXPRESSION; MICE; GLANDS; LEPTIN; SENSITIVITY; SECRETION; BUDS AB Peptide YY(3-36) is a satiation hormone released postprandially into the bloodstream from L-endocrine cells in the gut epithelia. In the current report, we demonstrate PYY(3-36) is also present in murine as well as in human saliva. In mice, salivary PYY(3-36) derives from plasma and is also synthesized in the taste cells in taste buds of the tongue. Moreover, the cognate receptor Y2R is abundantly expressed in the basal layer of the progenitor cells of the tongue epithelia and von Ebner's gland. The acute augmentation of salivary PYY(3-36) induced stronger satiation as demonstrated in feeding behavioral studies. The effect is mediated through the activation of the specific Y2 receptor expressed in the lingual epithelial cells. In a longterm study involving diet-induced obese (DIO) mice, a sustained increase in PYY(3-36) was achieved using viral vector-mediated gene delivery targeting salivary glands. The chronic increase in salivary PYY(3-36) resulted in a significant long-term reduction in food intake (FI) and body weight (BW). Thus this study provides evidence for new functions of the previously characterized gut peptide PYY(3-36) suggesting a potential simple and efficient alternative therapeutic approach for the treatment of obesity. C1 [Acosta, Andres; Hurtado, Maria D.; Gorbatyuk, Oleg; La Sala, Michael; Duncan, David; Aslanidi, George; Campbell-Thompson, Martha; Zolotukhin, Sergei] Univ Florida, Gainesville, FL 32611 USA. [Zhang, Lei; Herzog, Herbert] Garvan Inst Med Res, Sydney, NSW, Australia. [Voutetakis, Antonis; Baum, Bruce J.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Acosta, A (reprint author), Univ Florida, Gainesville, FL 32611 USA. EM szlt@ufl.edu OI Campbell-Thompson, Martha/0000-0001-6878-1235 FU NIH/NIDDK [1R01DK62302-01]; The Division of Intramural Research of the National Institute of Dental and Craniofacial Research; NHMRC of Australia FX The study was funded by the following: SZ - 1R01DK62302-01 (NIH/NIDDK); BB - The Division of Intramural Research of the National Institute of Dental and Craniofacial Research in part supported this research, HH is funded by a NHMRC of Australia Senior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 24 Z9 25 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2011 VL 6 IS 10 AR e26137 DI 10.1371/journal.pone.0026137 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OO UT WOS:000295971700043 PM 22028819 ER PT J AU Hu, Y Galkin, AV Wu, CL Reddy, V Su, AI AF Hu, Yue Galkin, Anna V. Wu, Chunlei Reddy, Venkateshwar Su, Andrew I. TI CAFET Algorithm Reveals Wnt/PCP Signature in Lung Squamous Cell Carcinoma SO PLOS ONE LA English DT Article ID BETA-CATENIN; GENE-EXPRESSION; PROMOTER HYPERMETHYLATION; NEGATIVE REGULATOR; SIGNALING PATHWAY; MICROARRAY DATA; DIX DOMAIN; CANCER; WNT; ADENOCARCINOMA AB We analyzed the gene expression patterns of 138 Non-Small Cell Lung Cancer (NSCLC) samples and developed a new algorithm called Coverage Analysis with Fisher's Exact Test (CAFET) to identify molecular pathways that are differentially activated in squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes. Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity (PCP) pathway and inhibition of the canonical Wnt signaling branch. Further real time RT-PCR follow-up with additional primary tumor samples and lung cancer cell lines confirmed enrichment of Wnt/PCP pathway associated genes in the SCC subtype. Dysregulation of the canonical Wnt pathway, characterized by increased levels of beta-catenin and epigenetic silencing of negative regulators, has been reported in adenocarcinoma of the lung. Our results suggest that SCC and AC utilize different branches of the Wnt pathway during oncogenesis. C1 [Hu, Yue; Galkin, Anna V.; Wu, Chunlei; Reddy, Venkateshwar; Su, Andrew I.] Novartis Res Fdn, Genom Inst, San Diego, CA USA. RP Hu, Y (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM asu@scripps.edu OI Su, Andrew I./0000-0002-9859-4104 NR 45 TC 4 Z9 4 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2011 VL 6 IS 10 AR e25807 DI 10.1371/journal.pone.0025807 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OO UT WOS:000295971700019 PM 22016777 ER PT J AU Ji, JP Kinders, RJ Zhang, YP Rubinstein, L Kummar, S Parchment, RE Tomaszewski, JE Doroshow, JH AF Ji, Jiuping Kinders, Robert J. Zhang, Yiping Rubinstein, Larry Kummar, Shivaani Parchment, Ralph E. Tomaszewski, Joseph E. Doroshow, James H. TI Ribose) Polymerase Inhibitor ABT-888 in Human Peripheral Blood Mononuclear Cells SO PLOS ONE LA English DT Article ID 0 CLINICAL-TRIAL; POLY(ADP-RIBOSE) POLYMERASE; DRUG DEVELOPMENT; PARP INHIBITORS; BIOMARKERS; EXPRESSION; TUMORS; ASSAY AB Background: Poly(ADP-ribose) polymerase (PARP) facilitates DNA repair and PARP inhibitors may potentiate the effect of DNA-damaging chemotherapeutic agents in patients with cancer. Collection of peripheral blood mononuclear cells (PBMCs) as a surrogate tissue to monitor PARP inhibitor pharmacodynamic effects has several advantages over tumor biopsy collection, including minimally invasive sample collection and the ability to collect multiple samples for longitudinal assessment of drug effect. Methodology/Principal Findings: Using our previously validated immunoassay for measuring poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies, we validated a method to quantify PAR levels in PBMCs to monitor the pharmacodynamic effects of the PARP inhibitor ABT-888 in clinical trials. The inter-individual variation in PAR levels was large. No significant difference (P = 0.67) was measured between median baseline PAR levels in 144 healthy volunteers (131.7 pg/1 x 10(7) PBMCs [interquartile range, 79.5-241.6]) and 49 patients with cancer (149.2 pg/1610 7 PBMCs [interquartile range, 83.2-249.3]). In addition, PAR levels monitored in healthy volunteers over 3 weeks had considerable intra-and inter-individual variation (range, 44-1073 pg PAR/1 x 10(7) PBMCs). As a pharmacodynamic model, we quantified changes in PAR levels in human PBMCs treated ex vivo with clinically relevant concentrations of ABT-888. Of 40 healthy volunteer PBMC samples treated with ABT-888, 47.5% had greater than 50% PAR reduction compared to vehicle-treated controls. Considerable inter-sample heterogeneity in PAR levels was measured, and several ABT-888-insensitive samples were identified. Conclusions/Significance: Our results emphasize the importance of using a validated method to measure PAR levels, and support further investigation into the role of PARP in PBMCs. To this end, the PAR immunoassay has been validated for use with PBMCs and incorporated into clinical trials to assess PBMCs as a potential pharmacodynamic surrogate for tumor biopsies in clinical trials of PARP inhibitors. C1 [Ji, Jiuping; Zhang, Yiping] NCI, Natl Clin Target Validat Lab, Frederick, MD 21701 USA. [Kinders, Robert J.; Parchment, Ralph E.] NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, SAIC Frederick Inc, Frederick, MD 21701 USA. [Rubinstein, Larry; Kummar, Shivaani; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kummar, Shivaani; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ji, JP (reprint author), NCI, Natl Clin Target Validat Lab, Frederick, MD 21701 USA. EM jijiupi@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health (NIH) National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 23 Z9 23 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 OCT 10 PY 2011 VL 6 IS 10 AR e26152 DI 10.1371/journal.pone.0026152 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OO UT WOS:000295971700045 PM 22028822 ER PT J AU Mercer, N Ramakrishnan, B Boeggeman, E Qasba, PK AF Mercer, Natalia Ramakrishnan, Boopathy Boeggeman, Elizabeth Qasba, Pradman K. TI Applications of Site-Specific Labeling to Study HAMLET, a Tumoricidal Complex of alpha-Lactalbumin and Oleic Acid SO PLOS ONE LA English DT Article ID TUMOR-CELL DEATH; MOLTEN GLOBULE STATE; BREAST CARCINOMAS; PROGNOSTIC-SIGNIFICANCE; N-ACETYLGLUCOSAMINE; CRYSTAL-STRUCTURE; MAMMARY-GLAND; APOPTOSIS; PROTEIN; LETHAL AB Background: Alpha-lactalbumin (a-LA) is a calcium-bound mammary gland-specific protein that is found in milk. This protein is a modulator of beta 1,4-galactosyltransferase enzyme, changing its acceptor specificity from N-acetyl-glucosamine to glucose, to produce lactose, milk's main carbohydrate. When calcium is removed from alpha-LA, it adopts a molten globule form, and this form, interestingly, when complexed with oleic acid (OA) acquires tumoricidal activity. Such a complex made from human alpha-LA (hLA) is known as HAMLET (Human A-lactalbumin Made Lethal to Tumor cells), and its tumoricidal activity has been well established. Methodology/Principal Findings: In the present work, we have used site-specific labeling, a technique previously developed in our laboratory, to label HAMLET with biotin, or a fluoroprobe for confocal microscopy studies. In addition to full length hLA, the alpha-domain of hLA (alpha D-hLA) alone is also included in the present study. We have engineered these proteins with a 17-amino acid C-terminal extension (hLA-ext and alpha D-hLA-ext). A single Thr residue in this extension is glycosylated with 2-acetonyl-galactose (C2-keto-galactose) using polypeptide-alpha-N-acetylgalactosaminyltransferase II (ppGalNAc-T2) and further conjugated with aminooxy-derivatives of fluoroprobe or biotin molecules. Conclusions/Significance: We found that the molten globule form of hLA and alpha D-hLA proteins, with or without C-terminal extension, and with and without the conjugated fluoroprobe or biotin molecule, readily form a complex with OA and exhibits tumoricidal activity similar to HAMLET made with full-length hLA protein. The confocal microscopy studies with fluoroprobe-labeled samples show that these proteins are internalized into the cells and found even in the nucleus only when they are complexed with OA. The HAMLET conjugated with a single biotin molecule will be a useful tool to identify the cellular components that are involved with it in the tumoricidal activity. C1 [Mercer, Natalia; Ramakrishnan, Boopathy; Boeggeman, Elizabeth; Qasba, Pradman K.] NCI Frederick, Struct Glycobiol Sect, CCR Nanobiol Program, Ctr Canc Res, Frederick, MD USA. [Ramakrishnan, Boopathy; Boeggeman, Elizabeth] NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Frederick, MD USA. RP Mercer, N (reprint author), NCI Frederick, Struct Glycobiol Sect, CCR Nanobiol Program, Ctr Canc Res, Frederick, MD USA. EM qasba@helix.nih.gov FU NCI, NIH [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This project has been funded in part with Federal funds from NCI, NIH under contract HHSN261200800001E. This research was supported ( in part) by the Intramural Research Program at the National Institutes of Health, National Cancer Institute, Center for Cancer Research. No external funding was received for this study. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 10 Z9 10 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2011 VL 6 IS 10 AR e26093 DI 10.1371/journal.pone.0026093 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OO UT WOS:000295971700038 PM 22016817 ER PT J AU Reinhold, WC Erliandri, I Liu, HF Zoppoli, G Pommier, Y Larionov, V AF Reinhold, William C. Erliandri, Indri Liu, Hongfang Zoppoli, Gabriele Pommier, Yves Larionov, Vladimir TI Identification of a Predominant Co-Regulation among Kinetochore Genes, Prospective Regulatory Elements, and Association with Genomic Instability SO PLOS ONE LA English DT Article ID CELL-LINE PANEL; CENP-A; CHROMOSOME SEGREGATION; MICROTUBULE INTERFACE; EXPRESSION PROFILES; OUTER KINETOCHORE; COLORECTAL-CANCER; CENTROMERE; COMPLEX; ANEUPLOIDY AB The NCI-60 cell line panel is the most extensively characterized set of cells in existence, and has been used extensively as a screening tool for drug discovery. Previously, the potential of this panel has not been applied to the fundamental cellular processes of chromosome segregation. In the current study, we used data from multiple microarray platforms accumulated for the NCI-60 to characterize an expression pattern of genes involved in kinetochore assembly. This analysis revealed that 17 genes encoding the constitutive centromere associated network of the kinetochore core (the CCAN complex) plus four additional genes with established importance in kinetochore maintenance (CENPE, CENPF, INCENP, and MIS12) exhibit similar patterns of expression in the NCI-60, suggesting a mechanism for co-regulated transcription of these genes which is maintained despite the multiple genetic and epigenetic rearrangements accumulated in these cells (such as variations in DNA copy number and karyotypic complexity). A complex group of potential regulatory influences are identified for these genes, including the transcription factors CREB1, E2F1, FOXE1, and FOXM1, DNA copy number variation, and microRNAs has-miR-200a, 23a, 23b, 30a, 30c, 27b, 374b, 365. Thus, our results provide a template for experimental studies on the regulation of genes encoding kinetochore proteins, the process that, when aberrant, leads to the aneuploidy that is a hallmark of many cancers. We propose that the comparison of expression profiles in the NCI-60 cell line panel could be a tool for the identification of other gene groups whose products are involved in the assembly of organelle protein complexes. C1 [Reinhold, William C.; Erliandri, Indri; Liu, Hongfang; Zoppoli, Gabriele; Pommier, Yves; Larionov, Vladimir] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, Hongfang] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Zoppoli, Gabriele] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. RP Reinhold, WC (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; larionov@mail.nih.gov RI Zoppoli, Gabriele/B-6935-2016 OI Zoppoli, Gabriele/0000-0003-3890-5588 FU National Cancer Institute FX Funding for this work is from the National Cancer Institute's intramural funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2011 VL 6 IS 10 AR e25991 DI 10.1371/journal.pone.0025991 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OO UT WOS:000295971700031 PM 22016797 ER PT J AU Fairfield, KM Murray, K Lucas, FL Wierman, HR Earle, CC Trimble, EL Small, L Warren, JL AF Fairfield, Kathleen M. Murray, Kimberly Lucas, F. Lee Wierman, Heidi R. Earle, Craig C. Trimble, Edward L. Small, Laurie Warren, Joan L. TI Completion of Adjuvant Chemotherapy and Use of Health Services for Older Women With Epithelial Ovarian Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ELDERLY-PATIENTS; CO-MORBIDITY; POPULATION; AGE; CARCINOMA; SURVIVAL; CARE; EXPERIENCE; PATTERNS; OUTCOMES AB Purpose This analysis identifies factors associated with completion of adjuvant chemotherapy for patients with ovarian cancer and subsequent use of health services. Patients and Methods We used the Surveillance, Epidemiology, and End Results (SEER) -Medicare database to identify 4,617 women age 65 years or older with ovarian cancer diagnosed from 2001 to 2005. By using multivariable analyses with completion of chemotherapy as the outcome of interest, we describe factors associated with completion of treatment, including age, race, marital status, comorbidities, and sociodemographic factors. Use of health services was captured from Medicare claims. Results Among 4,617 patients with untreated ovarian cancer, 1,329 (28.8%) received no chemotherapy, 1,139 (24.7%) received a partial course of chemotherapy, and 2,149 (46.5%) completed chemotherapy. Women age 75 years or older were at greater risk of incomplete chemotherapy versus women age 65 to 74 years (odds ratio [OR], 1.64; 95% CI, 1.33 to 2.04). Having two or more comorbidities was also significantly associated with incomplete chemotherapy (OR, 1.83; 95% CI, 1.34 to 2.50). Among women who received either a partial or complete course of chemotherapy, we did not find an increase in use of health services (hospitalizations, emergency department visits, or physician visits) for the oldest women (age 80 years or older) compared with younger women. Conclusion There is considerable room for improvement in helping older patients with ovarian cancer initiate and complete chemotherapy. The oldest women who completed chemotherapy in this study did not use health services more than younger women did. Treatment teams for older patients with ovarian cancer should include expertise in geriatric assessment, should carefully identify medical and psychosocial barriers to completing treatment, and should support patients throughout treatment. C1 [Fairfield, Kathleen M.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Portland, ME 04102 USA. [Earle, Craig C.] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Trimble, Edward L.; Warren, Joan L.] NCI, Bethesda, MD 20892 USA. RP Fairfield, KM (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, Res Inst, 22 Bramhall St, Portland, ME 04102 USA. EM fairfk@mmc.org FU Maine Medical Center FX Supported by a grant from Maine Medical Center's Research Strategic Plan Program (K.M.F.). NR 27 TC 18 Z9 19 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2011 VL 29 IS 29 BP 3921 EP 3926 DI 10.1200/JCO.2010.34.1552 PG 6 WC Oncology SC Oncology GA 833LE UT WOS:000295886200017 PM 21911719 ER PT J AU Holland, MG Schwope, DM Stoppacher, R Gillen, SB Huestis, MA AF Holland, Michael G. Schwope, David M. Stoppacher, Robert Gillen, Shane B. Huestis, Marilyn A. TI Postmortem redistribution of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Postmortem redistribution; THC; Tetrahydrocannabinol; Cannabinoids; Cannabis; Marijuana ID DRUG REDISTRIBUTION; DELTA-9-TETRAHYDROCANNABINOL THC; BLOOD CANNABINOIDS; PLASMA THC; MARIJUANA; URINE; TIME; PERFORMANCE; TOXICOLOGY; STABILITY AB Introduction: Postmortem redistribution (PMR), a well-described phenomenon in forensic toxicology for certain drugs, can result in increased central blood concentrations relative to peripheral blood concentrations. Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis or marijuana, is the illicit substance most commonly implicated in driving under the influence of drugs (DUID) cases and fatally-injured drivers. No investigation of PMR of THC in human blood has been reported to date. Methods: Matched heart and iliac postmortem blood specimens were collected from 19 medical examiner cases (16 Males, 3 Females) with positive cannabinoid urine immunoassay screens. THC, its equipotent metabolite 11-hydroxy-THC (11-OH-THC) and non-psychoactive metabolite 11-nor-9-carboxy-THC (THCCOOH) were quantified by two-dimensional gas chromatography-mass spectrometry with cryofocusing, with 0.5 ng/mL limits of quantification (LOQ) for all analytes. Results: 10 cases had quantifiable THC and 11-OH-THC; THCCOOH was present in all 19. Median (range) heart: iliac blood ratios were 1.5 for THC (range: 0.3-3.1); 1.6 for 11-OH-THC (range: 0.3-2.7); and 1.8 for THCCOOH (range: 0.5-3.0). Discussion: Cannabinoids, in general, exhibited a mean and median central: peripheral (C:P) concentration ratio of less than 2 following death. A trend was observed for greater PMR with increasing postmortem interval between death and sampling. To our knowledge, these are the first data on THC PMR in humans, providing important scientific data to aid in the interpretation of postmortem cannabinoid concentrations in medico-legal investigations. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Holland, Michael G.] SUNY Upstate Med Univ, Dept Emergency Med, Syracuse, NY 13210 USA. [Holland, Michael G.] Upstate New York Poison Ctr, Syracuse, NY USA. [Schwope, David M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Stoppacher, Robert] SUNY Upstate Med Univ, Dept Pathol, Syracuse, NY 13210 USA. [Stoppacher, Robert; Gillen, Shane B.] Onondaga Cty Med Examiners Off, Syracuse, NY USA. RP Holland, MG (reprint author), 135 North Rd, Wilton, NY 12831 USA. EM mholland@glensfallshosp.org FU National Institute on Drug Abuse, National Institutes of Health; SUNY Upstate Medical University Department of Emergency Medicine; Onondaga County Medical Examiner's Office FX The authors would like to thank the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health and SUNY Upstate Medical University Department of Emergency Medicine and the Onondaga County Medical Examiner's Office for supporting this research. Additionally, the authors would like to thank Allan Barnes and Karl Scheidweiler for technical assistance. NR 29 TC 7 Z9 7 U1 1 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD OCT 10 PY 2011 VL 212 IS 1-3 BP 247 EP 251 DI 10.1016/j.forsciint.2011.06.028 PG 5 WC Medicine, Legal SC Legal Medicine GA 814XK UT WOS:000294490300046 PM 21764230 ER PT J AU Moore, PD Patlolla, AK Tchounwou, PB AF Moore, Pamela D. Patlolla, Anita K. Tchounwou, Paul B. TI Cytogenetic evaluation of malathion-induced toxicity in Sprague-Dawley rats SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Malathion; Genotoxicity; Chromosomal aberrations; DNA damage; Sprague-Dawley rats ID LONGITUDINAL RISK ASSESSMENT; SISTER-CHROMATID EXCHANGE; CELL GEL-ELECTROPHORESIS; OXIDATIVE STRESS; DNA-DAMAGE; ORGANOPHOSPHORUS INSECTICIDE; CHROMOSOMAL-ABERRATIONS; PERIPHERAL LYMPHOCYTES; OCCUPATIONAL EXPOSURE; PESTICIDE PRODUCTION AB Malathion is a well known pesticide and is commonly used in many agricultural and non-agricultural settings. Its toxicity has been attributed primarily to the accumulation of acetylcholine (Ach) at nerve junctions, due to the inhibition of acetylcholinesterase (AChE), and consequently overstimulation of the nicotinic and muscarinic receptors. However, the genotoxicity of malathion has not been adequately studied; published studies suggest a weak interaction with the genetic material. In the present study, we investigated the genotoxic potential of malathion in bone marrow cells and peripheral blood obtained from Sprague-Dawley rats using chromosomal aberrations (CAs), mitotic index (MI), and DNA damage as toxicological endpoints. Four groups of four male rats, each weighing approximately 60 +/- 2 g, were injected intraperitoneally (i.p.) once a day for five days with doses of 2.5, 5, 10, and 20 mg/kg body weight (BW) of malathion dissolved in 1% DMSO. The control group was made up of four animals injected with 1% DMSO. All the animals were sacrificed 24h after the fifth day treatment. Chromosome preparations were obtained from bone marrow cells following standard protocols. DNA damage in peripheral blood leukocytes was determined using alkaline single-cell gel electrophoresis (comet assay). Malathion exposure significantly increased the number of structural chromosomal aberrations (CAs) and the percentages of DNA damage, and decreased the mitotic index (MI) in treated groups when compared with the control group. Our results demonstrate that malathion has a clastogenic/genotoxic potential as measured by the bone marrow CA and comet assay in Sprague-Dawley rats. (C) 2011 Elsevier B.V. All rights reserved. C1 [Moore, Pamela D.; Patlolla, Anita K.; Tchounwou, Paul B.] Jackson State Univ, Mol Toxicol Res Lab, Coll Sci Engn & Technol, NIH Ctr Environm Hlth, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Mol Toxicol Res Lab, Coll Sci Engn & Technol, NIH Ctr Environm Hlth, 1400 Lynch St,Box 18540, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsums.edu FU NIH-RCMI [5G12RR013459]; Department of the Army [W912HZ-04-2-0002] FX This research was financially supported in part by NIH-RCMI Grant No. 5G12RR013459 and in part by the Department of the Army Co-operative Agreement No. W912HZ-04-2-0002. NR 43 TC 11 Z9 11 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD OCT 9 PY 2011 VL 725 IS 1-2 BP 78 EP 82 DI 10.1016/j.mrgentox.2011.07.007 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 827NT UT WOS:000295435900009 PM 21835262 ER PT J AU Noskov, VN Lee, NCO Larionov, V Kouprina, N AF Noskov, Vladimir N. Lee, Nicholas C. O. Larionov, Vladimir Kouprina, Natalay TI Rapid generation of long tandem DNA repeat arrays by homologous recombination in yeast to study their function in mammalian genomes SO BIOLOGICAL PROCEDURES ONLINE LA English DT Article ID HUMAN ARTIFICIAL CHROMOSOME; GAMMA-SATELLITE DNA; CHROMATIN; CENTROMERE; SEQUENCE; CONSTRUCTION; KINETOCHORE; DYNAMICS; VECTORS AB We describe here a method to rapidly convert any desirable DNA fragment, as small as 100 bp, into long tandem DNA arrays up to 140 kb in size that are inserted into a microbe vector. This method includes rolling-circle phi29 amplification (RCA) of the sequence in vitro and assembly of the RCA products in vivo by homologous recombination in the yeast Saccharomyces cerevisiae. The method was successfully used for a functional analysis of centromeric and pericentromeric repeats and construction of new vehicles for gene delivery to mammalian cells. The method may have general application in elucidating the role of tandem repeats in chromosome organization and dynamics. Each cycle of the protocol takes similar to two weeks to complete. C1 [Noskov, Vladimir N.; Lee, Nicholas C. O.; Larionov, Vladimir; Kouprina, Natalay] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Kouprina, N (reprint author), NCI, Mol Pharmacol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov RI Lee, Nicholas/F-3668-2015; OI lee, nicholas/0000-0003-2628-6599 FU National Institutes of Health National Cancer Institute, Center for Cancer Research FX The research reported in this article was supported by the intramural research program of the National Institutes of Health National Cancer Institute, Center for Cancer Research. NR 30 TC 2 Z9 2 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1480-9222 J9 BIOL PROCED ONLINE JI Biol. Proced. Online PD OCT 7 PY 2011 VL 13 AR 8 DI 10.1186/1480-9222-13-8 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 892KZ UT WOS:000300286400001 PM 21982381 ER PT J AU Wang, XS Simon, R AF Wang, Xiaosheng Simon, Richard TI Microarray-based cancer prediction using single genes SO BMC BIOINFORMATICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPRESSION PROFILES; BREAST-CANCER; DNA MICROARRAY; PROGNOSTIC CLASSIFICATION; MOLECULAR CLASSIFICATION; EMBRYONAL TUMOR; SIMPLE RULES; SELECTION; PATTERNS AB Background: Although numerous methods of using microarray data analysis for cancer classification have been proposed, most utilize many genes to achieve accurate classification. This can hamper interpretability of the models and ease of translation to other assay platforms. We explored the use of single genes to construct classification models. We first identified the genes with the most powerful univariate class discrimination ability and then constructed simple classification rules for class prediction using the single genes. Results: We applied our model development algorithm to eleven cancer gene expression datasets and compared classification accuracy to that for standard methods including Diagonal Linear Discriminant Analysis, k-Nearest Neighbor, Support Vector Machine and Random Forest. The single gene classifiers provided classification accuracy comparable to or better than those obtained by existing methods in most cases. We analyzed the factors that determined when simple single gene classification is effective and when more complex modeling is warranted. Conclusions: For most of the datasets examined, the single-gene classification methods appear to work as well as more standard methods, suggesting that simple models could perform well in microarray-based cancer prediction. C1 [Wang, Xiaosheng; Simon, Richard] NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. EM rsimon@mail.nih.gov NR 51 TC 23 Z9 23 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 7 PY 2011 VL 12 AR 391 DI 10.1186/1471-2105-12-391 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 847GF UT WOS:000296959300001 PM 21982331 ER PT J AU Chen, JS Song, J Yuan, PX Tian, QJ Ji, YY Ren-Patterson, R Liu, GP Sei, Y Weinberger, DR AF Chen, Jingshan Song, Jian Yuan, Peixiong Tian, Qingjun Ji, Yuanyuan Ren-Patterson, Renee Liu, Guangping Sei, Yoshitasu Weinberger, Daniel R. TI Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons IMPLICATIONS FOR DRUG DEVELOPMENT SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA; HUMAN BRAIN; PROTEIN EXPRESSION; DOPAMINE CLEARANCE; PREFRONTAL CORTEX; GENETIC-VARIATION; ENZYME-ACTIVITY; LIVER TOXICITY; DEFICIENT MICE; COMT GENOTYPE AB Catechol-O-methyltransferase (COMT) is a key enzyme for inactivation and metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. It plays an important role in cognition, arousal, pain sensitivity, and stress reactivity in humans and in animal models. The human COMT gene is associated with a diverse spectrum of human behaviors and diseases from cognition and psychiatric disorders to chronic pain and cancer. There are two major forms of COMT proteins, membrane-bound (MB) COMT and soluble (S) COMT. MB-COMT is the main form in the brain. The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial. In this study, we demonstrate that MB-COMT is located in the cell body and in axons and dendrites of rat cortical neurons. Analyses of MB-COMT orientation with computer simulation, flow cytometry and a cell surface enzyme assay reveal that the C-terminal catalytic domain of MB-COMT is in the extracellular space, which suggests that MB-COMT can inactivate synaptic and extrasynaptic dopamine on the surface of presynaptic and postsynaptic neurons. Finally, we show that the COMT inhibitor tolcapone induces cell death via the mechanism of apoptosis, and its cytotoxicity is dependent on dosage and correlated with COMT Val/Met genotypes in human lymphoblastoid cells. These results suggest that MB-COMT specific inhibitors can be developed and that tolcapone may be less hazardous at low doses and in specific genetic backgrounds. C1 [Chen, Jingshan; Song, Jian; Yuan, Peixiong; Tian, Qingjun; Ji, Yuanyuan; Ren-Patterson, Renee; Liu, Guangping; Sei, Yoshitasu; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Room 3C-103A,10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov FU NIMH, National Institutes of Health FX This work was supported by NIMH, National Institutes of Health Intramural Research Program. NR 45 TC 28 Z9 30 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2011 VL 286 IS 40 BP 34752 EP 34760 DI 10.1074/jbc.M111.262790 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300029 PM 21846718 ER PT J AU Huang, SH Long, M Wu, CH Kwon-Chung, KJ Chang, YC Chi, F Lee, S Jong, A AF Huang, Sheng-He Long, Min Wu, Chun-Hua Kwon-Chung, Kyung J. Chang, Yun C. Chi, Feng Lee, Susan Jong, Ambrose TI Invasion of Cryptococcus neoformans into Human Brain Microvascular Endothelial Cells Is Mediated through the Lipid Rafts-Endocytic Pathway via the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 3 (DYRK3) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTORS; INTRACELLULAR TRAFFICKING; DEPENDENT ENDOCYTOSIS; CHOLERA-TOXIN; CYTOSKELETON; ACTIVATION; CAVEOLAE; PROTEIN; MEMBRANE; SURVIVAL AB Cryptococcus neoformans is a neurotropic fungal pathogen, which provokes the onset of devastating meningoencephalitis. Weused human brain microvascular endothelial cells (HBMEC) as the in vitro model to investigate how C. neoformans traverses across the blood-brain barrier. In this study, we present several lines of evidence indicating that C. neoformans invasion is mediated through the endocytic pathway via lipid rafts. Human CD44 molecules from lipid rafts can directly interact with hyaluronic acid, the C. neoformans ligand. Bikunin, which perturbs CD44 function in the lipid raft, can block C. neoformans adhesion and invasion of HBMEC. The lipid raft marker, ganglioside GM1, co-localizes with CD44 on the plasma membrane, and C. neoformans cells can adhere to the host cell in areas where GM1 is enriched. These findings suggest that C. neoformans entry takes place on the lipid rafts. Upon C. neoformans engagement, GM1 is internalized through vesicular structures to the nuclear membrane. This endocytic redistribution process is abolished by cytochalasin D, nocodazole, or anti-DYRK3 (dual specificity tyrosine-phosphorylation-regulated kinase 3) siRNA. Concomitantly, the knockdown of DYRK3 significantly reduces C. neoformans invasion across the HBMEC monolayer in vitro. Our data demonstrate that the lipid raft-dependent endocytosis process mediates C. neoformans internalization into HBMEC and that the CD44 protein of the hosts, cytoskeleton, and intracellular kinase-DYRK3 are involved in this process. C1 [Huang, Sheng-He; Long, Min; Wu, Chun-Hua; Chi, Feng; Jong, Ambrose] Univ So Calif, Saban Res Inst, Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA. [Lee, Susan] Univ So Calif, Dept Pathol, Keck Sch Med, Los Angeles, CA 90027 USA. [Kwon-Chung, Kyung J.; Chang, Yun C.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Jong, A (reprint author), Childrens Hosp, Div Hematol Oncol, Mailstop 57,4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM ajong@chla.usc.edu RI Chi, Feng/H-5895-2012 FU National Institutes of Health from USPHS [R01-NS047599, R01-AI40635]; National Institutes of Health from NIAID FX This work was supported, in whole or in part, by National Institutes of Health Grants R01-NS047599 (to A.J.) and R01-AI40635 from USPHS (to S.H.H.).; Supported by National Institutes of Health grants from the intramural program of NIAID. NR 47 TC 32 Z9 39 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2011 VL 286 IS 40 BP 34761 EP 34769 DI 10.1074/jbc.M111.219378 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300030 PM 21693704 ER PT J AU Hao, H Tummala, P Guzman, E Mali, RS Gregorski, J Swaroop, A Mitton, KP AF Hao, Hong Tummala, Padmaja Guzman, Eduardo Mali, Raghuveer S. Gregorski, Janina Swaroop, Anand Mitton, Kenneth P. TI The Transcription Factor Neural Retina Leucine Zipper (NRL) Controls Photoreceptor-specific Expression of Myocyte Enhancer Factor Mef2c from an Alternative Promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR RECEPTOR NR2E3; SEVERE MENTAL-RETARDATION; IN-VIVO; GENE-EXPRESSION; ROD PHOTORECEPTORS; DIFFERENTIATION FACTOR; CONE PHOTORECEPTORS; HISTONE ACETYLATION; HORMONE-RECEPTOR; RHODOPSIN GENE AB Neural retina leucine zipper (NRL) is an essential transcription factor for cell fate specification and functional maintenance of rod photoreceptors in the mammalian retina. In the Nrl(-/-) mouse retina, photoreceptor precursors fail to produce rods and generate functional cone photoreceptors that predominantly express S-opsin. Previous global expression analysis using microarrays revealed dramatically reduced expression of myocyte enhancer factor Mef2c in the adult Nrl(-/-) retina. We undertook this study to examine the biological relevance of Mef2c expression in retinal rod photoreceptors. Bioinformatics analysis, rapid analysis of cDNA ends (5'-RACE), and reverse transcription coupled with qPCR using splice site-specific oligonucleotides suggested that Mef2c is expressed in the mature retina from an alternative promoter. Chromatin immunoprecipitation (ChIP) studies showed the association of active RNA polymerase II and acetylated histone H3 just upstream of Mef2c exon 4, providing additional evidence for the utilization of an alternative promoter in the retina. In concordance, we observed the binding of NRL to a putative NRL-response element (NRE) at this location by ChIP-seq and electrophoretic mobility shift assays. NRL also activated the Mef2c alternative promoter in vitro and in vivo. Notably, MEF2C could support Rhodopsin promoter activity in rod photoreceptors. We conclude that Mef2c expression from an alternative promoter in the retina is regulated by NRL. Our studies also implicate MEF2C as a transcriptional regulator of homeostasis in rod photoreceptor cells. C1 [Tummala, Padmaja; Guzman, Eduardo; Mali, Raghuveer S.; Mitton, Kenneth P.] Oakland Univ, Eye Res Inst, Control Gene Express Lab, Rochester, MI 48309 USA. [Hao, Hong; Gregorski, Janina; Swaroop, Anand] NIH, Neurobiol Neurodegenerat & Repair Lab, NEI, Bethesda, MD 20892 USA. RP Mitton, KP (reprint author), Oakland Univ, Eye Res Inst, Control Gene Express Lab, Rm 412,Dodge Hall, Rochester, MI 48309 USA. EM mitton@oakland.edu OI Mitton, Kenneth/0000-0002-4751-7440; Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [EY14626, EY14803]; NEI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants EY14626 (to K. P. M.), EY14803 (Oakland University Eye Research Institute), and the intramural program of the NEI, National Institutes of Health. NR 67 TC 18 Z9 19 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2011 VL 286 IS 40 BP 34893 EP 34902 DI 10.1074/jbc.M111.271072 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300043 PM 21849497 ER PT J AU Gelmedin, V Brodigan, T Gao, X Krause, M Wang, Z Hawdon, JM AF Gelmedin, Verena Brodigan, Thomas Gao, Xin Krause, Michael Wang, Zhu Hawdon, John M. TI Transgenic C. elegans Dauer Larvae Expressing Hookworm Phospho Null DAF-16/FoxO Exit Dauer SO PLOS ONE LA English DT Article ID 3RD-STAGE INFECTIVE LARVAE; AGE-1 PI3 KINASE; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTOR; ANCYLOSTOMA-CANINUM; FEEDING INVITRO; LIFE-SPAN; PHOSPHORYLATION SITES; SIGNALING PATHWAY; FAMILY-MEMBER AB Parasitic hookworms and the free-living model nematode Caenorhabtidis elegans share a developmental arrested stage, called the dauer stage in C. elegans and the infective third-stage larva (L3) in hookworms. One of the key transcription factors that regulate entrance to and exit from developmental arrest is the forkhead transcription factor DAF-16/FoxO. During the dauer stage, DAF-16 is activated and localized in the nucleus. DAF-16 is negatively regulated by phosphorylation by the upstream kinase AKT, which causes DAF-16 to localize out of the nucleus and the worm to exit from dauer. DAF-16 is conserved in hookworms, and hypothesized to control recovery from L3 arrest during infection. Lacking reverse genetic techniques for use in hookworms, we used C. elegans complementation assays to investigate the function of Ancylostoma caninum DAF-16 during entrance and exit from L3 developmental arrest. We performed dauer switching assays and observed the restoration of the dauer phenotype when Ac-DAF-16 was expressed in temperature-sensitive dauer defective C. elegans daf-2(e1370);daf-16(mu86) mutants. AKT phosphorylation site mutants of Ac-DAF-16 were also able to restore the dauer phenotype, but surprisingly allowed dauer exit when temperatures were lowered. We used fluorescence microscopy to localize DAF-16 during dauer and exit from dauer in C. elegans DAF-16 mutant worms expressing Ac-DAF-16, and found that Ac-DAF-16 exited the nucleus during dauer exit. Surprisingly, Ac-DAF-16 with mutated AKT phosphorylation sites also exited the nucleus during dauer exit. Our results suggest that another mechanism may be involved in the regulation DAF-16 nuclear localization during recovery from developmental arrest. C1 [Gelmedin, Verena; Gao, Xin; Hawdon, John M.] Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Brodigan, Thomas; Krause, Michael] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Zhu] UT SW Med Sch, Dept Pharmacol, Dallas, TX USA. RP Gelmedin, V (reprint author), Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. EM mtmvxg@gwumc.edu RI Gao, Cyan/O-9316-2014; OI Krause, Michael/0000-0001-6127-3940; Hawdon, John/0000-0002-6164-1413 FU NIH from the National Institute of Allergy and Infectious Diseases [R01AI069293]; National Institute of Diabetes and Digestive and Kidney Diseases of the NIH; NIH [SIG S10RR025565]; NIH National Center for Research Resources (NCRR) FX This work was funded by NIH Grant R01AI069293 from the National Institute of Allergy and Infectious Diseases and, in part, by the National Institute of Diabetes and Digestive and Kidney Diseases of the Intramural Research Program of the NIH. The confocal microscope Zeiss 710 was funded by NIH SIG S10RR025565. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 8 Z9 10 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e25996 DI 10.1371/journal.pone.0025996 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300047 PM 22016799 ER PT J AU Jeong, SY Crooks, DR Wilson-Ollivierre, H Ghosh, MC Sougrat, R Lee, J Cooperman, S Mitchell, JB Beaumont, C Rouault, TA AF Jeong, Suh Young Crooks, Daniel R. Wilson-Ollivierre, Hayden Ghosh, Manik C. Sougrat, Rachid Lee, Jaekwon Cooperman, Sharon Mitchell, James B. Beaumont, Carole Rouault, Tracey A. TI Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice SO PLOS ONE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; REGULATORY PROTEIN-2; NEURODEGENERATIVE DISEASE; TRANSFERRIN RECEPTOR; TARGETED DELETION; KNOCKOUT MICE; H-FERRITIN; HOMEOSTASIS; DEFICIENT; TDP-43 AB Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice. C1 [Jeong, Suh Young; Crooks, Daniel R.; Wilson-Ollivierre, Hayden; Ghosh, Manik C.; Cooperman, Sharon; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. [Sougrat, Rachid] KAUST, Nanobiol Lab, Thuwal, Saudi Arabia. [Lee, Jaekwon] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. [Mitchell, James B.] NCI, NIH, Bethesda, MD 20892 USA. [Beaumont, Carole] Univ Paris Diderot, INSERM, U773, Ctr Rech Biomed Bichat Beaujon, Paris, France. RP Jeong, SY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov OI Sougrat, Rachid/0000-0001-6476-1886; Jeong, Suh Young/0000-0002-6376-7001 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the intramural program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 23 Z9 23 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e25404 DI 10.1371/journal.pone.0025404 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300011 PM 22003390 ER PT J AU Lee, YJ Mou, Y Maric, D Klimanis, D Auh, S Hallenbeck, JM AF Lee, Yang-Ja Mou, Yongshan Maric, Dragan Klimanis, Dace Auh, Sungyoung Hallenbeck, John M. TI Elevated Global SUMOylation in Ubc9 Transgenic Mice Protects Their Brains against Focal Cerebral Ischemic Damage SO PLOS ONE LA English DT Article ID IN-VITRO; MAMMALIAN HIBERNATION; ACTIVATING ENZYME; SUMO; STROKE; TOLERANCE; PATHOPHYSIOLOGY; INHIBITION; MECHANISM; CELLS AB We have previously shown that a massive increase in global SUMOylation occurs during torpor in ground squirrels, and that overexpression of Ubc9 and/or SUMO-1 in cell lines and cortical neurons protects against oxygen and glucose deprivation. To examine whether increased global SUMOylation protects against ischemic brain damage, we have generated transgenic mice in which Ubc9 is expressed strongly in all tissues under the chicken beta-actin promoter. Ubc9 expression levels in 10 founder lines ranged from 2 to 30 times the endogenous level, and lines that expressed Ubc9 at modestly increased levels showed robust resistance to brain ischemia compared to wild type mice. The infarction size was inversely correlated with the Ubc9 expression levels for up to five times the endogenous level. Although further increases showed no additional benefit, the Ubc9 expression level was highly correlated with global SUMO-1 conjugation levels (and SUMO-2,3 levels to a lesser extent) up to a five-fold Ubc9 increase. Most importantly, there were striking reciprocal relationships between SUMO-1 (and SUMO-2,3) conjugation levels and cerebral infarction volumes among all tested animals, suggesting that the limit in cytoprotection by global SUMOylation remains undefined. These results support efforts to further augment global protein SUMOylation in brain ischemia. C1 [Lee, Yang-Ja; Mou, Yongshan; Klimanis, Dace; Hallenbeck, John M.] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. [Auh, Sungyoung] NINDS, Clin Neurosci Program HNQ22, NIH, Bethesda, MD 20892 USA. RP Lee, YJ (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 45 Z9 46 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e25852 DI 10.1371/journal.pone.0025852 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300031 PM 22016779 ER PT J AU Sedegah, M Tamminga, C McGrath, S House, B Ganeshan, H Lejano, J Abot, E Banania, GJ Sayo, R Farooq, F Belmonte, M Manohar, N Richie, NO Wood, C Long, CA Regis, D Williams, FT Shi, M Chuang, I Spring, M Epstein, JE Mendoza-Silveiras, J Limbach, K Patterson, NB Bruder, JT Doolan, DL King, CR Soisson, L Diggs, C Carucci, D Dutta, S Hollingdale, MR Ockenhouse, CF Richie, TL AF Sedegah, Martha Tamminga, Cindy McGrath, Shannon House, Brent Ganeshan, Harini Lejano, Jennylynn Abot, Esteban Banania, Glenna J. Sayo, Renato Farooq, Fouzia Belmonte, Maria Manohar, Nalini Richie, Nancy O. Wood, Chloe Long, Carole A. Regis, David Williams, Francis T. Shi, Meng Chuang, Ilin Spring, Michele Epstein, Judith E. Mendoza-Silveiras, Jose Limbach, Keith Patterson, Noelle B. Bruder, Joseph T. Doolan, Denise L. King, C. Richter Soisson, Lorraine Diggs, Carter Carucci, Daniel Dutta, Sheetij Hollingdale, Michael R. Ockenhouse, Christian F. Richie, Thomas L. TI Adenovirus 5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part A: Safety and Immunogenicity in Seronegative Adults SO PLOS ONE LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; T-CELL EPITOPES; CANDIDATE MALARIA VACCINE; PLASMODIUM-BERGHEI SPOROZOITES; NATURAL IMMUNE-RESPONSES; PRIME-BOOST REGIMENS; BLOOD-STAGE MALARIA; PHASE I/IIA SAFETY; CIRCUMSPOROZOITE PROTEIN; PROTECTIVE IMMUNITY AB Background: Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers. Methodology/Principal Findings: The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2x10(boolean AND) 10 particle units (1610(boolean AND) 10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-gamma responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-gamma, TNF-alpha or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites. Significance: As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1x10(boolean AND) 11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-gamma responses. C1 [Sedegah, Martha; Tamminga, Cindy; House, Brent; Ganeshan, Harini; Lejano, Jennylynn; Abot, Esteban; Banania, Glenna J.; Sayo, Renato; Farooq, Fouzia; Belmonte, Maria; Manohar, Nalini; Regis, David; Chuang, Ilin; Epstein, Judith E.; Mendoza-Silveiras, Jose; Limbach, Keith; Patterson, Noelle B.; Doolan, Denise L.; Carucci, Daniel; Richie, Thomas L.] USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [McGrath, Shannon; Richie, Nancy O.; Wood, Chloe; Spring, Michele; Dutta, Sheetij; Ockenhouse, Christian F.] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [McGrath, Shannon; Richie, Nancy O.; Wood, Chloe; Dutta, Sheetij] Clin Res Management, Hinckley, OH USA. [Ganeshan, Harini; Lejano, Jennylynn; Abot, Esteban; Banania, Glenna J.; Sayo, Renato; Farooq, Fouzia; Belmonte, Maria; Manohar, Nalini; Spring, Michele; Mendoza-Silveiras, Jose; Limbach, Keith; Patterson, Noelle B.] Henry M Jackson Fdn Adv Mil Med, Rockville, MD USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Williams, Francis T.] Natl Naval Med Ctr, Bethesda, MD USA. [Shi, Meng] Walter Reed Army Inst Res, Div Med Audio Visual Lib & Stat Serv, Silver Spring, MD USA. [Shi, Meng] Allied Technol Grp Inc, Rockville, MD USA. [Bruder, Joseph T.; King, C. Richter] GenVec Inc, Gaithersburg, MD USA. [Soisson, Lorraine; Diggs, Carter] USAID, Washington, DC USA. [Hollingdale, Michael R.] NMRC, Malaria Dept, USMMVP, Silver Spring, MD USA. RP Sedegah, M (reprint author), USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. EM Martha.Sedegah@med.navy.mil RI Belmonte, Maria/A-8032-2011; Doolan, Denise/F-1969-2015; OI Richie, Thomas/0000-0002-2946-5456 FU Pfizer Australia; Congressionally Directed Medical Research Program [W81XWH-05-2-0041] FX SM NOR CW worked for Clinical Research Management and performed some of the experiments, JTB CRK worked for GenVec and helped design the vaccine. DLD held a Pfizer Australia Senior Research Fellowship and helped design the vaccine. The following funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript: Congressionally Directed Medical Research Program "Development of Recombinant Adenoviral-based Vaccines against Malaria'' Grant #: W81XWH-05-2-0041. Website:https://cdmrp.org. Military Infectious ResearcCongressionally Directed Medical Research Programh Program "Phase 1/2a clinical trials assessing the safety, tolerability, immunogenicity & protective efficacy of Ad5-CA, a two-antigen, adenovirus-vectored Plasmodium falciparum malaria vaccine, in healthy, malaria-naive adults'', work unit. Website: https://midrp.amedd.army.mil. NR 83 TC 38 Z9 38 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e24586 DI 10.1371/journal.pone.0024586 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300004 PM 22003383 ER PT J AU Siebers, B Zaparty, M Raddatz, G Tjaden, B Albers, SV Bell, SD Blombach, F Kletzin, A Kyrpides, N Lanz, C Plagens, A Rampp, M Rosinus, A von Jan, M Makarova, KS Klenk, HP Schuster, SC Hensel, R AF Siebers, Bettina Zaparty, Melanie Raddatz, Guenter Tjaden, Britta Albers, Sonja-Verena Bell, Steve D. Blombach, Fabian Kletzin, Arnulf Kyrpides, Nikos Lanz, Christa Plagens, Andre Rampp, Markus Rosinus, Andrea von Jan, Mathias Makarova, Kira S. Klenk, Hans-Peter Schuster, Stephan C. Hensel, Reinhard TI The Complete Genome Sequence of Thermoproteus tenax: A Physiologically Versatile Member of the Crenarchaeota SO PLOS ONE LA English DT Article ID CENTRAL CARBOHYDRATE-METABOLISM; RIBULOSE MONOPHOSPHATE PATHWAY; TRANSFER-RNA GENES; METHANOBACTERIUM-THERMOAUTOTROPHICUM; SULFOLOBUS-SOLFATARICUS; BINDING-PROTEIN; PYROBACULUM-AEROPHILUM; IGNICOCCUS-HOSPITALIS; ACIDIANUS-AMBIVALENS; DNA-REPLICATION AB Here, we report on the complete genome sequence of the hyperthermophilic Crenarchaeum Thermoproteus tenax (strain Kra 1, DSM 2078(T)) a type strain of the crenarchaeotal order Thermoproteales. Its circular 1.84-megabase genome harbors no extrachromosomal elements and 2,051 open reading frames are identified, covering 90.6% of the complete sequence, which represents a high coding density. Derived from the gene content, T. tenax is a representative member of the Crenarchaeota. The organism is strictly anaerobic and sulfur-dependent with optimal growth at 86 degrees C and pH 5.6. One particular feature is the great metabolic versatility, which is not accompanied by a distinct increase of genome size or information density as compared to other Crenarchaeota. T. tenax is able to grow chemolithoautotrophically (CO2/H-2) as well as chemoorganoheterotrophically in presence of various organic substrates. All pathways for synthesizing the 20 proteinogenic amino acids are present. In addition, two presumably complete gene sets for NADH:quinone oxidoreductase (complex I) were identified in the genome and there is evidence that either NADH or reduced ferredoxin might serve as electron donor. Beside the typical archaeal A(0)A(1)-ATP synthase, a membrane-bound pyrophosphatase is found, which might contribute to energy conservation. Surprisingly, all genes required for dissimilatory sulfate reduction are present, which is confirmed by growth experiments. Mentionable is furthermore, the presence of two proteins (ParA family ATPase, actin-like protein) that might be involved in cell division in Thermoproteales, where the ESCRT system is absent, and of genes involved in genetic competence (DprA, ComF) that is so far unique within Archaea. C1 [Siebers, Bettina] Univ Duisburg Essen, Biofilm Ctr, Fac Chem, Essen, Germany. [Zaparty, Melanie] Univ Regensburg, Inst Mol & Cellular Anat, Regensburg, Germany. [Raddatz, Guenter] Max Planck Inst Biol Cybernet, Tubingen, Germany. [Tjaden, Britta; Albers, Sonja-Verena; Plagens, Andre; Hensel, Reinhard] Max Planck Inst Terr Microbiol, D-35043 Marburg, Germany. [Bell, Steve D.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Blombach, Fabian] Wageningen Univ, Microbiol Lab, Wageningen, Netherlands. [Kletzin, Arnulf] Tech Univ Darmstadt, Inst Microbiol & Genet, Darmstadt, Germany. [Kyrpides, Nikos] DOE Joint Genome Inst, Walnut Creek, CA USA. [Lanz, Christa; Rosinus, Andrea] Max Planck Inst Dev Biol, Genome Ctr, Tubingen, Germany. [Rampp, Markus] Max Planck Inst Plasma Phys, Comp Ctr Garching, Max Planck Soc RZG, Munich, Germany. [von Jan, Mathias; Klenk, Hans-Peter] German Collect Microorganisms & Cell Cultures, DSMZ, Braunschweig, Germany. [Makarova, Kira S.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Schuster, Stephan C.] Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. RP Siebers, B (reprint author), Univ Duisburg Essen, Biofilm Ctr, Fac Chem, Essen, Germany. EM bettina.siebers@uni-due.de; melanie.zaparty@vkl.uni-regensburg.de RI Albers, Sonja-Verena/H-1213-2012; Kyrpides, Nikos/A-6305-2014; OI Kyrpides, Nikos/0000-0002-6131-0462; Albers, Sonja-Verena/0000-0003-2459-2226; Blombach, Fabian/0000-0001-5337-8662 FU University of Duisburg-Essen (Germany); Deutsche Forschungsgemeinschaft (DFG) [SPP1112, He1238/16-2]; Dutch Science Organization (NWO); Max Planck society FX This work was supported by the University of Duisburg-Essen (Germany) and the Deutsche Forschungsgemeinschaft (DFG; SPP1112) by grant He1238/16-2, 3 (Dr. Hensel). Dr. Albers was supported by a VIDI grant of the Dutch Science Organization (NWO) and intramural funds of the Max Planck society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 119 TC 23 Z9 39 U1 2 U2 19 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 OCT 7 PY 2011 VL 6 IS 10 AR e24222 DI 10.1371/journal.pone.0024222 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300002 PM 22003381 ER PT J AU Tamminga, C Sedegah, M Regis, D Chuang, I Epstein, JE Spring, M Mendoza-Silveiras, J McGrath, S Maiolatesi, S Reyes, S Steinbeiss, V Fedders, C Smith, K House, B Ganeshan, H Lejano, J Abot, E Banania, GJ Sayo, R Farooq, F Belmonte, M Murphy, J Komisar, J Williams, J Shi, M Brambilla, D Manohar, N Richie, NO Wood, C Limbach, K Patterson, NB Bruder, JT Doolan, DL King, CR Diggs, C Soisson, L Carucci, D Levine, G Dutta, S Hollingdale, MR Ockenhouse, CF Richie, TL AF Tamminga, Cindy Sedegah, Martha Regis, David Chuang, Ilin Epstein, Judith E. Spring, Michele Mendoza-Silveiras, Jose McGrath, Shannon Maiolatesi, Santina Reyes, Sharina Steinbeiss, Victoria Fedders, Charlotte Smith, Kathryn House, Brent Ganeshan, Harini Lejano, Jennylynn Abot, Esteban Banania, Glenna J. Sayo, Renato Farooq, Fouzia Belmonte, Maria Murphy, Jittawadee Komisar, Jack Williams, Jackie Shi, Meng Brambilla, Donald Manohar, Nalini Richie, Nancy O. Wood, Chloe Limbach, Keith Patterson, Noelle B. Bruder, Joseph T. Doolan, Denise L. King, C. Richter Diggs, Carter Soisson, Lorraine Carucci, Daniel Levine, Gail Dutta, Sheetij Hollingdale, Michael R. Ockenhouse, Christian F. Richie, Thomas L. TI Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component SO PLOS ONE LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; MALARIA-NAIVE ADULTS; T-CELL RESPONSES; NATURAL IMMUNE-RESPONSES; BLOOD-STAGE VACCINE; PHASE 2A TRIAL; PLASMODIUM-FALCIPARUM; CIRCUMSPOROZOITE PROTEIN; RECOMBINANT PROTEIN; ADENOVIRAL VECTORS AB Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1x1 (0) over cap 10 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. C1 [Tamminga, Cindy; Sedegah, Martha; Regis, David; Chuang, Ilin; Epstein, Judith E.; Mendoza-Silveiras, Jose; Maiolatesi, Santina; Reyes, Sharina; Steinbeiss, Victoria; Fedders, Charlotte; Smith, Kathryn; House, Brent; Ganeshan, Harini; Lejano, Jennylynn; Abot, Esteban; Banania, Glenna J.; Sayo, Renato; Farooq, Fouzia; Belmonte, Maria; Shi, Meng; Manohar, Nalini; Limbach, Keith; Patterson, Noelle B.; Doolan, Denise L.; Carucci, Daniel; Richie, Thomas L.] USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [Spring, Michele; McGrath, Shannon; Murphy, Jittawadee; Komisar, Jack; Williams, Jackie; Shi, Meng; Richie, Nancy O.; Wood, Chloe; Dutta, Sheetij; Ockenhouse, Christian F.] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [McGrath, Shannon; Williams, Jackie; Richie, Nancy O.; Wood, Chloe; Dutta, Sheetij] Clin Res Management, Hinckley, OH USA. [Spring, Michele; Mendoza-Silveiras, Jose; Maiolatesi, Santina; Reyes, Sharina; Steinbeiss, Victoria; Fedders, Charlotte; Smith, Kathryn; Ganeshan, Harini; Lejano, Jennylynn; Abot, Esteban; Banania, Glenna J.; Sayo, Renato; Farooq, Fouzia; Belmonte, Maria; Manohar, Nalini; Limbach, Keith; Patterson, Noelle B.] Henry M Jackson Fdn Adv Mil Med, Rockville, MD USA. [Brambilla, Donald] RTI Rockville, Rockville, MD USA. [Bruder, Joseph T.; King, C. Richter] GenVec Inc, Gaithersburg, MD USA. [Diggs, Carter; Soisson, Lorraine] USAID, Washington, DC USA. [Levine, Gail] Fdn Natl Inst Hlth, Bethesda, MD USA. [Hollingdale, Michael R.] NMRC, USMMVP, Malaria Dept, Silver Spring, MD USA. RP Tamminga, C (reprint author), USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. EM cindy.tamminga@med.navy.mil RI Belmonte, Maria/A-8032-2011; Doolan, Denise/F-1969-2015; OI Richie, Thomas/0000-0002-2946-5456 FU USAID [GHA-P00-03-00006-01, 936-3118]; Congressionally Directed Medical Research Program [W81XWH-05-2-0041] FX The following funder played a role in study design: CD and LS from USAID: "Development of Adenovirus-Vectored Malaria Vaccines" Grant #: GHA-P00-03-00006-01, PROJECT NUMBER 936-3118. Web site: http://www.usaid.gov. SM, NOR, CW, and SD are employees of Clinical Research Management and performed some of the experiments and SM also participated in writing the manuscript. JTB and CRK employees of GenVec, Inc., and participated in the design of the vaccines. The following funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript: Congressionally Directed Medical Research Program "Development of Recombinant Adenoviral-based Vaccines against Malaria" Grant #: W81XWH-05-2-0041. Website: https://cdmrp.org. Military Infectious Research Program "Phase 1/2a clinical trials assessing the safety, tolerability, immunogenicity & protective efficacy of Ad5-CA, a two-antigen, adenovirus-vectored Plasmodium falciparum malaria vaccine, in healthy, malaria-naive adults", work unit. Website: https://midrp.amedd.army.mil. NR 84 TC 41 Z9 41 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e25868 DI 10.1371/journal.pone.0025868 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300034 PM 22003411 ER PT J AU Yamamoto, M Kato, T Hotta, C Nishiyama, A Kurotaki, D Yoshinari, M Takami, M Ichino, M Nakazawa, M Matsuyama, T Kamijo, R Kitagawa, S Ozato, K Tamura, T AF Yamamoto, Michio Kato, Takayuki Hotta, Chie Nishiyama, Akira Kurotaki, Daisuke Yoshinari, Masahiro Takami, Masamichi Ichino, Motohide Nakazawa, Masatoshi Matsuyama, Toshifumi Kamijo, Ryutaro Kitagawa, Seiichi Ozato, Keiko Tamura, Tomohiko TI Shared and Distinct Functions of the Transcription Factors IRF4 and IRF8 in Myeloid Cell Development SO PLOS ONE LA English DT Article ID SEQUENCE-BINDING-PROTEIN; INTERFERON-REGULATORY FACTOR-4; PROGENITOR CELLS; STEM-CELLS; LEUKEMIA; MACROPHAGES; EXPRESSION; DIFFERENTIATION; ICSBP; RESPONSES AB Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development. The ectopic expression of IRF4 in myeloid progenitor cells in vitro inhibits cell growth, promotes macrophages, but hinders granulocytic cell differentiation. We also show that IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS). Furthermore, we demonstrate that Irf8(-/-)Irf4(-/-) mice exhibit a more severe chronic myeloid leukemia (CML)-like disease than Irf8(-/-) mice, involving a disproportionate expansion of granulocytes at the expense of monocytes/macrophages. Irf4(-/-) mice, however, display no obvious abnormality in myeloid cell development, presumably because IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors. Our results also suggest that IRF8 and IRF4 have not only common but also specific activities in myeloid cells. Since the expression of both the IRF8 and IRF4 genes is downregulated in CML patients, these results may add to our understanding of CML pathogenesis. C1 [Yamamoto, Michio; Hotta, Chie; Nishiyama, Akira; Kurotaki, Daisuke; Yoshinari, Masahiro; Ichino, Motohide; Tamura, Tomohiko] Yokohama City Univ, Dept Immunol, Grad Sch Med, Yokohama, Kanagawa 232, Japan. [Kato, Takayuki; Kitagawa, Seiichi; Tamura, Tomohiko] Osaka City Univ, Dept Physiol, Grad Sch Med, Osaka 558, Japan. [Takami, Masamichi; Kamijo, Ryutaro] Showa Univ, Sch Dent, Dept Biochem, Tokyo 142, Japan. [Nakazawa, Masatoshi] Yokohama City Univ, Dept Expt Anim Sci, Grad Sch Med, Yokohama, Kanagawa 232, Japan. [Matsuyama, Toshifumi] Nagasaki Univ, Dept Mol Microbiol & Immunol, Grad Sch Biomed Sci, Nagasaki 852, Japan. [Ozato, Keiko; Tamura, Tomohiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Yamamoto, M (reprint author), Yokohama City Univ, Dept Immunol, Grad Sch Med, Yokohama, Kanagawa 232, Japan. EM tamurat@yokohama-cu.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Yokohama City University; Takeda Science Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Uehara Memorial Foundation; Kato Memorial Bioscience Foundation; Yokohama Foundation for Advancement of Medical Science FX This work was supported by the Grant-in-Aid for Scientific Research (B), the Grant-in-Aid for Exploratory Research, and the research grant for the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Grant for Strategic Research Promotion from Yokohama City University, and research grants from the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Uehara Memorial Foundation, the Kato Memorial Bioscience Foundation, and the Yokohama Foundation for Advancement of Medical Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 34 Z9 34 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2011 VL 6 IS 10 AR e25812 DI 10.1371/journal.pone.0025812 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300028 PM 22003407 ER PT J AU Cameron, JM Janer, A Levandovskiy, V MacKay, N Rouault, TA Tong, WH Ogilvie, I Shoubridge, EA Robinson, BH AF Cameron, Jessie M. Janer, Alexandre Levandovskiy, Valeriy MacKay, Nevena Rouault, Tracey A. Tong, Wing-Hang Ogilvie, Isla Shoubridge, Eric A. Robinson, Brian H. TI Mutations in Iron-Sulfur Cluster Scaffold Genes NFU1 and BOLA3 Cause a Fatal Deficiency of Multiple Respiratory Chain and 2-Oxoacid Dehydrogenase Enzymes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROTEIN-INTERACTION MAP; ESCHERICHIA-COLI; LIPOYL SYNTHASE; SUCCINATE-DEHYDROGENASE; COMPLEX; ACONITASE; IDENTIFICATION; BIOSYNTHESIS; BIOGENESIS; EXPRESSION AB Severe combined deficiency of the 2-oxoacid dehydrogenases, associated with a defect in lipoate synthesis and accompanied by defects in complexes I, II, and III of the mitochondrial respiratory chain, is a rare autosomal recessive syndrome with no obvious causative gene defect. A candidate locus for this syndrome was mapped to chromosomal region 2p14 by microcell-mediated chromosome transfer in two unrelated families. Unexpectedly, analysis of genes in this area identified mutations in two different genes, both of which are involved in [Fe-S] cluster biogenesis. A homozygous missense mutation, c.545G>A, near the splice donor of exon 6 in NFU1 predicting a p.Arg182Gln substitution was found in one of the families. The mutation results in abnormal mRNA splicing of exon 6, and no mature protein could be detected in fibroblast mitochondria. A single base-pair duplication c.123dupA was identified in BOLA3 in the second family, causing a frame shift that produces a premature stop codon (p.Glu42Argfs*13). Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes. NFU1 was previously proposed to be an alternative scaffold to ISCU for the biogenesis of [Fe-S] centers in mitochondria, and the function of BOLA3 was previously unknown. Our results demonstrate that both play essential roles in the production of [Fe-S] centers for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases, and for the assembly of the respiratory chain complexes. C1 [Cameron, Jessie M.; Levandovskiy, Valeriy; MacKay, Nevena; Robinson, Brian H.] Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada. [Janer, Alexandre; Ogilvie, Isla; Shoubridge, Eric A.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 2B4, Canada. [Janer, Alexandre; Ogilvie, Isla; Shoubridge, Eric A.] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. [Rouault, Tracey A.; Tong, Wing-Hang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Robinson, Brian H.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Robinson, Brian H.] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A8, Canada. RP Robinson, BH (reprint author), Hosp Sick Children, Res Inst, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM bhr@sickkids.ca FU MitoMarch for Kirkland; Canadian Institutes of Health Research FX We thank "MitoMarch for Kirkland" and the Canadian Institutes of Health Research (E.A.S.) for funding this project. E.A.S. is an International Scholar of the Howard Hughes Medical Institute. The authors declare no conflict of interests. NR 33 TC 78 Z9 84 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 7 PY 2011 VL 89 IS 4 BP 486 EP 495 DI 10.1016/j.ajhg.2011.08.011 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 834HV UT WOS:000295951300003 PM 21944046 ER PT J AU Denny, JC Crawford, DC Ritchie, MD Bielinski, SJ Basford, MA Bradford, Y Chai, HS Bastarache, L Zuvich, R Peissig, P Carrell, D Ramirez, AH Pathak, J Wilke, RA Rasmussen, L Wang, XM Pacheco, JA Kho, AN Hayes, MG Weston, N Matsumoto, M Kopp, PA Newton, KM Jarvik, GP Li, RL Manolio, TA Kullo, IJ Chute, CG Chisholm, RL Larson, EB McCarty, CA Masys, DR Roden, DM de Andrade, M AF Denny, Joshua C. Crawford, Dana C. Ritchie, Marylyn D. Bielinski, Suzette J. Basford, Melissa A. Bradford, Yuki Chai, High Seng Bastarache, Lisa Zuvich, Rebecca Peissig, Peggy Carrell, David Ramirez, Andrea H. Pathak, Jyotishman Wilke, Russell A. Rasmussen, Luke Wang, Xiaoming Pacheco, Jennifer A. Kho, Abel N. Hayes, M. Geoffrey Weston, Noah Matsumoto, Martha Kopp, Peter A. Newton, Katherine M. Jarvik, Gail P. Li, Rongling Manolio, Teri A. Kullo, Iftikhar J. Chute, Christopher G. Chisholm, Rex L. Larson, Eric B. McCarty, Catherine A. Masys, Daniel R. Roden, Dan M. de Andrade, Mariza TI Variants Near FOXE1 Are Associated with Hypothyroidism and Other Thyroid Conditions: Using Electronic Medical Records for Genome- and Phenome-wide Studies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PHYSICIAN ORDER ENTRY; CLEFT-PALATE; SERUM TSH; SUBCLINICAL HYPOTHYROIDISM; AUTOIMMUNE-THYROIDITIS; GENETIC SUSCEPTIBILITY; PERSONALIZED MEDICINE; RHEUMATOID-ARTHRITIS; PANCREATIC-CANCER; HEALTH RECORDS AB We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 x 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 x 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 x 10(-5)), nodular (OR = 0.76, p = 3.1 x 10(-5)) and multinodular (OR = 0.69, p = 3.9 x 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 x 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 x 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost. C1 [Denny, Joshua C.; Ritchie, Marylyn D.; Bastarache, Lisa; Masys, Daniel R.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. [Denny, Joshua C.; Ramirez, Andrea H.; Wilke, Russell A.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Crawford, Dana C.; Ritchie, Marylyn D.; Zuvich, Rebecca] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Ritchie, Marylyn D.; Bradford, Yuki; Zuvich, Rebecca] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Bielinski, Suzette J.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Basford, Melissa A.; Wang, Xiaoming] Vanderbilt Univ, Res Off, Nashville, TN 37232 USA. [Chai, High Seng; Pathak, Jyotishman; Matsumoto, Martha; Chute, Christopher G.; de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Peissig, Peggy; Rasmussen, Luke; Newton, Katherine M.] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. [Carrell, David; Weston, Noah; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Kho, Abel N.; Hayes, M. Geoffrey; Kopp, Peter A.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Jarvik, Gail P.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98105 USA. [Li, Rongling; Manolio, Teri A.] Natl Human Genome Res Inst, Off Populat Genom, Bethesda, MD 20892 USA. [Kullo, Iftikhar J.] Mayo Clin, Dept Med, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Pacheco, Jennifer A.; Kopp, Peter A.; Chisholm, Rex L.] Northwestern Univ, Dept Ctr Genet Med, Chicago, IL USA. [McCarty, Catherine A.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. RP Denny, JC (reprint author), Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37232 USA. EM josh.denny@vanderbilt.edu RI Crawford, Dana/C-1054-2012; Ritchie, Marylyn/C-1114-2012; Jarvik, Gail/N-6476-2014; Bielinski, Suzette/A-2238-2009; OI Jarvik, Gail/0000-0002-6710-8708; Bielinski, Suzette/0000-0002-2905-5430; Rasmussen, Luke/0000-0002-4497-8049 FU National Human Genome Research Institute (NHGRI) [U01-HG-004610, U01-HG-004608, U01-HG-004599, U01-HG-004609, U01-HG-004603]; National Institute of General Medical Sciences (NIGMS); Mayo Foundation, Mayo Clinic Genome-wide Association Study of Venous Thromboembolism from the NHGRI (GENEVA Consortium) [HG-004735]; National Cancer Institute [P50CA102701] FX The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI) through the following grants: U01-HG-004610 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01-HG-004599 (Mayo Clinic); U01-HG-004609 (Northwestern University); and U01-HG-004603 (Vanderbilt University, also serving as the Coordinating Center). The National Institute of General Medical Sciences (NIGMS) provided additional funding to the eMERGE Network through these grants. The Mayo Genome Consortia are supported by the Mayo Foundation, Mayo Clinic Genome-wide Association Study of Venous Thromboembolism (HG-004735) from the NHGRI (GENEVA Consortium), and the Mayo Clinic SPORE in Pancreatic Cancer (P50CA102701) from the National Cancer Institute. NR 67 TC 105 Z9 106 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 7 PY 2011 VL 89 IS 4 BP 529 EP 542 DI 10.1016/j.ajhg.2011.09.008 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 834HV UT WOS:000295951300007 PM 21981779 ER PT J AU Kouns, NA Nakielna, J Behensky, F Krause, MW Kostrouch, Z Kostrouchova, M AF Kouns, Nathaniel A. Nakielna, Johana Behensky, Frantisek Krause, Michael W. Kostrouch, Zdenek Kostrouchova, Marta TI NHR-23 dependent collagen and hedgehog-related genes required for molting SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Nuclear hormone receptor; Caenorhabditis elegans; NHR-23; Transcription; Gene expression; Development; Hedgehog; Molting; ROR ID CAENORHABDITIS-ELEGANS; C-ELEGANS; DROSOPHILA METAMORPHOSIS; ECDYSONE RECEPTOR; NUCLEAR RECEPTORS; ROR-ALPHA; EXPRESSION; PROTEIN; LARVAL; DHR3 AB NHR-23, a conserved member of the nuclear receptor family of transcription factors, is required for normal development in Caenorhabditis elegans where it plays a critical role in growth and molting. In a search for NHR-23 dependent genes, we performed whole genome comparative expression microarrays on both control and nhr-23 inhibited synchronized larvae. Genes that decreased in response to nhr-23 RNAi included several collagen genes. Unexpectedly, several hedgehog-related genes were also down-regulated after nhr-23 RNAi. A homozygous nhr-23 deletion allele was used to confirm the RNAi knockdown phenotypes and the changes in gene expression. Our results indicate that NHR-23 is a critical co-regulator of functionally linked genes involved in growth and molting and reveal evolutionary parallels among the ecdysozoa. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kouns, Nathaniel A.; Nakielna, Johana; Behensky, Frantisek; Kostrouch, Zdenek; Kostrouchova, Marta] Charles Univ Prague, Lab Model Syst, Inst Inherited Metab Disorders, Fac Med 1, CZ-12801 Prague 2, Czech Republic. [Krause, Michael W.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kostrouchova, M (reprint author), Charles Univ Prague, Lab Model Syst, Inst Inherited Metab Disorders, Fac Med 1, Ke Karlovu 2, CZ-12801 Prague 2, Czech Republic. EM marta.kostrouchova@lf1.cuni.cz OI Krause, Michael/0000-0001-6127-3940 FU Ministry of Education, Youth and Sports of the Czech Republic [0021620806]; Czech Science Foundation [304/08/0970]; Charles University in Prague [SVV262502]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, USA FX We thank Dr. A. Fire for vector L4440 and HT115 cells host. This work was supported by Grant 0021620806 from the Ministry of Education, Youth and Sports of the Czech Republic, and Grant 304/08/0970, from the Czech Science Foundation. N.A.K. and J.N. were supported by the Grant SVV262502 from the Charles University in Prague. M.W.K. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, USA. NR 38 TC 10 Z9 11 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 7 PY 2011 VL 413 IS 4 BP 515 EP 520 DI 10.1016/j.bbrc.2011.08.124 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 833VK UT WOS:000295912800004 PM 21910973 ER PT J AU Lim, HJ Deschamps, JR Jacobson, AE Rice, KC AF Lim, Hwan Jung Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. TI Diastereoselective One-Pot Synthesis of 7-and 8-Substituted 5-Phenylmorphans SO ORGANIC LETTERS LA English DT Article ID RECEPTOR-MEDIATED PHENOMENA; AGONIST DELTA-ANTAGONIST; PROBES; MORPHINE; LIGANDS AB Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzy1-4-ary1-1,2,3,6-tetrahydropyridine by a highly efficient and diastereoselective reaction series, "one-pot" alkylation and ene-imine cyclization followed by sodium borohydride reduction. Mild cyclization conditions gave the desired substituted 5-phenylmorphans in good yield as a single diastereomer. C1 [Lim, Hwan Jung; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Rockville, MD 20852 USA. [Lim, Hwan Jung; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, DHHS, Rockville, MD 20852 USA. [Deschamps, Jeffrey R.] USN, Ctr Bimol Sci & Engn, Res Lab, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDA, Drug Design & Synth Sect, CBRB,5625 Fishers Lane,Room 4N03, Rockville, MD 20852 USA. EM kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism (NIAAA); NIDA with the Naval Research Laboratory [Y1-DA1101] FX The work of the Drug Design and Synthesis Section was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory. We thank Dr. K. Gawrisch and Dr. W. Teague (NIAAA), for NMR data, N. Whittaker and Dr. H. Yeh (Laboratory of Analytical Chemistry, NIDDK), for MS and 1H NMR data, and Dr. Jason A. Deck (Division of Food Contact Notifications, Office of Food AdditiveSafety, Center for Food Safety and Applied Nutrition, FDA) and Dr. Malliga Iyer (NIDA) for discussions and suggestions. NR 13 TC 2 Z9 2 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD OCT 7 PY 2011 VL 13 IS 19 BP 5322 EP 5325 DI 10.1021/ol2021862 PG 4 WC Chemistry, Organic SC Chemistry GA 825WX UT WOS:000295313900088 PM 21905747 ER PT J AU Krivega, M Dean, A AF Krivega, Margarita Dean, Ann TI Insulators Organize Chromatin: Emerging Rules of the Game SO MOLECULAR CELL LA English DT Editorial Material ID GENOME C1 [Krivega, Margarita; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov RI Krivega, Margarita/G-9239-2015 OI Krivega, Margarita/0000-0003-0478-7122 FU Intramural NIH HHS [ZIA DK015508-23] NR 11 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 7 PY 2011 VL 44 IS 1 BP 1 EP 2 DI 10.1016/j.molcel.2011.09.009 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 832AC UT WOS:000295771200001 PM 21981911 ER PT J AU Ramanathan, HN Ye, YH AF Ramanathan, Harish N. Ye, Yihong TI Revoking the Cellular License to Replicate: Yet Another AAA Assignment SO MOLECULAR CELL LA English DT Editorial Material ID DNA-REPLICATION; CDC48/P97; ATPASE; UBIQUITIN; COMPLEX C1 [Ramanathan, Harish N.; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov RI RAMANATHAN, HARISH/B-1274-2013 OI RAMANATHAN, HARISH/0000-0001-6073-2981 FU Intramural NIH HHS [ZIA DK033008-03, ZIA DK033008-04, Z01 DK033008-03, ZIA DK033008-05, Z99 DK999999] NR 10 TC 4 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 7 PY 2011 VL 44 IS 1 BP 3 EP 4 DI 10.1016/j.molcel.2011.09.006 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 832AC UT WOS:000295771200002 PM 21981912 ER PT J AU Abi-Rached, L Jobin, MJ Kulkarni, S McWhinnie, A Dalva, K Gragert, L Babrzadeh, F Gharizadeh, B Luo, M Plummer, FA Kimani, J Carrington, M Middleton, D Rajalingam, R Beksac, M Marsh, SGE Maiers, M Guethlein, LA Tavoularis, S Little, AM Green, RE Norman, PJ Parham, P AF Abi-Rached, Laurent Jobin, Matthew J. Kulkarni, Subhash McWhinnie, Alasdair Dalva, Klara Gragert, Loren Babrzadeh, Farbod Gharizadeh, Baback Luo, Ma Plummer, Francis A. Kimani, Joshua Carrington, Mary Middleton, Derek Rajalingam, Raja Beksac, Meral Marsh, Steven G. E. Maiers, Martin Guethlein, Lisbeth A. Tavoularis, Sofia Little, Ann-Margaret Green, Richard E. Norman, Paul J. Parham, Peter TI The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans SO SCIENCE LA English DT Article ID HLA-B ALLELES; HAPLOTYPE MAP; MHC; HISTORY; POLYMORPHISM; POPULATION; DIVERSITY; EVOLUTION; MIGRATION; SELECTION AB Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems. C1 [Abi-Rached, Laurent; Kulkarni, Subhash; Guethlein, Lisbeth A.; Norman, Paul J.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Abi-Rached, Laurent; Kulkarni, Subhash; Guethlein, Lisbeth A.; Norman, Paul J.; Parham, Peter] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Jobin, Matthew J.] Santa Clara Univ, Dept Anthropol, Santa Clara, CA 95050 USA. [Jobin, Matthew J.] Stanford Univ, Dept Anthropol, Stanford, CA 94305 USA. [McWhinnie, Alasdair; Marsh, Steven G. E.; Little, Ann-Margaret] Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. [Dalva, Klara; Beksac, Meral] Ankara Univ, Dept Hematol, TR-06520 Ankara, Turkey. [Gragert, Loren; Maiers, Martin] Natl Marrow Donor Program, Minneapolis, MN 55413 USA. [Babrzadeh, Farbod; Gharizadeh, Baback] Stanford Univ, Sch Med, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Luo, Ma; Plummer, Francis A.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Luo, Ma; Plummer, Francis A.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. [Kimani, Joshua] Univ Nairobi, Dept Med Microbiol, Nairobi 00202, Kenya. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. [Middleton, Derek] Univ Liverpool, Royal Liverpool Univ Hosp, Sch Infect & Host Def, Div Immunol, Liverpool L7 8XP, Merseyside, England. [Rajalingam, Raja] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, UCLA Immunogenet Ctr, Los Angeles, CA 90095 USA. [Marsh, Steven G. E.; Little, Ann-Margaret] UCL, UCL Canc Inst, London WC1E 6BT, England. [Tavoularis, Sofia] Canadian Blood Serv, Head Off, HLA Lab, Ottawa, ON K1G 4J5, Canada. [Green, Richard E.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. RP Parham, P (reprint author), Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. EM peropa@stanford.edu RI Abi-Rached, Laurent/H-7236-2012; Beksac, Meral/D-6411-2013; OI Maiers, Martin/0000-0002-0198-2064 FU NIH [AI031168]; Yerkes Center [RR000165]; NSF [CNS-0619926, TG-DBS100006]; National Cancer Institute (NCI), NIH [HHSN261200800001E]; NCI, NIH, Center for Cancer Research FX We thank individual investigators and the Bone Marrow Donors Worldwide (BMDW) organization for kindly providing HLA class I typing data, as well as bone marrow registries from Australia, Austria, Belgium, Canada, Cyprus, Czech Republic, France, Ireland, Israel, Italy, Lithuania, Norway, Poland, Portugal, Singapore, Spain, Sweden, Switzerland, Turkey, United Kingdom, and United States for contributing typing data through BMDW. We thank E. Watkin for technical support. We are indebted to the large genome sequencing centers for early access to the gorilla genome data. We used sequence reads generated at the Wellcome Trust Sanger Institute as part of the gorilla reference genome sequencing project. These data can be obtained from the National Center for Biotechnology Information (NCBI) Trace Archive (www.ncbi.nlm.nih.gov/Traces). We also used reads generated by Washington University School of Medicine; these data were produced by the Genome Institute at Washington University School of Medicine in St. Louis and can be obtained from the NCBI Trace Archive (www.ncbi.nlm.nih.gov/Traces/). Funded by NIH grant AI031168, Yerkes Center base grant RR000165, NSF awards (CNS-0619926, TG-DBS100006), by federal funds from the National Cancer Institute (NCI), NIH (contract HHSN261200800001E), and by the Intramural Research Program of the NCI, NIH, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. government. Sequence data have been deposited in GenBank under accession nos. JF974053 to 70. NR 30 TC 171 Z9 176 U1 20 U2 173 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 7 PY 2011 VL 334 IS 6052 BP 89 EP 94 DI 10.1126/science.1209202 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829KW UT WOS:000295580300046 PM 21868630 ER PT J AU Rebuffo-Scheer, C Bose, M He, J Khaja, S Ulatowski, M Beck, ET Fan, J Kumar, S Nelson, MI Henrickson, KJ AF Rebuffo-Scheer, Cecilia Bose, Michael He, Jie Khaja, Shamim Ulatowski, Michael Beck, Eric T. Fan, Jiang Kumar, Swati Nelson, Martha I. Henrickson, Kelly J. TI Whole Genome Sequencing and Evolutionary Analysis of Human Respiratory Syncytial Virus A and B from Milwaukee, WI 1998-2010 SO PLOS ONE LA English DT Article ID G-PROTEIN GENE; MOLECULAR EPIDEMIOLOGY; SUBGROUP-B; GROUP-A; TRANSCRIPTION TERMINATION; CIRCULATION PATTERNS; 60-NUCLEOTIDE DUPLICATION; MONOCLONAL-ANTIBODIES; CONSECUTIVE SEASONS; G-GLYCOPROTEIN AB Background: Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory-tract infections in infants and young children worldwide. Despite this, only six complete genome sequences of original strains have been previously published, the most recent of which dates back 35 and 26 years for RSV group A and group B respectively. Methodology/Principal Findings: We present a semi-automated sequencing method allowing for the sequencing of four RSV whole genomes simultaneously. We were able to sequence the complete coding sequences of 13 RSV A and 4 RSV B strains from Milwaukee collected from 1998-2010. Another 12 RSV A and 5 RSV B strains sequenced in this study cover the majority of the genome. All RSV A and RSV B sequences were analyzed by neighbor-joining, maximum parsimony and Bayesian phylogeny methods. Genetic diversity was high among RSV A viruses in Milwaukee including the circulation of multiple genotypes (GA1, GA2, GA5, GA7) with GA2 persisting throughout the 13 years of the study. However, RSV B genomes showed little variation with all belonging to the BA genotype. For RSV A, the same evolutionary patterns and clades were seen consistently across the whole genome including all intergenic, coding, and non-coding regions sequences. Conclusions/Significance: The sequencing strategy presented in this work allows for RSV A and B genomes to be sequenced simultaneously in two working days and with a low cost. We have significantly increased the amount of genomic data that is available for both RSV A and B, providing the basic molecular characteristics of RSV strains circulating in Milwaukee over the last 13 years. This information can be used for comparative analysis with strains circulating in other communities around the world which should also help with the development of new strategies for control of RSV, specifically vaccine development and improvement of RSV diagnostics. C1 [Rebuffo-Scheer, Cecilia; Bose, Michael; He, Jie; Khaja, Shamim; Ulatowski, Michael; Beck, Eric T.; Fan, Jiang; Kumar, Swati; Henrickson, Kelly J.] Midwest Resp Virus Program, Milwaukee, WI 53214 USA. [Rebuffo-Scheer, Cecilia; Bose, Michael; He, Jie; Khaja, Shamim; Ulatowski, Michael; Beck, Eric T.; Fan, Jiang; Kumar, Swati; Henrickson, Kelly J.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Henrickson, Kelly J.] Childrens Res Inst, Milwaukee, WI USA. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Rebuffo-Scheer, C (reprint author), Midwest Resp Virus Program, Milwaukee, WI 53214 USA. EM Khenrick@mcw.edu FU National Institute of Allergy and Infectious Diseases (NIAID) from the National Institutes of Health (NIH) [U01-AI-066584, U01-AI-070428, U01-AI-077988] FX This work was supported with funds from the National Institute of Allergy and Infectious Diseases (NIAID) grants U01-AI-066584, U01-AI-070428, and U01-AI-077988 from the National Institutes of Health (NIH) (http://www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 33 Z9 33 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2011 VL 6 IS 10 AR e25468 DI 10.1371/journal.pone.0025468 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NO UT WOS:000295968700011 PM 21998661 ER PT J AU Wahl-Jensen, V Cann, JA Rubins, KH Huggins, JW Fisher, RW Johnson, AJ de Kok-Mercado, F Larsen, T Raymond, JL Hensley, LE Jahrling, PB AF Wahl-Jensen, Victoria Cann, Jennifer A. Rubins, Kathleen H. Huggins, John W. Fisher, Robert W. Johnson, Anthony J. de Kok-Mercado, Fabian Larsen, Thomas Raymond, Jo Lynne Hensley, Lisa E. Jahrling, Peter B. TI Progression of Pathogenic Events in Cynomolgus Macaques Infected with Variola Virus SO PLOS ONE LA English DT Article ID GLOBAL ERADICATION; SMALLPOX; PREGNANCY; HISTOLOGY; MOUSEPOX AB Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections - an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions. C1 [Wahl-Jensen, Victoria; Cann, Jennifer A.; Johnson, Anthony J.; de Kok-Mercado, Fabian; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21701 USA. [Rubins, Kathleen H.] MIT, Whitehead Inst Biomed Res, Cambridge, MA USA. [Huggins, John W.; Fisher, Robert W.; Larsen, Thomas; Raymond, Jo Lynne; Hensley, Lisa E.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Wahl-Jensen, V (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21701 USA. EM jahrlingp@niaid.nih.gov FU U.S. Department of Homeland Security for the management for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC) [HSHQDC-07-C-00020]; National Institute of Allergy and Infectious Diseases [HHSN27220020000161] FX This study was funded in part under agreement no. HSHQDC-07-C-00020 awarded by the U.S. Department of Homeland Security for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The principal authors (WWJ and JAC) are employees of Battelle Memorial Institute under its prime contract with National Institute of Allergy and Infectious Diseases # HHSN27220020000161. NR 28 TC 11 Z9 13 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2011 VL 6 IS 10 AR e24832 DI 10.1371/journal.pone.0024832 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NO UT WOS:000295968700005 PM 21998632 ER PT J AU Rao, NH Babu, PB Rajendra, L Sriraman, R Pang, YYS Schiller, JT Srinivasan, VA AF Rao, N. Hanumantha Babu, P. Baji Rajendra, L. Sriraman, R. Pang, Yuk-Ying S. Schiller, John T. Srinivasan, V. A. TI Expression of codon optimized major capsid protein (L1) of human papillomavirus type 16 and 18 in Pichia pastoris; purification and characterization of the virus-like particles SO VACCINE LA English DT Article DE Cervical cancer; Prophylactic vaccine; Virus like particles; Yeast; Pseudovirus neutralization assay ID VIRION-LIKE PARTICLES; CERVICAL-CANCER; HPV VACCINATION; VACCINES; DISEASES; ANTIBODIES; PROMISE; TRIAL; INDIA AB The major capsid protein (L1) of human papillomaviruses (HPV) expressed in heterologous systems assembles into virus-like particles (VLPs). We report cloning and expression of codon optimized HPV L1 genes of the two high-risk HPV types 16 and 18 in methylotropic yeast. Pichia pastoris. The VLPs produced in P. pastoris were subjected to three step purification method involving density gradient centrifugations and size exclusion chromatography. The enriched VLPs were characterized using conformation-specific monoclonal antibodies in ELISA and by transmission electron microscopy. Mice immunized with a bivalent HPV16 and HPV18 VLPs developed high serum antibody titers to both HPV types that persisted for 190 days post vaccination. Serum of mice immunized with the HPV-VLP preparations could neutralize homologous pseudoviruses in an in vitro assays. Our results demonstrate that the L1 proteins expressed in P. pastoris fold properly as evidenced by assembly into VLPs and induction of type-specific neutralizing antibody response in mice. This work constitutes a step towards developing an alternate production platform for generating an affordable HPV vaccine to meet the needs of developing countries. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Rao, N. Hanumantha; Babu, P. Baji; Rajendra, L.; Sriraman, R.; Srinivasan, V. A.] Indian Immunol Ltd, Ctr Res & Dev, Hyderabad 500032, Andhra Pradesh, India. [Pang, Yuk-Ying S.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Srinivasan, VA (reprint author), Indian Immunol Ltd, Ctr Res & Dev, Hyderabad 500032, Andhra Pradesh, India. EM srini@indimmune.com NR 37 TC 9 Z9 9 U1 2 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 6 PY 2011 VL 29 IS 43 BP 7326 EP 7334 DI 10.1016/j.vaccine.2011.07.071 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 838SC UT WOS:000296311500006 ER PT J AU Bernstein, DI El Sahly, HM Keitel, WA Wolff, M Simone, G Segawa, C Wong, S Shelly, D Young, NS Dempsey, W AF Bernstein, David I. El Sahly, Hana M. Keitel, Wendy A. Wolff, Mark Simone, Gina Segawa, Claire Wong, Susan Shelly, Daniel Young, Neal S. Dempsey, Walla TI Safety and immunogenicity of a candidate parvovirus B19 vaccine SO VACCINE LA English DT Article DE Parvovirus; B19; Vaccine; VLP; MF59 ID PHOSPHOLIPASE A(2); SEVERE ANEMIA; INFECTION; DISEASE; CHILDREN; VENOM AB Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 mu g dose of parvovirus B19 recombinant capsid; 2.5 and 25 mu g doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bernstein, David I.] Univ Cincinnati, Cincinnati Chidrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [El Sahly, Hana M.; Keitel, Wendy A.] Baylor Coll Med, Houston, TX 77030 USA. [Wolff, Mark; Simone, Gina; Segawa, Claire] EMMES Corp, Rockville, MD USA. [Wong, Susan; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Shelly, Daniel] Meridian Biosci Inc, Cincinnati, OH USA. [Dempsey, Walla] NIAID, NIH, Bethesda, MD 20892 USA. RP Bernstein, DI (reprint author), Univ Cincinnati, Cincinnati Chidrens Hosp Med Ctr, 3333 Burnet Ave,ML 6014, Cincinnati, OH 45229 USA. EM David.Bernstein@cchmc.org FU National Institute of Health [AI 45248, AI 25465] FX This work was supported by the National Institute of Health Contracts; No.: AI 45248 to Cincinnati Children's Hospital Medical Center and AI 25465 to Baylor College of Medicine, Houston, TX, United States. NR 19 TC 23 Z9 26 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 6 PY 2011 VL 29 IS 43 BP 7357 EP 7363 DI 10.1016/j.vaccine.2011.07.080 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 838SC UT WOS:000296311500010 PM 21807052 ER PT J AU Abbas, MA Spackman, E Fouchier, R Smith, D Ahmed, Z Siddique, N Sarmento, L Naeem, K McKinley, ET Hameed, A Rehmani, S Swayne, DE AF Abbas, Muhammad Athar Spackman, Erica Fouchier, Ron Smith, Derek Ahmed, Zaheer Siddique, Naila Sarmento, Luciana Naeem, Khalid McKinley, Enid T. Hameed, Abdul Rehmani, Shafqat Swayne, David E. TI H7 avian influenza virus vaccines protect chickens against challenge with antigenically diverse isolates SO VACCINE LA English DT Article DE Antigenic cartography; Avian influenza virus; H7; Poultry; Vaccination ID PAKISTAN; POULTRY; HEMAGGLUTININ; PCR AB \ Vaccination has been a critical tool in the control of some avian influenza viruses (AIV) and has been used routinely in Pakistan to help control sporadic outbreaks of highly pathogenic (HP) H7 AIV since 1995. During that time, several AIV isolates were utilized as inactivated vaccines with varying degrees of success. In order to evaluate which H7 AIV strains may serve as optimal vaccines for diverse H7 AIVs from Pakistan we conducted vaccination-challenge studies with five H7 vaccines against challenge with two HPAIVs: A/chicken/Murree/NARC-1/1995 H7N3 and A/chicken/Karachi/SPVC-4/2004 H7N3. To further characterize the isolates antigenic cartography was used to visually demonstrate the antigenic relationships among the isolates. All vaccines provided similar protection against mortality, morbidity and shedding of challenge virus from the respiratory tract. However, some minor (not statistically significant) differences were observed and correlated with antibody levels induced by the vaccine prior to challenge. Published by Elsevier Ltd. C1 [Spackman, Erica; Sarmento, Luciana; McKinley, Enid T.; Swayne, David E.] USDA ARS, SE Poultry Res Lab, Athens, GA 30605 USA. [Abbas, Muhammad Athar; Ahmed, Zaheer; Siddique, Naila; Naeem, Khalid] NARC, Natl Reference Lab Poultry Dis, Islamabad 45500, Pakistan. [Fouchier, Ron; Smith, Derek] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Abbas, Muhammad Athar; Hameed, Abdul] Quaid I Azam Univ, Dept Microbiol & Biotechnol, Islamabad 45320, Pakistan. [Smith, Derek] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Smith, Derek] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Rehmani, Shafqat] Sindh Poultry Vaccine Ctr, Karachi, Pakistan. [Rehmani, Shafqat] Univ Vet & Anim Sci Lahore, Lahore, Pakistan. RP Spackman, E (reprint author), USDA ARS, SE Poultry Res Lab, 934 Coll Stn Rd, Athens, GA 30605 USA. EM Erica.spackman@ars.usda.gov RI hameed, Abdul/F-5145-2015; Fouchier, Ron/A-1911-2014 OI Fouchier, Ron/0000-0001-8095-2869 FU FAO [OSRO/RAS/703]; NIH [DP1-0D000490-01]; NIAID/NIH [HHSN266200700010C]; European Union [223498 EMPERIE]; United States Department of State Biosecurity Engagement FX The authors gratefully acknowledge Joan Beck, Scott Lee, Kira Moresco and James Doster for technical assistance with this work. Funding was partly provided by the United States Department of State Biosecurity Engagement Program through a Memorandum of Agreement with the United States Department of Agriculture, Agricultural Research Service and by the FAO grant OSRO/RAS/703. DJS was supported by an NIH Director's Pioneer Award DP1-0D000490-01, RF by NIAID/NIH contract HHSN266200700010C and both DJS and RF by FP7 grant 223498 EMPERIE from the European Union. NR 17 TC 25 Z9 26 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 6 PY 2011 VL 29 IS 43 BP 7424 EP 7429 DI 10.1016/j.vaccine.2011.07.064 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 838SC UT WOS:000296311500018 PM 21803098 ER PT J AU Gowda, M Godder, K Kmieciak, M Worschech, A Ascierto, ML Wang, E Marincola, FM Manjili, MH AF Gowda, Madhu Godder, Kamar Kmieciak, Maciej Worschech, Andrea Ascierto, Maria-Libera Wang, Ena Marincola, Francesco M. Manjili, Masoud H. TI Distinct signatures of the immune responses in low risk versus high risk neuroblastoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Neuroblastoma; innate immunity; adaptive immunity; prognostic biomarkers ID NEURAL PRECURSOR CELLS; RETINOIC ACID; IFN-GAMMA; PROGENITOR CELLS; BREAST-CANCER; T-LYMPHOCYTES; IN-VIVO; DIFFERENTIATION; PATHWAY; ACTIVATION AB Background: Over 90% of low risk (LR) neuroblastoma patients survive whereas less than 30% of high risk (HR) patients are long term survivors. Age (children younger than 18 months old) is associated with LR disease. Considering that adaptive immune system is well developed in older children, and that T cells were shown to be involved in tumor escape and progression of cancers, we sought to determine whether HR patients may tend to show a signature of adaptive immune responses compared to LR patients who tend to have diminished T-cell responses but an intact innate immune response. Methods: We performed microarray analysis of RNA extracted from the tumor specimens of HR and LR patients. Flow cytometry was performed to determine the cellular constituents in the blood while multiplex cytokine array was used to detect the cytokine profile in patients' sera. A HR tumor cell line, SK-N-SH, was also used for detecting the response to IL-1 beta, a cytokines which is involved in the innate immune responses. Results: Distinct patterns of gene expression were detected in HR and LR patients indicating an active T-cell response and a diminished adaptive immune response, respectively. A diminished adaptive immune response in LR patients was evident by higher levels of IL-10 in the sera. In addition, HR patients had lower levels of circulating myeloid derived suppressor cells (MDSC) compared with a control LR patient. LR patients showed slightly higher levels of cytokines of the innate immune responses. Treatment of the HR tumor line with IL-1b induced expression of cytokines of the innate immune responses. Conclusions: This data suggests that adaptive immune responses may play an important role in the progression of HR disease whereas innate immune responses may be active in LR patients. C1 [Gowda, Madhu; Godder, Kamar] Childrens Hosp Richmond, Dept Pediat, Richmond, VA USA. [Kmieciak, Maciej; Manjili, Masoud H.] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Microbiol & Immunol, Richmond, VA USA. [Worschech, Andrea; Ascierto, Maria-Libera; Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. [Worschech, Andrea; Ascierto, Maria-Libera; Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Worschech, Andrea] Univ Wurzburg, Inst Biochem, D-97074 Wurzburg, Germany. RP Gowda, M (reprint author), Childrens Hosp Richmond, Dept Pediat, Richmond, VA USA. EM MSGowda@mcvh-vcu.edu; mmanjili@vcu.edu RI Ascierto, Maria Libera/A-9239-2012; Worschech, Andrea/I-3919-2012 OI Worschech, Andrea/0000-0002-4303-8653 FU Maynard Childhood Cancer Research Foundation; Massey/Pediatrics Cancer Research [50215]; NIH [R01 CA104757, P30CA16059]; Hyundai Hope on Wheals Childhood Cancer Research Fund; VCU Massey Cancer Center; Commonwealth Foundation for Cancer Research FX This work was supported by grants from the Maynard Childhood Cancer Research Foundation, Massey/Pediatrics Cancer Research (50215), NIH R01 CA104757 grant (MHM), Hyundai Hope on Wheals Childhood Cancer Research Fund (MG) and flow cytometry shared resources facility supported in part by the NIH grant P30CA16059. We thank Children's Oncology Group, Children's Hospital of Philadelphia. We gratefully acknowledge the support of VCU Massey Cancer Center and the Commonwealth Foundation for Cancer Research. NR 33 TC 18 Z9 18 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 6 PY 2011 VL 9 AR 170 DI 10.1186/1479-5876-9-170 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 834DN UT WOS:000295939700001 PM 21978632 ER PT J AU Jain, A Kovacs, JA Nelson, DL Migueles, SA Pittaluga, S Fanslow, W Fan, XY Wong, DW Massey, J Hornung, R Brown, MR Spinner, JJ Liu, SY Davey, V Hill, HA Ochs, H Fleisher, TA AF Jain, Ashish Kovacs, Joseph A. Nelson, David L. Migueles, Stephen A. Pittaluga, Stefania Fanslow, William Fan, Xiying Wong, Duane W. Massey, Justin Hornung, Ronald Brown, Margaret R. Spinner, Jacob J. Liu, Shuying Davey, Victoria Hill, Harry A. Ochs, Hans Fleisher, Thomas A. TI Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand SO BLOOD LA English DT Article ID DENDRITIC CELLS; HYPERSENSITIVITY REACTIONS; IMMUNOLOGICAL FEATURES; DEFICIENCY; ACTIVATION; IMMUNODEFICIENCY; MICE; AGAMMAGLOBULINEMIA; TRANSPLANTATION; MUTATIONS AB X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40 ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell-dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. With rCD40L treatment, patient T cells developed a new capacity to respond to T-cell mitogens with synthesis of IFN-gamma and TNF-alpha. Intracellular cytokine staining studies showed that both CD4(+) and CD8(+) T cells participated in this response. Finally, CD40L therapy was associated with changes in lymph node size and architecture based on comparison of biopsies taken before and after therapy. This clinical study showed that rCD40L is capable of improving T cell-immune function in patients with XHM. (Blood. 2011; 118(14):3811-3817) C1 [Jain, Ashish; Fan, Xiying; Massey, Justin; Spinner, Jacob J.; Liu, Shuying] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Nelson, David L.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Migueles, Stephen A.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Fanslow, William] Amgen Inc, Seattle, WA USA. [Wong, Duane W.] Arizona Allergy Associates, Phoenix, AZ USA. [Hornung, Ronald] NCI Frederick, Clin Serv Program, SAIC Frederick Inc, NIH, Bethesda, MD USA. [Brown, Margaret R.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Davey, Victoria] NIAID, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hill, Harry A.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Ochs, Hans] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Jain, A (reprint author), NIAID, Host Def Lab, NIH, 10 Ctr Dr,Rm 5W 3950, Bethesda, MD 20892 USA. EM ajain@nih.gov OI Fan, Xiying/0000-0003-3090-381X 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 45 TC 18 Z9 19 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 6 PY 2011 VL 118 IS 14 BP 3811 EP 3817 DI 10.1182/blood-2011-04-351254 PG 7 WC Hematology SC Hematology GA 832LY UT WOS:000295807700012 PM 21841160 ER PT J AU Elliott, NE Cleveland, SM Grann, V Janik, J Waldmann, TA Dave, UP AF Elliott, Natalina E. Cleveland, Susan M. Grann, Victor Janik, John Waldmann, Thomas A. Dave, Utpal P. TI FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma SO BLOOD LA English DT Article ID LEUKEMIA-VIRUS TYPE-1; HTLV-I; CONSTITUTIVE ACTIVATION; GENE-EXPRESSION; DOWN-REGULATION; JANUS KINASES; GAMMA-CHAIN; TAX PROTEIN; PROLIFERATION; TRANSPLANTATION AB Adult T-cell leukemia/lymphoma (ATLL) is an incurable disease where most patients succumb within the first year of diagnosis. Both standard chemotherapy regimens and mAbs directed against ATLL tumor markers do not alter this aggressive clinical course. Therapeutic development would be facilitated by the discovery of genes and pathways that drive or initiate ATLL, but so far amenable drug targets have not been forthcoming. Because the IL-2 signaling pathway plays a prominent role in ATLL pathogenesis, mutational analysis of pathway components should yield interesting results. In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from the IL-2R, where activating mutations have been found in diverse neoplasms. We screened 36 ATLL patients and 24 ethnically matched controls and found 4 patients with mutations in JAK3. These somatic, missense mutations occurred in the N-terminal FERM (founding members: band 4.1, ezrin, radixin, and moesin) domain and induced gain of function in JAK3. Importantly, we show that these mutant JAK3s are inhibited with a specific kinase inhibitor already in human clinical testing. Our findings underscore the importance of this pathway in ATLL development and offer a therapeutic handle for this incurable cancer. (Blood. 2011;118(14):3911-3921) C1 [Dave, Utpal P.] Vanderbilt Univ, Div Hematol Oncol, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Elliott, Natalina E.; Cleveland, Susan M.; Dave, Utpal P.] Vanderbilt Univ, Dept Canc Biol, Med Ctr, Nashville, TN 37232 USA. [Grann, Victor] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Janik, John] Bristol Myers Squibb Co, Discovery Med & Clin Pharmacol, Lawrenceville, NJ USA. [Waldmann, Thomas A.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Dave, UP (reprint author), Vanderbilt Univ, Div Hematol Oncol, Med Ctr, Dept Med, 777 Preston Res Bldg, Nashville, TN 37232 USA. EM utpal.dave@vanderbilt.edu FU Vanderbilt Ingram Cancer Center [P30 CA68485]; Vanderbilt Digestive Disease Research Center [DK058404]; National Heart, Lung, and Blood Institute [K08HL089403]; Doris Duke Charitable Foundation; Leukemia & Lymphoma Society; Monforton family grant; T. J. Martell Foundation; National Institutes of Health [U54 CA101598, U54 CA101388]; NIH [P30CA0113696] FX The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). This work was supported by award K08HL089403 from the National Heart, Lung, and Blood Institute. This work was also supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award (U. P. D.); the Leukemia & Lymphoma Society; the Vanderbilt Ingram Cancer Center (P30 CA68485); a Monforton family grant; the T. J. Martell Foundation (U. P. D.); and U54 National Institutes of Health grants CA101598, CA101388, and NIH P30CA0113696 (V.G.). NR 55 TC 37 Z9 39 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 6 PY 2011 VL 118 IS 14 BP 3911 EP 3921 DI 10.1182/blood-2010-12-319467 PG 11 WC Hematology SC Hematology GA 832LY UT WOS:000295807700023 PM 21821710 ER PT J AU Ehret, GB Munroe, PB Rice, KM Bochud, M Johnson, AD Chasman, DI Smith, AV Tobin, MD Verwoert, GC Hwang, SJ Pihur, V Vollenweider, P O'Reilly, PF Amin, N Bragg-Gresham, JL Teumer, A Glazer, NL Launer, L Zhao, JH Aulchenko, Y Heath, S Sober, S Parsa, A Luan, JA Arora, P Dehghan, A Zhang, F Lucas, G Hicks, AA Jackson, AU Peden, JF Tanaka, T Wild, SH Rudan, I Igl, W Milaneschi, Y Parker, AN Fava, C Chambers, JC Fox, ER Kumari, M Go, MJ van der Harst, P Kao, WHL Sjogren, M Vinay, DG Alexander, M Tabara, Y Shaw-Hawkins, S Whincup, PH Liu, YM Shi, G Kuusisto, J Tayo, B Seielstad, M Sim, X Nguyen, KDH Lehtimaki, T Matullo, G Wu, Y Gaunt, TR Onland-Moret, NC Cooper, MN Platou, CGP Org, E Hardy, R Dahgam, S Palmen, J Vitart, V Braund, PS Kuznetsova, T Uiterwaal, CSPM Adeyemo, A Palmas, W Campbell, H Ludwig, B Tomaszewski, M Tzoulaki, I Palmer, ND Aspelund, T Garcia, M Chang, YPC O'Connell, JR Steinle, NI Grobbee, DE Arking, DE Kardia, SL Morrison, AC Hernandez, D Najjar, S McArdle, WL Hadley, D Brown, MJ Connell, JM Hingorani, AD Day, INM Lawlor, DA Beilby, JP Lawrence, RW Clarke, R Hopewell, JC Ongen, H Dreisbach, AW Li, YL Young, JH Bis, JC Kahonen, M Viikari, J Adair, LS Lee, NR Chen, MH Olden, M Pattaro, C Bolton, JAH Kottgen, A Bergmann, S Mooser, V Chaturvedi, N Frayling, TM Islam, M Jafar, TH Erdmann, J Kulkarni, SR Bornstein, SR Grassler, J Groop, L Voight, BF Kettunen, J Howard, P Taylor, A Guarrera, S Ricceri, F Emilsson, V Plump, A Barroso, IS Khaw, KT Weder, AB Hunt, SC Sun, YV Bergman, RN Collins, FS Bonnycastle, LL Scott, LJ Stringham, HM Peltonen, L Perola, M Vartiainen, E Brand, SM Staessen, JA Wang, TJ Burton, PR Artigas, MS Dong, YB Snieder, H Wang, XL Zhu, HD Lohman, KK Rudock, ME Heckbert, SR Smith, NL Wiggins, KL Doumatey, A Shriner, D Veldre, G Viigimaa, M Kinra, S Prabhakaran, D Tripathy, V Langefeld, CD Rosengren, A Thelle, DS Corsi, AM Singleton, A Forrester, T Hilton, G McKenzie, CA Salako, T Iwai, N Kita, Y Ogihara, T Ohkubo, T Okamura, T Ueshima, H Umemura, S Eyheramendy, S Meitinger, T Wichmann, HE Cho, YS Kim, HL Lee, JY Scott, J Sehmi, JS Zhang, WH Hedblad, B Nilsson, P Smith, GD Wong, A Narisu, N Stancakova, A Raffel, LJ Yao, J Kathiresan, S O'Donnell, CJ Schwartz, SM Ikram, MA Longstreth, WT Mosley, TH Seshadri, S Shrine, NRG Wain, LV Morken, MA Swift, AJ Laitinen, J Prokopenko, I Zitting, P Cooper, JA Humphries, SE Danesh, J Rasheed, A Goel, A Hamsten, A Watkins, H Bakker, SJL van Gilst, WH Janipalli, CS Mani, KR Yajnik, CS Hofman, A Mattace-Raso, FUS Oostra, BA Demirkan, A Isaacs, A Rivadeneira, F Lakatta, EG Orru, M Scuteri, A Ala-Korpela, M Kangas, AJ Lyytikainen, LP Soininen, P Tukiainen, T Wurtz, P Ong, RTH Dorr, M Kroemer, HK Volker, U Volzke, H Galan, P Hercberg, S Lathrop, M Zelenika, D Deloukas, P Mangino, M Spector, TD Zhai, GJ Meschia, JF Nalls, MA Sharma, P Terzic, J Kumar, MVK Denniff, M Zukowska-Szczechowska, E Wagenknecht, LE Fowkes, FGR Charchar, FJ Schwarz, PEH Hayward, C Guo, XQ Rotimi, C Bots, ML Brand, E Samani, NJ Polasek, O Talmud, PJ Nyberg, F Kuh, D Laan, M Hveem, K Palmer, LJ van der Schouw, YT Casas, JP Mohlke, KL Vineis, P Raitakari, O Ganesh, SK Wong, TY Tai, ES Cooper, RS Laakso, M Rao, DC Harris, TB Morris, RW Dominiczak, AF Kivimaki, M Marmot, MG Miki, T Saleheen, D Chandak, GR Coresh, J Navis, G Salomaa, V Han, BG Zhu, XF Kooner, JS Melander, O Ridker, PM Bandinelli, S Gyllensten, UB Wright, AF Wilson, JF Ferrucci, L Farrall, M Tuomilehto, J Pramstaller, PP Elosua, R Soranzo, N Sijbrands, EJG Altshuler, D Loos, RJF Shuldiner, AR Gieger, C Meneton, P Uitterlinden, AG Wareham, NJ Gudnason, V Rotter, JI Rettig, R Uda, M Strachan, DP Witteman, JCM Hartikainen, AL Beckmann, JS Boerwinkle, E Vasan, RS Boehnke, M Larson, MG Jarvelin, MR Psaty, BM Abecasis, GR Chakravarti, A Elliott, P van Duijn, CM Newton-Cheh, C Levy, D Caulfield, MJ Johnson, T AF Ehret, Georg B. Munroe, Patricia B. Rice, Kenneth M. Bochud, Murielle Johnson, Andrew D. Chasman, Daniel I. Smith, Albert V. Tobin, Martin D. Verwoert, Germaine C. Hwang, Shih-Jen Pihur, Vasyl Vollenweider, Peter O'Reilly, Paul F. Amin, Najaf Bragg-Gresham, Jennifer L. Teumer, Alexander Glazer, Nicole L. Launer, Lenore Zhao, Jing Hua Aulchenko, Yurii Heath, Simon Sober, Siim Parsa, Afshin Luan, Jian'an Arora, Pankaj Dehghan, Abbas Zhang, Feng Lucas, Gavin Hicks, Andrew A. Jackson, Anne U. Peden, John F. Tanaka, Toshiko Wild, Sarah H. Rudan, Igor Igl, Wilmar Milaneschi, Yuri Parker, Alex N. Fava, Cristiano Chambers, John C. Fox, Ervin R. Kumari, Meena Go, Min Jin van der Harst, Pim Kao, Wen Hong Linda Sjogren, Marketa Vinay, D. G. Alexander, Myriam Tabara, Yasuharu Shaw-Hawkins, Sue Whincup, Peter H. Liu, Yongmei Shi, Gang Kuusisto, Johanna Tayo, Bamidele Seielstad, Mark Sim, Xueling Khanh-Dung Hoang Nguyen Lehtimaki, Terho Matullo, Giuseppe Wu, Ying Gaunt, Tom R. Onland-Moret, N. Charlotte Cooper, Matthew N. Platou, Carl G. P. Org, Elin Hardy, Rebecca Dahgam, Santosh Palmen, Jutta Vitart, Veronique Braund, Peter S. Kuznetsova, Tatiana Uiterwaal, Cuno S. P. M. Adeyemo, Adebowale Palmas, Walter Campbell, Harry Ludwig, Barbara Tomaszewski, Maciej Tzoulaki, Ioanna Palmer, Nicholette D. Aspelund, Thor Garcia, Melissa Chang, Yen-Pei C. O'Connell, Jeffrey R. Steinle, Nanette I. Grobbee, Diederick E. Arking, Dan E. Kardia, Sharon L. Morrison, Alanna C. Hernandez, Dena Najjar, Samer McArdle, Wendy L. Hadley, David Brown, Morris J. Connell, John M. Hingorani, Aroon D. Day, Ian N. M. Lawlor, Debbie A. Beilby, John P. Lawrence, Robert W. Clarke, Robert Hopewell, Jemma C. Ongen, Halit Dreisbach, Albert W. Li, Yali Young, J. Hunter Bis, Joshua C. Kahonen, Mika Viikari, Jorma Adair, Linda S. Lee, Nanette R. Chen, Ming-Huei Olden, Matthias Pattaro, Cristian Bolton, Judith A. Hoffman Koettgen, Anna Bergmann, Sven Mooser, Vincent Chaturvedi, Nish Frayling, Timothy M. Islam, Muhammad Jafar, Tazeen H. Erdmann, Jeanette Kulkarni, Smita R. Bornstein, Stefan R. Graessler, Juergen Groop, Leif Voight, Benjamin F. Kettunen, Johannes Howard, Philip Taylor, Andrew Guarrera, Simonetta Ricceri, Fulvio Emilsson, Valur Plump, Andrew Barroso, Ine S. Khaw, Kay-Tee Weder, Alan B. Hunt, Steven C. Sun, Yan V. Bergman, Richard N. Collins, Francis S. Bonnycastle, Lori L. Scott, Laura J. Stringham, Heather M. Peltonen, Leena Perola, Markus Vartiainen, Erkki Brand, Stefan-Martin Staessen, Jan A. Wang, Thomas J. Burton, Paul R. Artigas, Maria Soler Dong, Yanbin Snieder, Harold Wang, Xiaoling Zhu, Haidong Lohman, Kurt K. Rudock, Megan E. Heckbert, Susan R. Smith, Nicholas L. Wiggins, Kerri L. Doumatey, Ayo Shriner, Daniel Veldre, Gudrun Viigimaa, Margus Kinra, Sanjay Prabhakaran, Dorairaj Tripathy, Vikal Langefeld, Carl D. Rosengren, Annika Thelle, Dag S. Corsi, Anna Maria Singleton, Andrew Forrester, Terrence Hilton, Gina McKenzie, Colin A. Salako, Tunde Iwai, Naoharu Kita, Yoshikuni Ogihara, Toshio Ohkubo, Takayoshi Okamura, Tomonori Ueshima, Hirotsugu Umemura, Satoshi Eyheramendy, Susana Meitinger, Thomas Wichmann, H. -Erich Cho, Yoon Shin Kim, Hyung-Lae Lee, Jong-Young Scott, James Sehmi, Joban S. Zhang, Weihua Hedblad, Bo Nilsson, Peter Smith, George Davey Wong, Andrew Narisu, Narisu Stancakova, Alena Raffel, Leslie J. Yao, Jie Kathiresan, Sekar O'Donnell, Christopher J. Schwartz, Stephen M. Ikram, M. Arfan Longstreth, W. T., Jr. Mosley, Thomas H. Seshadri, Sudha Shrine, Nick R. G. Wain, Louise V. Morken, Mario A. Swift, Amy J. Laitinen, Jaana Prokopenko, Inga Zitting, Paavo Cooper, Jackie A. Humphries, Steve E. Danesh, John Rasheed, Asif Goel, Anuj Hamsten, Anders Watkins, Hugh Bakker, Stephan J. L. van Gilst, Wiek H. Janipalli, Charles S. Mani, K. Radha Yajnik, Chittaranjan S. Hofman, Albert Mattace-Raso, Francesco U. S. Oostra, Ben A. Demirkan, Ayse Isaacs, Aaron Rivadeneira, Fernando Lakatta, Edward G. Orru, Marco Scuteri, Angelo Ala-Korpela, Mika Kangas, Antti J. Lyytikainen, Leo-Pekka Soininen, Pasi Tukiainen, Taru Wurtz, Peter Ong, Rick Twee-Hee Doerr, Marcus Kroemer, Heyo K. Voelker, Uwe Voelzke, Henry Galan, Pilar Hercberg, Serge Lathrop, Mark Zelenika, Diana Deloukas, Panos Mangino, Massimo Spector, Tim D. Zhai, Guangju Meschia, James F. Nalls, Michael A. Sharma, Pankaj Terzic, Janos Kumar, M. V. Kranthi Denniff, Matthew Zukowska-Szczechowska, Ewa Wagenknecht, Lynne E. Fowkes, F. Gerald R. Charchar, Fadi J. Schwarz, Peter E. H. Hayward, Caroline Guo, Xiuqing Rotimi, Charles Bots, Michiel L. Brand, Eva Samani, Nilesh J. Polasek, Ozren Talmud, Philippa J. Nyberg, Fredrik Kuh, Diana Laan, Maris Hveem, Kristian Palmer, Lyle J. van der Schouw, Yvonne T. Casas, Juan P. Mohlke, Karen L. Vineis, Paolo Raitakari, Olli Ganesh, Santhi K. Wong, Tien Y. Tai, E. Shyong Cooper, Richard S. Laakso, Markku Rao, Dabeeru C. Harris, Tamara B. Morris, Richard W. Dominiczak, Anna F. Kivimaki, Mika Marmot, Michael G. Miki, Tetsuro Saleheen, Danish Chandak, Giriraj R. Coresh, Josef Navis, Gerjan Salomaa, Veikko Han, Bok-Ghee Zhu, Xiaofeng Kooner, Jaspal S. Melander, Olle Ridker, Paul M. Bandinelli, Stefania Gyllensten, Ulf B. Wright, Alan F. Wilson, James F. Ferrucci, Luigi Farrall, Martin Tuomilehto, Jaakko Pramstaller, Peter P. Elosua, Roberto Soranzo, Nicole Sijbrands, Eric J. G. Altshuler, David Loos, Ruth J. F. Shuldiner, Alan R. Gieger, Christian Meneton, Pierre Uitterlinden, Andre G. Wareham, Nicholas J. Gudnason, Vilmundur Rotter, Jerome I. Rettig, Rainer Uda, Manuela Strachan, David P. Witteman, Jacqueline C. M. Hartikainen, Anna-Liisa Beckmann, Jacques S. Boerwinkle, Eric Vasan, Ramachandran S. Boehnke, Michael Larson, Martin G. Jarvelin, Marjo-Riitta Psaty, Bruce M. Abecasis, Goncalo R. Chakravarti, Aravinda Elliott, Paul van Duijn, Cornelia M. Newton-Cheh, Christopher Levy, Daniel Caulfield, Mark J. Johnson, Toby CA Int Consortium Blood Pressure Geno CARDIoGRAM Consortium CKDGen Consortium KidneyGen Consortium EchoGen Consortium CHARGE-HF Consortium TI Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; HYPERTENSION; METAANALYSIS; LOCI; POPULATION; RELEVANCE; RECEPTOR; CLONING; HEALTH AB Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. 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[Peden, John F.; Ongen, Halit; Goel, Anuj; Watkins, Hugh; Farrall, Martin] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX3 7BN, England. [Tanaka, Toshiko; Milaneschi, Yuri; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21250 USA. [Wild, Sarah H.; Rudan, Igor; Campbell, Harry; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor; Campbell, Harry] Univ Edinburgh, Coll Med & Vet Med, Inst Genet & Mol Med, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Split 21000, Croatia. [Igl, Wilmar; Gyllensten, Ulf B.] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden. [Parker, Alex N.] Amgen Inc, Cambridge, MA 02139 USA. [Fava, Cristiano; Sjogren, Marketa; Hedblad, Bo; Nilsson, Peter; Melander, Olle] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Fava, Cristiano] Univ Verona, Dept Med, I-37134 Verona, Italy. [Chambers, John C.; Sehmi, Joban S.; Kooner, Jaspal S.] Ealing Gen Hosp, London UB1 3HJ, England. [Fox, Ervin R.; Dreisbach, Albert W.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Kumari, Meena; Taylor, Andrew] UCL, Genet Epidemiol Grp, London WC1E 6BT, England. [Go, Min Jin; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Han, Bok-Ghee] Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea. [van der Harst, Pim; van Gilst, Wiek H.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands. [Kao, Wen Hong Linda; Bolton, Judith A. Hoffman; Koettgen, Anna; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Kao, Wen Hong Linda; Young, J. Hunter; Coresh, Josef] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Vinay, D. G.; Janipalli, Charles S.; Mani, K. Radha; Kumar, M. V. Kranthi; Chandak, Giriraj R.] CSIR, CCMB, Hyderabad 500007, Andhra Pradesh, India. 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[Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu 90014, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Oulu 90101, Finland. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [van Duijn, Cornelia M.] NGI Erasmus Med Ctr, Ctr Med Syst Biol CMSB 1 2, Rotterdam, Netherlands. RP Chakravarti, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. EM p.b.munroe@qmul.ac.uk; aravinda@jhmi.edu; cnewtoncheh@chgr.mgh.harvard.edu; levyd@nhlbi.nih.gov; m.j.caulfield@qmul.ac.uk RI Erdmann, Jeanette/P-7513-2014; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Franke, Andre/B-2151-2010; Davey Smith, George/A-7407-2013; Boban, Mladen/E-2777-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Hernandez-Fuentes, Maria/B-5011-2010; Maxwell, Patrick/C-5557-2008; Lyytikainen, Leo-Pekka/C-8544-2016; Shi, Gang/D-3301-2016; Soler Artigas, Maria/L-6529-2013; Burton, Paul/H-7527-2016; Smith, Albert/K-5150-2015; Matullo, Giuseppe/K-6383-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Eggermann, Thomas/F-3807-2014; Boehm, Bernhard/F-8750-2015; Bakker, Stephan/J-4023-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Staessen, Jan/A-1065-2011; Mattace- Raso, Francesco/L-2541-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Colaus, PsyColaus/K-6607-2013; Okamura, Tomonori/L-1693-2013; Aulchenko, Yurii/M-8270-2013; Altshuler, David/A-4476-2009; Grobbee, Diederick/C-7651-2014; Schnabel, Renate/F-6527-2014; Pramstaller, Peter/C-2357-2008; Cooper, Matthew/J-4420-2014; Willenborg, Christina/D-2668-2012; Palmer, Lyle/K-3196-2014; Gaunt, Tom/O-3918-2014; Kronenberg, Florian/B-1736-2008; Kottgen, Anna/D-2920-2012; Lucas, Gavin/D-4346-2012; Spector, Tim/F-6533-2012; Abecasis, Goncalo/B-7840-2010; Singleton, Andrew/C-3010-2009; Arora, Pankaj/F-3437-2011; Laan, Maris/A-4100-2011; Stark, Klaus/D-3813-2009; Soininen, Pasi/B-9716-2008; Aspelund, Thor/C-5983-2008; EHRET, Georg/A-9532-2009; Kivimaki, Mika/B-3607-2012; Beckmann, Jacques S /A-9772-2008; Rudan, Igor/I-1467-2012; Hadley, David/I-6902-2012; Heath, Simon/J-4138-2012; Rice, Kenneth/A-4150-2013; Deloukas, Panos/B-2922-2013; gurrapu, gopi/A-9801-2011; Fuchsberger, Christian/C-9646-2010; Giallauria, Francesco/B-5681-2013; Cavalieri, Margherita/G-8053-2012; Johnson, Andrew/G-6520-2013; Kuznetsova, Tatiana/I-6882-2013; Gale, Daniel/D-5594-2013; OI Kumari, Meena/0000-0001-9716-1035; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Watkins, Hugh/0000-0002-5287-9016; Marmot, Michael/0000-0002-2431-6419; Shrine, Nick/0000-0003-3641-4371; Zgaga, Lina/0000-0003-4089-9703; Ramachandran, Vasan/0000-0001-7357-5970; Erdmann, Jeanette/0000-0002-4486-6231; Humphries, Stephen E/0000-0002-8221-6547; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Adeyemo, Adebowale/0000-0002-3105-3231; Fuchsberger, Christian/0000-0002-5918-8947; Monsalve, Beatriz Elena/0000-0002-5994-866X; Johnson, Toby/0000-0002-5998-3270; Ikram, Mohammad Arfan/0000-0003-0372-8585; MATULLO, Giuseppe/0000-0003-0674-7757; Org, Elin/0000-0003-1451-9375; Larson, Martin/0000-0002-9631-1254; ELOSUA, ROBERTO/0000-0001-8235-0095; Sijbrands, Eric/0000-0001-8857-7389; Magi, Reedik/0000-0002-2964-6011; Kivimaki, Mika/0000-0002-4699-5627; Whincup, Peter/0000-0002-5589-4107; Talmud, Philippa/0000-0002-5560-1933; Franke, Andre/0000-0003-1530-5811; Davey Smith, George/0000-0002-1407-8314; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Alexander, Myriam/0000-0002-6848-9370; Abecasis, Goncalo/0000-0003-1509-1825; Seielstad, Mark/0000-0001-5783-1401; Seshadri, Sudha/0000-0001-6135-2622; Sternberg, Michael/0000-0002-1884-5445; Felix, Janine/0000-0002-9801-5774; Hernandez-Fuentes, Maria/0000-0002-7558-9441; Maxwell, Patrick/0000-0002-0338-2679; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Soler Artigas, Maria/0000-0002-3213-1107; Smith, Albert/0000-0003-1942-5845; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Bakker, Stephan/0000-0003-3356-6791; Gudnason, Vilmundur/0000-0001-5696-0084; Staessen, Jan/0000-0002-3026-1637; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Okamura, Tomonori/0000-0003-0488-0351; Aulchenko, Yurii/0000-0002-7899-1575; Altshuler, David/0000-0002-7250-4107; Grobbee, Diederick/0000-0003-4472-4468; Cooper, Matthew/0000-0003-1139-3682; Willenborg, Christina/0000-0001-5217-6882; Palmer, Lyle/0000-0002-1628-3055; Gaunt, Tom/0000-0003-0924-3247; Kronenberg, Florian/0000-0003-2229-1120; Arora, Pankaj/0000-0003-2420-3550; Laan, Maris/0000-0002-8519-243X; Stark, Klaus/0000-0002-7832-1942; Aspelund, Thor/0000-0002-7998-5433; EHRET, Georg/0000-0002-5730-0675; Beckmann, Jacques S /0000-0002-9741-1900; Rudan, Igor/0000-0001-6993-6884; Rice, Kenneth/0000-0001-5779-4495; Deloukas, Panos/0000-0001-9251-070X; Giallauria, Francesco/0000-0003-4119-9397; Kuznetsova, Tatiana/0000-0003-3564-7405; Gale, Daniel/0000-0002-9170-1579; Prabhakaran, Dorairaj/0000-0002-3172-834X; Lawlor, Debbie A/0000-0002-6793-2262; Tai, E Shyong/0000-0003-2929-8966; Johansson, Asa/0000-0002-2915-4498; Morris, Richard/0000-0001-7240-4563; Bergmann, Sven/0000-0002-6785-9034; Kleber, Marcus/0000-0003-0663-7275; Hypponen, Elina/0000-0003-3670-9399; Dehghan, Abbas/0000-0001-6403-016X; Wain, Louise/0000-0003-4951-1867; Wurtz, Peter/0000-0002-5832-0221 FU NIH/NHLBI FX A number of the participating studies and authors are members of the CHARGE and Global BPgen consortia. Many funding mechanisms by NIH/NHLBI, European and private funding agencies contributed to this work and a full list is provided in section 21 of the Supplementary Materials. NR 28 TC 759 Z9 777 U1 25 U2 201 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 6 PY 2011 VL 478 IS 7367 BP 103 EP 109 DI 10.1038/nature10405 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829JN UT WOS:000295575400043 PM 21909115 ER PT J AU Hoover, RN Hyer, M Pfeiffer, RM Adam, E Bond, B Cheville, AL Colton, T Hartge, P Hatch, EE Herbst, AL Karlan, BY Kaufman, R Noller, KL Palmer, JR Robboy, SJ Saal, RC Strohsnitter, W Titus-Ernstoff, L Troisi, R AF Hoover, Robert N. Hyer, Marianne Pfeiffer, Ruth M. Adam, Ervin Bond, Brian Cheville, Andrea L. Colton, Theodore Hartge, Patricia Hatch, Elizabeth E. Herbst, Arthur L. Karlan, Beth Y. Kaufman, Raymond Noller, Kenneth L. Palmer, Julie R. Robboy, Stanley J. Saal, Robert C. Strohsnitter, William Titus-Ernstoff, Linda Troisi, Rebecca TI Adverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID YOUNG-WOMEN; MEDICAL RECORDS; BREAST-CANCER; FOLLOW-UP; PREGNANCY; STILBESTROL; RISK; VAGINA; NATIONAL-COOPERATIVE-DIETHYLSTILBESTROL-ADENOSIS-(DESAD)-PROJECT; ADENOCARCINOMA AB BACKGROUND Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.) C1 [Hoover, Robert N.; Pfeiffer, Ruth M.; Hartge, Patricia; Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hyer, Marianne] Informat Management Serv Inc, Rockville, MD USA. [Saal, Robert C.] Westat Corp, Rockville, MD USA. [Adam, Ervin] Baylor Coll Med, Dept Virol & Epidemiol, Houston, TX 77030 USA. [Kaufman, Raymond] Methodist Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Bond, Brian; Strohsnitter, William] Boston Univ, Sch Publ Hlth, Dept Obstet & Gynecol, Tufts Med Ctr, Boston, MA USA. [Colton, Theodore; Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA USA. [Cheville, Andrea L.] Mayo Clin, Dept Phys Med & Rehabil, Rochester, MN USA. [Herbst, Arthur L.] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Div Gynecol Oncol, Los Angeles, CA 90048 USA. [Noller, Kenneth L.] Amer Board Obstet & Gynecol, Dallas, TX USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH USA. [Titus-Ernstoff, Linda] Norris Cotton Canc Ctr, Lebanon, NH USA. [Titus-Ernstoff, Linda] Hood Ctr Children & Families, Lebanon, NH USA. RP Hoover, RN (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hooverr@mail.nih.gov FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute; UCB, Belgium; IRIS International FX Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute.; Dr. Robboy reports receiving consulting fees from UCB, Belgium. Dr. Karlan reports holding stock in and receiving board membership fees from IRIS International. No other potential conflict of interest relevant to this article was reported. NR 41 TC 125 Z9 131 U1 2 U2 20 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 6 PY 2011 VL 365 IS 14 BP 1304 EP 1314 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 829KL UT WOS:000295578700008 PM 21991952 ER PT J AU Hart-Unger, S Korach, KS AF Hart-Unger, Sarah Korach, Kenneth S. TI Estrogens and Obesity: Is It All in Our Heads? SO CELL METABOLISM LA English DT Editorial Material ID RECEPTOR GENE; RESISTANCE AB Estrogens have preventative effects on weight gain and associated comorbidities, but the tissue-specific targets remain unknown. Here, Xu et al. (2011) demonstrate that ablation of estrogen signaling in two populations of hypothalamic neurons leads to weight gain and subsequent metabolic dysregulation and could be important target sites of estrogen actions. C1 [Hart-Unger, Sarah; Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Hart-Unger, Sarah] Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Korach, KS (reprint author), NIEHS, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [ZIA ES070065-37] NR 9 TC 7 Z9 8 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD OCT 5 PY 2011 VL 14 IS 4 BP 435 EP 436 DI 10.1016/j.cmet.2011.09.003 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 837SN UT WOS:000296223600001 PM 21982701 ER PT J AU Birkenfeld, AL Lee, HY Guebre-Egziabher, F Alves, TC Jurczak, MJ Jornayvaz, FR Zhang, DY Hsiao, JJ Martin-Montalvo, A Fischer-Rosinsky, A Spranger, J Pfeiffer, AF Jordan, J Fromm, MF Konig, J Lieske, S Carmean, CM Frederick, DW Weismann, D Knauf, F Irusta, PM De Cabo, R Helfand, SL Samuel, VT Shulman, GI AF Birkenfeld, Andreas L. Lee, Hui-Young Guebre-Egziabher, Fitsum Alves, Tiago C. Jurczak, Michael J. Jornayvaz, Francois R. Zhang, Dongyang Hsiao, Jennifer J. Martin-Montalvo, Alejandro Fischer-Rosinsky, Antje Spranger, Joachim Pfeiffer, Andreas F. Jordan, Jens Fromm, Martin F. Koenig, Joerg Lieske, Stefanie Carmean, Christopher M. Frederick, David W. Weismann, Dirk Knauf, Felix Irusta, Pablo M. De Cabo, Rafael Helfand, Stephen L. Samuel, Varman T. Shulman, Gerald I. TI Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice (vol 14, pg 184, 2011) SO CELL METABOLISM LA English DT Correction C1 [Birkenfeld, Andreas L.; Lee, Hui-Young; Guebre-Egziabher, Fitsum; Alves, Tiago C.; Jurczak, Michael J.; Jornayvaz, Francois R.; Zhang, Dongyang; Hsiao, Jennifer J.; Carmean, Christopher M.; Frederick, David W.; Weismann, Dirk; Knauf, Felix; Samuel, Varman T.; Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. [Birkenfeld, Andreas L.; Lee, Hui-Young; Guebre-Egziabher, Fitsum; Alves, Tiago C.; Jurczak, Michael J.; Jornayvaz, Francois R.; Zhang, Dongyang; Hsiao, Jennifer J.; Carmean, Christopher M.; Frederick, David W.; Weismann, Dirk; Knauf, Felix; Samuel, Varman T.; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Birkenfeld, Andreas L.; Lee, Hui-Young; Guebre-Egziabher, Fitsum; Alves, Tiago C.; Jurczak, Michael J.; Jornayvaz, Francois R.; Zhang, Dongyang; Hsiao, Jennifer J.; Carmean, Christopher M.; Frederick, David W.; Weismann, Dirk; Knauf, Felix; Helfand, Stephen L.; Samuel, Varman T.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Birkenfeld, Andreas L.; Fischer-Rosinsky, Antje; Spranger, Joachim; Pfeiffer, Andreas F.; Lieske, Stefanie] German Inst Human Nutr Potsdam Rehbrucke, D-14558 Nuthetal, Germany. [Birkenfeld, Andreas L.; Fischer-Rosinsky, Antje; Spranger, Joachim; Pfeiffer, Andreas F.; Lieske, Stefanie] Charite, Sch Med, D-10117 Berlin, Germany. [Martin-Montalvo, Alejandro; De Cabo, Rafael] Natl Inst Aging, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Jordan, Jens] Hannover Med Sch, Inst Clin Pharmacol, D-30625 Hannover, Germany. [Fromm, Martin F.; Koenig, Joerg] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, D-91023 Erlangen, Germany. [Irusta, Pablo M.] Georgetown Univ, Dept Human Sci, Washington, DC 20057 USA. [Helfand, Stephen L.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. RP Shulman, GI (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, 333 Cedar St, New Haven, CT 06520 USA. EM gerald.shulman@yale.edu RI Martin-Montalvo, Alejandro/C-2031-2017 OI Martin-Montalvo, Alejandro/0000-0002-3886-5355 NR 3 TC 1 Z9 1 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD OCT 5 PY 2011 VL 14 IS 4 BP 567 EP 567 DI 10.1016/j.cmet.2011.09.005 PG 1 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 837SN UT WOS:000296223600016 ER PT J AU Gril, B Palmieri, D Qian, Y Anwar, T Ileva, L Bernardo, M Choyke, P Liewehr, DJ Steinberg, SM Steeg, PS AF Gril, Brunilde Palmieri, Diane Qian, Yong Anwar, Talha Ileva, Lilia Bernardo, Marcelino Choyke, Peter Liewehr, David J. Steinberg, Seth M. Steeg, Patricia S. TI The B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER CELLS; P42/P44 MAP KINASE; PHASE-II; OVARIAN-CANCER; COMBINATION THERAPY; MUTATION ANALYSIS; LUNG-CANCER; OPEN-LABEL; HA-RAS AB Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis. C1 [Gril, Brunilde; Palmieri, Diane; Qian, Yong; Anwar, Talha; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ileva, Lilia; Bernardo, Marcelino] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Bernardo, Marcelino; Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, Frederick, MD 21701 USA. [Liewehr, David J.; Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gril, B (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM grilbrun@mail.nih.gov RI Palmieri, Diane/B-4258-2015 FU National Cancer Institute; Department of Defense [W81XWH-062-0033]; GlaxoSmithKline FX This work was supported by the intramural program of the National Cancer Institute, by grant W81XWH-062-0033 from the Department of Defense Breast Cancer Research Program, and by funding from GlaxoSmithKline. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 5 Z9 5 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2011 VL 6 IS 10 AR e25625 DI 10.1371/journal.pone.0025625 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NA UT WOS:000295966900037 PM 21998674 ER PT J AU Jia, ZW Wang, L Chen, RY Li, DM Wang, L Qin, QQ Ding, ZW Ding, GW Zang, CP Wang, N AF Jia, Zhongwei Wang, Lu Chen, Ray Y. Li, Dongmin Wang, Lan Qin, Qianqian Ding, Zhengwei Ding, Guowei Zang, Chunpeng Wang, Ning TI Tracking the Evolution of HIV/AIDS in China from 1989-2009 to Inform Future Prevention and Control Efforts SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; MIGRANT WORKERS; HIV; EPIDEMIOLOGY; SHANGHAI; PROGRAM AB Background: To determine policy implications, this analysis tracks the evolution of HIV/AIDS infection across China to understand current trends and potential risk factors. Methods and Principal Findings: A retrospective study with spatial analytical model and multilevel spatial models was conducted among 326,157 HIV/AIDS cases reported from 1989-2009. The results indicate that the distribution of HIV/AIDS was clustered at the county level with different directional distributions across China from 2003 to 2009. Compared to 2003, by 2009 there was a 122% increase in HIV cases among rural residents, 294% increase among urban residents, 211% increase among migrants, and 237% increase among permanent residents. The overall proportion of HIV by different routes of transmission showed dramatic changes with a 504% increase in sexual transmission of HIV, 90% decrease in blood/plasma transmission, and 35% decrease in injecting drug user transmission. Sexual transmission was the major transmission route among women (44%) and the elderly (59% in men, 44% in women) as well as among permanent (36%) and urban residents (33%). Among those < 65 years old, women increased more than men, but among those >= 65 years, men increased more than women. Migrants contributed to the variance of HIV infection between counties but not within counties. The length of highway and urbanization combined with illiteracy were risk factors for HIV/AIDS. Conclusions/Significance: Rates of HIV/AIDS among permanent urban residents, particularly women and elderly men, have increased significantly in recent years. To prevent HIV from spreading further among the general population, additional attention should be paid to these populations as well as to migrants. C1 [Jia, Zhongwei] Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. [Jia, Zhongwei; Wang, Lu; Li, Dongmin; Wang, Lan; Qin, Qianqian; Ding, Zhengwei; Ding, Guowei; Zang, Chunpeng; Wang, Ning] China CDC, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. [Chen, Ray Y.] US Embassy, NIAID, US Natl Inst Hlth, Beijing, Peoples R China. RP Jia, ZW (reprint author), Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. EM wangnbj@163.com OI Chen, Ray/0000-0001-6344-1442 FU Eleventh Five-year Plan [2008ZX100 (01-003), 03-008]; National Natural Science Foundation [30973981]; U.S. NIH Fogarty [R24 TW007988]; Beijing Municipal Commission of Education [KM201010025010] FX The Eleventh Five-year Plan (No. 2008ZX100 (01-003), (03-008)), National Natural Science Foundation (No. 30973981), and U.S. NIH Fogarty R24 TW007988, and Beijing Municipal Commission of Education (No. KM201010025010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 17 Z9 23 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2011 VL 6 IS 10 AR e25671 DI 10.1371/journal.pone.0025671 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NA UT WOS:000295966900042 PM 21998679 ER PT J AU Marsh, AA Crowe, SL Yu, HH Gorodetsky, EK Goldman, D Blair, RJR AF Marsh, Abigail A. Crowe, Samantha L. Yu, Henry H. Gorodetsky, Elena K. Goldman, David Blair, R. J. R. TI Serotonin Transporter Genotype (5-HTTLPR) Predicts Utilitarian Moral Judgments SO PLOS ONE LA English DT Article ID NEGATIVE AFFECTIVITY; PREFRONTAL CORTEX; SUSCEPTIBILITY; POLYMORPHISM; PSYCHOPATHY; DEPRESSION; AMYGDALA; RISK; GENE AB Background: The psychological and neurobiological processes underlying moral judgment have been the focus of extensive recent research. Here we show that serotonin transporter (5-HTTLPR) genotype predicts responses to moral dilemmas featuring foreseen harm to an innocent. Methodology/Principal Findings: Participants in this study judged the acceptability of actions that would unintentionally or intentionally harm an innocent victim in order to save others' lives. An analysis of variance revealed a genotype 6 scenario interaction, F(2, 63)=4.52, p=.02. Results showed that, relative to long allele homozygotes (LL), carriers of the short (S) allele showed particular reluctance to endorse utilitarian actions resulting in foreseen harm to an innocent individual. LL genotype participants rated perpetrating unintentional harm as more acceptable (M=4.98, SEM=0.20) than did SL genotype participants (M=4.65, SEM=0.20) or SS genotype participants (M=4.29, SEM=0.30). No group differences in moral judgments were observed in response to scenarios featuring intentional harm. Conclusions/Significance: The results indicate that inherited variants in a genetic polymorphism that influences serotonin neurotransmission influence utilitarian moral judgments as well. This finding is interpreted in light of evidence that the S allele is associated with elevated emotional responsiveness. C1 [Marsh, Abigail A.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Marsh, Abigail A.; Crowe, Samantha L.; Yu, Henry H.; Blair, R. J. R.] NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. [Gorodetsky, Elena K.; Goldman, David] NIAAA, Sect Human Neurogenet, Bethesda, MD 90034 USA. RP Marsh, AA (reprint author), Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. EM aam72@georgetown.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute of Mental Health/Nathional Institutes of Health FX This research was supported by the Intramural Research Program at the National Institute of Mental Health/Nathional Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 12 Z9 13 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2011 VL 6 IS 10 AR e25148 DI 10.1371/journal.pone.0025148 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NA UT WOS:000295966900010 PM 21998637 ER PT J AU Xiong, Y Zhang, L Holloway, AK Wu, XL Su, L Kebebew, E AF Xiong, Yin Zhang, Lisa Holloway, Alisha K. Wu, Xiaolin Su, Ling Kebebew, Electron TI MiR-886-3p Regulates Cell Proliferation and Migration, and Is Dysregulated in Familial Non-Medullary Thyroid Cancer SO PLOS ONE LA English DT Article ID CDNA MICROARRAY DATA; SUSCEPTIBILITY LOCUS; LINKAGE ANALYSIS; EXPRESSION; CARCINOMA; ZYXIN; TUMORS; PREDISPOSITION; NORMALIZATION; REPLICATION AB Background: The molecular basis and characteristics of familial non-medullary thyroid cancer are poorly understood. In this study, we performed microRNA (miRNA) profiling of familial and sporadic papillary thyroid cancer tumor samples. Methodology/Principal Findings: Genome wide miRNA profiling of sporadic and familial papillary thyroid cancer was performed. Differentially expressed miRNAs were validated by quantitative RT-PCR. Ectopic expression of miR-886-3p in thyroid cancer lines was performed to identify pathways targeted by the miRNA, as well as, to determine its effect on tumor cell biology. We found four differentially expressed miRNAs between familial and sporadic papillary thyroid cancer tumor samples. MiR-886-3p and miR-20a were validated to be differentially expressed by 3- and 4-fold, respectively. Pathway analysis of genome-wide expression data on cells overexpressing miR-886-3p and target prediction analysis showed genes involved in DNA replication and focal adhesion pathways were regulated by miR-886-3p. Overexpression of miR-886-3p in thyroid cancer cell lines significantly inhibited cellular proliferation, the number and size of spheroids and cellular migration. Additionally, overexpression of miR-886-3p increased the number of cells in S phase. Conclusions/Significance: Our findings for the first time suggest that miR-886-3p plays an important role in thyroid cancer tumor cell biology and regulates genes involved in DNA replication and focal adhesion. Thus, miR-886-3p may play a role in the initiation and or progression of papillary thyroid cancer. C1 [Xiong, Yin; Zhang, Lisa; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Holloway, Alisha K.] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94143 USA. [Wu, Xiaolin; Su, Ling] NCI, Lab Mol Technol, Sci Applicat Int Coorporat Frederick Inc, Frederick, MD 21701 USA. RP Xiong, Y (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Holloway, Alisha/H-9574-2013 OI Holloway, Alisha/0000-0001-9810-389X FU National Cancer Institute, Center for Cancer Research FX This study was funded by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 20 Z9 23 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2011 VL 6 IS 10 AR e24717 DI 10.1371/journal.pone.0024717 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NA UT WOS:000295966900004 PM 21998631 ER PT J AU Zhang, XB Zhang, SC Sun, DJ Hu, J Wali, A Pass, H Fernandez-Madrid, F Harbut, MR Tang, NM AF Zhang, Xinbo Zhang, Siyu Crystal Sun, Dejun Hu, Jiang Wali, Anil Pass, Harvey Fernandez-Madrid, Felix Harbut, Michael R. Tang, Naimei TI New Insight into the Molecular Mechanisms of the Biological Effects of DNA Minor Groove Binders SO PLOS ONE LA English DT Article ID HOECHST 33342-INDUCED APOPTOSIS; 33342 INDUCES APOPTOSIS; BOX-BINDING PROTEIN; I IN-VIVO; BC3H-1 MYOCYTES; TOPOISOMERASE-I; HL-60 CELLS; AGENTS; 33258-HOECHST; CONDENSATION AB Background: Bisbenzimides, or Hoechst 33258 (H258), and its derivative Hoechst 33342 (H342) are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear. Methodology/Principal Findings: To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects. Conclusions/Significance: A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug development process. Further analysis of H258-upregulated genes of transcription regulation may identify the genes that enhance transgene overexpression in gene therapy and promote recombinant protein products in biopharmaceutical companies. Data Deposition: The microarray data reported in this article have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.GSE28616). C1 [Zhang, Xinbo; Zhang, Siyu Crystal] Wayne State Univ, MedStart Program, Detroit, MI 48202 USA. [Harbut, Michael R.; Tang, Naimei] Karmanos Canc Inst, Environm Canc Initiat, Natl Ctr Vermiculite & Asbestos Related Canc, Detroit, MI USA. [Sun, Dejun] Res Inst Resp & Crit Care Med, Baotou, Inner Mongolia, Peoples R China. [Hu, Jiang] Cent Hosp, Dept Surg, Baotou, Inner Mongolia, Peoples R China. [Wali, Anil] NCI, Ctr Reduce Canc Hlth Dispar, Rockville, MD USA. [Pass, Harvey] NYU, Med Ctr, Dept Cardiothorac Surg, New York, NY 10016 USA. [Harbut, Michael R.] Providence Hosp, Ctr Occupat & Environm Med, Southfield, MI 48037 USA. RP Zhang, XB (reprint author), Wayne State Univ, MedStart Program, Detroit, MI 48202 USA. EM ntang@med.wayne.edu NR 58 TC 10 Z9 11 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2011 VL 6 IS 10 AR e25822 DI 10.1371/journal.pone.0025822 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NA UT WOS:000295966900059 PM 21998702 ER PT J AU Foster, MC Hwang, SJ Porter, SA Massaro, JM Hoffmann, U Fox, CS AF Foster, Meredith C. Hwang, Shih-Jen Porter, Stacy A. Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI Development and reproducibility of a computed tomography-based measurement of renal sinus fat SO BMC NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; BODY-MASS INDEX; COMMUNITY-BASED POPULATION; IMPROVING GLOBAL OUTCOMES; CARDIOVASCULAR-DISEASE; LIPID-ACCUMULATION; METABOLIC SYNDROME; RISK-FACTORS; UNITED-STATES; OBESITY AB Background: Renal sinus fat may mediate obesity-related vascular disease, although this fat depot has not been assessed in a community-based sample. We sought to develop a protocol to quantify renal sinus fat accumulation using multi-detector computed tomography (MDCT). Methods: Protocol development was performed in participants in the Framingham Offspring cohort who underwent MDCT. Volumetric renal sinus fat was measured separately within the right and left kidneys, and renal sinus fat area within a single MDCT scan slice was measured in the right kidney. Due to the high correlation of volumetric and single-slice renal sinus fat in the right kidney (Pearson correlation [r] = 0.85, p < 0.0001), we optimized a single-slice protocol to capture renal sinus fat in the right kidney alone. Pearson correlation coefficients were used to compare to assess the correlation of volumetric and single-slice renal sinus fat in the right kidney with other measures of adiposity. Inter-and intra-reader reproducibility was assessed using intra-class correlation coefficients. Results: Single-slice measurements were obtained in 92 participants (mean age 60 years, 49% women, median renal sinus fat 0.43 cm(2)). Intra- and inter-reader intra-class correlation coefficients were 0.93 and 0.86, respectively. Single-slice renal sinus fat was correlated with body mass index (r = 0.35, p = 0.0006), waist circumference (r = 0.31, p = 0.003), and abdominal visceral fat (r = 0.48, p < 0.0001). Similar correlations were observed for volumetric renal sinus fat in the right kidney. Conclusions: Measuring renal sinus fat is feasible and reproducible using MDCT scans in a community-based sample. C1 [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Foster, Meredith C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Porter, Stacy A.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol & Metab, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute [N01-HC-25195] FX The Framingham Heart Study is supported by the National Heart, Lung and Blood Institute (N01-HC-25195). The funding body did not play a role in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, or the decision to submit the manuscript for publication. NR 43 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 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD OCT 4 PY 2011 VL 12 AR 52 DI 10.1186/1471-2369-12-52 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 946PV UT WOS:000304366000001 PM 21970591 ER PT J AU Romagnoli, R Baraldi, PG Lopez-Cara, C Cruz-Lopez, O Carrion, MD Salvador, MK Bermejo, J Estevez, S Estevez, F Balzarini, J Brancale, A Ricci, A Chen, LC Kim, JG Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Lopez-Cara, Carlota Cruz-Lopez, Olga Carrion, Maria Dora Salvador, Maria Kimatrai Bermejo, Jaime Estevez, Sara Estevez, Francisco Balzarini, Jan Brancale, Andrea Ricci, Antonio Chen, Longchuan Kim, Jae Gwan Hamel, Ernest TI Synthesis and Antitumor Molecular Mechanism of Agents Based on Amino 2-(3 ',4 ',5 '-Trimethoxybenzoyl)benzo[b]furan: Inhibition of Tubulin and Induction of Apoptosis SO CHEMMEDCHEM LA English DT Article DE antiproliferative agents; apoptosis; caspase activation; colchicine binding site; tubulin ID ALPHA-HALOGENOACRYLIC DERIVATIVES; VASCULAR DISRUPTING AGENT; BLOOD-FLOW STASIS; CELL-DEATH; COMBRETASTATIN ANALOGS; ANTINEOPLASTIC AGENTS; BIOLOGICAL EVALUATION; MICROTUBULE DYNAMICS; MEDICINAL CHEMISTRY; ANTIMITOTIC AGENTS AB Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3', 4', 5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3h), which inhibits cancer cell growth at nanomolar concentrations (IC(50)=16-24 nm), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3h in a concentration-dependent manner. We also show that compound 3h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an alpha-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Lopez-Cara, Carlota; Cruz-Lopez, Olga; Carrion, Maria Dora; Salvador, Maria Kimatrai] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Bermejo, Jaime] Univ La Laguna, Inst Canario Invest Canc, Inst Univ Bioorgan Antonio Gonzalez, Inst Prod Nat & Agrobiol CSIC, E-38206 Tenerife, Spain. [Estevez, Sara; Estevez, Francisco] Univ Las Palmas Gran Canaria, Dept Bioquim, Unidad Asociada CSIC, Las Palmas Gran Canaria 35016, Spain. [Estevez, Sara; Estevez, Francisco] Inst Canario Invest Canc, Las Palmas Gran Canaria 35016, Spain. [Balzarini, Jan] Catholic Univ Louvain, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Brancale, Andrea; Ricci, Antonio] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales. [Chen, Longchuan] VA Med Ctr, Dept Pathol, Long Beach, CA 90822 USA. [Kim, Jae Gwan] Gwangju Inst Sci & Technol, Dept Informat & Commun, Kwangju 500712, South Korea. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it RI Brancale, Andrea/N-9445-2014; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Estevez, Francisco/K-5125-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017 OI Brancale, Andrea/0000-0002-9728-3419; Carrion, M. Dora/0000-0002-6794-3949; Estevez, Francisco/0000-0002-9728-2774; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; FU Ministry of Science and Innovation of Spain; European Regional Development Fund [SAF2010-21380]; Instituto Canario de Investigacion del Cancer; Ministry of Education of Spain FX This work was supported by a grant from the Ministry of Science and Innovation of Spain, from the European Regional Development Fund (SAF2010-21380 to F. E.), and the Instituto Canario de Investigacion del Cancer (RED PRODNAT CANCER to J.B.). S. E. thanks the Ministry of Education of Spain for financial support. The authors thank Maria Teresa Marrero, Dr. Alberto Casolari, Dr. Erika Marzola, and Dr. Elisa Durini for excellent technical assistance. NR 58 TC 7 Z9 7 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD OCT 4 PY 2011 VL 6 IS 10 BP 1841 EP 1853 DI 10.1002/cmdc.201100279 PG 13 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 840CX UT WOS:000296417000011 PM 21805646 ER PT J AU Nazarian, S Hansford, R Roguin, A Goldsher, D Zviman, MM Lardo, AC Caffo, BS Frick, KD Kraut, MA Kamel, IR Calkins, H Berger, RD Bluemke, DA Halperin, HR AF Nazarian, Saman Hansford, Rozann Roguin, Ariel Goldsher, Dorith Zviman, Menekhem M. Lardo, Albert C. Caffo, Brian S. Frick, Kevin D. Kraut, Michael A. Kamel, Ihab R. Calkins, Hugh Berger, Ronald D. Bluemke, David A. Halperin, Henry R. TI A Prospective Evaluation of a Protocol for Magnetic Resonance Imaging of Patients With Implanted Cardiac Devices SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CARDIOVERTER-DEFIBRILLATORS; INDUSTRY VIEWPOINT; 1.5 TESLA; IN-VIVO; PERMANENT PACEMAKERS; SAFE PERFORMANCE; ABSORPTION RATE; MRI; ICDS; LEADS AB Background: Magnetic resonance imaging (MRI) is avoided in most patients with implanted cardiac devices because of safety concerns. Objective: To define the safety of a protocol for MRI at the commonly used magnetic strength of 1.5 T in patients with implanted cardiac devices. Design: Prospective nonrandomized trial. (ClinicalTrials.gov registration number: NCT01130896) Setting: One center in the United States (94% of examinations) and one in Israel. Patients: 438 patients with devices (54% with pacemakers and 46% with defibrillators) who underwent 555 MRI studies. Intervention: Pacing mode was changed to asynchronous for pacemaker-dependent patients and to demand for others. Tachyarrhythmia functions were disabled. Blood pressure, electrocardiography, oximetry, and symptoms were monitored by a nurse with experience in cardiac life support and device programming who had immediate backup from an electrophysiologist. Measurements: Activation or inhibition of pacing, symptoms, and device variables. Results: In 3 patients (0.7% [95% CI, 0% to 1.5%]), the device reverted to a transient back-up programming mode without long-term effects. Right ventricular (RV) sensing (median change, 0 mV [interquartile range {IQR}, -0.7 to 0 V]) and atrial and right and left ventricular lead impedances (median change, -2 Omega [IQR, -13 to 0 Omega], -4 Omega [IQR, -16 to 0 Omega], and -11 Omega [IQR, -40 to 0 Omega], respectively) were reduced immediately after MRI. At long-term follow-up (61% of patients), decreased RV sensing (median, 0 mV, [IQR, -1.1 to 0.3 mV]), decreased RV lead impedance (median, -3 Omega, [IQR, -29 to 15 Omega]), increased RV capture threshold (median, 0 V, IQR, [0 to 0.2 Omega]), and decreased battery voltage (median, -0.01 V, IQR, -0.04 to 0 V) were noted. The observed changes did not require device revision or reprogramming. Limitations: Not all available cardiac devices have been tested. Long-term in-person or telephone follow-up was unavailable in 43 patients (10%), and some data were missing. Those with missing long-term capture threshold data had higher baseline right atrial and right ventricular capture thresholds and were more likely to have undergone thoracic imaging. Defibrillation threshold testing and random assignment to a control group were not performed. Conclusion: With appropriate precautions, MRI can be done safely in patients with selected cardiac devices. Because changes in device variables and programming may occur, electrophysiologic monitoring during MRI is essential. C1 Johns Hopkins Univ, Baltimore, MD USA. Technion Israel Inst Technol, Rambam Med Ctr, Haifa, Israel. Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Nazarian, S (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St, Baltimore, MD 21287 USA. EM snazarian@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-HL64795, R01-HL094610, K23-HL089333]; PJ Schafer Memorial Research Award FX By National Institutes of Health grants R01-HL64795 and R01-HL094610 to Dr. Halperin and K23-HL089333 to Dr. Nazarian, and a PJ Schafer Memorial Research Award. NR 39 TC 101 Z9 100 U1 0 U2 22 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 4 PY 2011 VL 155 IS 7 BP 415 EP U39 DI 10.7326/0003-4819-155-7-201110040-00004 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 833OC UT WOS:000295893800002 PM 21969340 ER PT J AU Liu, G Xie, J Zhang, F Wang, ZY Luo, K Zhu, L Quan, QM Niu, G Lee, S Ai, H Chen, XY AF Liu, Gang Xie, Jin Zhang, Fan Wang, Zhiyong Luo, Kui Zhu, Lei Quan, Qimeng Niu, Gang Lee, Seulki Ai, Hua Chen, Xiaoyuan TI N-Alkyl-PEI-Functionalized Iron Oxide Nanoclusters for Efficient siRNA Delivery SO SMALL LA English DT Article ID MULTIFUNCTIONAL MAGNETIC NANOPARTICLES; GENE DELIVERY; RNA INTERFERENCE; GOLD NANOPARTICLES; IN-VIVO; POLYETHYLENIMINE PEI; MAMMALIAN-CELLS; BIOMEDICAL APPLICATIONS; CANCER-THERAPY; PLASMID DNA AB Small-interfering RNA (siRNA) is an emerging class of therapeutics, which works by regulating the expression of a specific gene involved in disease progression. Despite the promises, effective transport of siRNA with minimal side effects remains a challenge. In this study, a nonviral nanoparticle gene carrier is developed and its efficiency for siRNA delivery and transfection is validated at both in vitro and in vivo levels. Such a nanocarrier, abbreviated as Alkyl-PEI2k-IO, was constructed with a core of iron oxide nanoparticles (IOs) and a shell of alkylated polyethyleneimine of 2000 kDa molecualr weight (Alkyl-PEI2k). It is found to be able to bind with siRNA, resulting in well-dispersed nanoparticles with a controlled clustering structure and narrow size distribution. Electrophoresis studies show that the Alkyl-PEI2k-IOs could retard siRNA completely at N:P ratios (i.e., PEI nitrogen to nucleic acid phosphate) above 10, protect siRNA from enzymatic degradation in serum, and release complexed siRNA efficiently in the presence of polyanionic heparin. The knockdown efficiency of the siRNA-loaded nanocarriers is assessed with 4T1 cells stably expressing luciferase (fluc-4T1) and further, with a fluc-4T1 xenograft model. Significant down-regulation of luciferase is observed, and unlike high-molecular-weight analogues, the Alkyl-PEI2k-coated IOs show good biocompatibility. In conclusion, Alkyl-PEI2k-IOs demonstrate highly efficient delivery of siRNA and an innocuous toxic profile, making it a potential carrier for gene therapy. C1 [Liu, Gang; Wang, Zhiyong; Luo, Kui; Ai, Hua] Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. [Liu, Gang; Xie, Jin; Zhang, Fan; Zhu, Lei; Quan, Qimeng; Niu, Gang; Lee, Seulki; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Liu, Gang] N Sichuan Med Coll, Affiliated Hosp, Sichuan Key Lab Med Imaging, Dept Radiol, Nanchong 637007, Peoples R China. [Ai, Hua] Sichuan Univ, Dept Radiol, W China Hosp, Chengdu 610041, Peoples R China. RP Ai, H (reprint author), Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. EM huaai@scu.edu.cn; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institutes of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009]; NIH [K99/R00]; Program for New Century Excellent Talents in University [NCET-06-0781]; Distinguished Young Scholars Project of Sichuan Province [06ZQ026-0027, 2011JQ0032]; National Natural Science Foundation of China [20974065, 50603015, 50830107] FX This work was supported by the Intramural Research Program (IRP) of the National Institutes of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the International Cooperative Program of National Science Foundation of China (NSFC) (81028009). J.X. was partially supported by the NIH Pathway to Independence (K99/R00) Fellowship. The work also was supported by Program for New Century Excellent Talents in University (NCET-06-0781), Distinguished Young Scholars Project of Sichuan Province (06ZQ026-0027 and 2011JQ0032), and National Natural Science Foundation of China (20974065, 50603015, and 50830107). NR 54 TC 57 Z9 60 U1 6 U2 64 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1613-6810 J9 SMALL JI Small PD OCT 4 PY 2011 VL 7 IS 19 BP 2742 EP 2749 DI 10.1002/smll.201100825 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 826VJ UT WOS:000295383300008 PM 21861295 ER PT J AU Du, YCN Chou, CK Klimstra, DS Varmus, H AF Du, Yi-Chieh Nancy Chou, Chen-Kung Klimstra, David S. Varmus, Harold TI Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-MIGRATION; RHAMM; EXPRESSION; ACTIVATION; CARCINOMA; PATHWAY; DISEASE; SURFACE; CYCLE AB The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMMB) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMMB-expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMMB did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMMB, we found that RHAMMB induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMMB promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling. C1 [Du, Yi-Chieh Nancy; Varmus, Harold] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10065 USA. [Du, Yi-Chieh Nancy] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Chou, Chen-Kung] Chang Gung Univ, Dept Biomed Sci, Tao Yuan 333, Taiwan. [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Varmus, Harold] NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, Bethesda, MD 20892 USA. RP Varmus, H (reprint author), Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10065 USA. EM nad2012@med.cornell.edu; harold.varmus@nih.gov FU National Institutes of Health [5P01CA094060] FX We thank members in the H. V. laboratory, especially Jennifer Demers, Mary Ann Melnick, Andreas Giannakou, Gabriela Sanchez, and Raymond Dematteo for technical assistance; Katrina Podsypanina and Romel Somwar for insightful discussions; Levi Beverly for 293T cell line and reagents. We thank Danny Huang for mouse database design; and Irina Linkov for protocols. We thank Leigh Selesner in the Y.-C.N.D. laboratory for technical assistance; Hua-Chien Chen at Chang-Gung University for RHAMM expression data from HCC samples; Mouse Genetics Core Facility and Research Animal Resource Center for foster service and animal husbandry; and Memorial Sloan-Kettering Cancer Center's Molecular Cytology, Flow Cytometry, and Small-Animal Imaging Cores for technical assistance. This work was funded in part by a grant from the National Institutes of Health (5P01CA094060). NR 25 TC 16 Z9 16 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 4 PY 2011 VL 108 IS 40 BP 16753 EP 16758 DI 10.1073/pnas.1114022108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 828WX UT WOS:000295536000055 PM 21940500 ER PT J AU Arighi, CN Lu, ZY Krallinger, M Cohen, KB Wilbur, WJ Valencia, A Hirschman, L Wu, CH AF Arighi, Cecilia N. Lu, Zhiyong Krallinger, Martin Cohen, Kevin B. Wilbur, W. John Valencia, Alfonso Hirschman, Lynette Wu, Cathy H. TI Overview of the BioCreative III Workshop SO BMC BIOINFORMATICS LA English DT Article ID INFORMATION EXTRACTION; BIOLOGY; CORPUS AB Background: The overall goal of the BioCreative Workshops is to promote the development of text mining and text processing tools which are useful to the communities of researchers and database curators in the biological sciences. To this end BioCreative I was held in 2004, BioCreative II in 2007, and BioCreative II. 5 in 2009. Each of these workshops involved humanly annotated test data for several basic tasks in text mining applied to the biomedical literature. Participants in the workshops were invited to compete in the tasks by constructing software systems to perform the tasks automatically and were given scores based on their performance. The results of these workshops have benefited the community in several ways. They have 1) provided evidence for the most effective methods currently available to solve specific problems; 2) revealed the current state of the art for performance on those problems; 3) and provided gold standard data and results on that data by which future advances can be gauged. This special issue contains overview papers for the three tasks of BioCreative III. Results: The BioCreative III Workshop was held in September of 2010 and continued the tradition of a challenge evaluation on several tasks judged basic to effective text mining in biology, including a gene normalization (GN) task and two protein-protein interaction (PPI) tasks. In total the Workshop involved the work of twenty-three teams. Thirteen teams participated in the GN task which required the assignment of EntrezGene IDs to all named genes in full text papers without any species information being provided to a system. Ten teams participated in the PPI article classification task (ACT) requiring a system to classify and rank a PubMed (R) record as belonging to an article either having or not having "PPI relevant" information. Eight teams participated in the PPI interaction method task (IMT) where systems were given full text documents and were required to extract the experimental methods used to establish PPIs and a text segment supporting each such method. Gold standard data was compiled for each of these tasks and participants competed in developing systems to perform the tasks automatically. BioCreative III also introduced a new interactive task (IAT), run as a demonstration task. The goal was to develop an interactive system to facilitate a user's annotation of the unique database identifiers for all the genes appearing in an article. This task included ranking genes by importance (based preferably on the amount of described experimental information regarding genes). There was also an optional task to assist the user in finding the most relevant articles about a given gene. For BioCreative III, a user advisory group (UAG) was assembled and played an important role 1) in producing some of the gold standard annotations for the GN task, 2) in critiquing IAT systems, and 3) in providing guidance for a future more rigorous evaluation of IAT systems. Six teams participated in the IAT demonstration task and received feedback on their systems from the UAG group. Besides innovations in the GN and PPI tasks making them more realistic and practical and the introduction of the IAT task, discussions were begun on community data standards to promote interoperability and on user requirements and evaluation metrics to address utility and usability of systems. Conclusions: In this paper we give a brief history of the BioCreative Workshops and how they relate to other text mining competitions in biology. This is followed by a synopsis of the three tasks GN, PPI, and IAT in BioCreative III with figures for best participant performance on the GN and PPI tasks. These results are discussed and compared with results from previous BioCreative Workshops and we conclude that the best performing systems for GN, PPI-ACT and PPI-IMT in realistic settings are not sufficient for fully automatic use. This provides evidence for the importance of interactive systems and we present our vision of how best to construct an interactive system for a GN or PPI like task in the remainder of the paper. C1 [Arighi, Cecilia N.; Wu, Cathy H.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19716 USA. [Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Krallinger, Martin; Valencia, Alfonso] Spanish Natl Canc Res Ctr, Struct & Computat Biol Grp, Madrid, Spain. [Cohen, Kevin B.] Univ Colorado Denver, Sch Med, Ctr Computat Pharmacol, Aurora, CO USA. [Hirschman, Lynette] Mitre Corp, Bedford, MA 01730 USA. RP Wu, CH (reprint author), Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19716 USA. EM wuc@udel.edu RI Valencia, Alfonso/I-3127-2015; OI Valencia, Alfonso/0000-0002-8937-6789; Arighi, Cecilia/0000-0002-0803-4817 FU NIH, National Library of Medicine; UNIDEL Foundation; eTOX [115002]; Eurocancercoms 7th framework programme (FP7) project; ISCIII combiomed network; NSF [DBI-0850319] FX The work at NCBI (ZL, WJW) is supported by the Intramural Research Program of the NIH, National Library of Medicine. The work at University of Delaware (CNA, CHW) is partially supported by the UNIDEL Foundation grant to CHW. The work at CNIO was funded by eTOX (Grant Agreement no 115002 - Innovative Medicines Initiative Joint Undertaking), the Eurocancercoms 7th framework programme (FP7) project and the ISCIII combiomed network. BioCreative III was supported under NSF grant DBI-0850319 to CHW and LH. The authors would like to thank the referees for many helpful suggestions which improved this paper. NR 25 TC 34 Z9 35 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2011 VL 12 SU 8 AR S1 DI 10.1186/1471-2105-12-S8-S1 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 940ZX UT WOS:000303932700001 PM 22151647 ER PT J AU Arighi, CN Roberts, PM Agarwal, S Bhattacharya, S Cesareni, G Chatr-aryamontri, A Clematide, S Gaudet, P Giglio, MG Harrow, I Huala, E Krallinger, M Leser, U Li, DH Liu, FF Lu, ZY Maltais, LJ Okazaki, N Perfetto, L Rinaldi, F Saetre, R Salgado, D Srinivasan, P Thomas, PE Toldo, L Hirschman, L Wu, CH AF Arighi, Cecilia N. Roberts, Phoebe M. Agarwal, Shashank Bhattacharya, Sanmitra Cesareni, Gianni Chatr-aryamontri, Andrew Clematide, Simon Gaudet, Pascale Giglio, Michelle Gwinn Harrow, Ian Huala, Eva Krallinger, Martin Leser, Ulf Li, Donghui Liu, Feifan Lu, Zhiyong Maltais, Lois J. Okazaki, Naoaki Perfetto, Livia Rinaldi, Fabio Saetre, Rune Salgado, David Srinivasan, Padmini Thomas, Philippe E. Toldo, Luca Hirschman, Lynette Wu, Cathy H. TI BioCreative III interactive task: an overview SO BMC BIOINFORMATICS LA English DT Article ID TEXT; GENE; BIOLOGY; IDENTIFICATION; EXTRACTION; CHALLENGE; COMMUNITY; ONTOLOGY; ARTICLES; MENTIONS AB Background: The BioCreative challenge evaluation is a community-wide effort for evaluating text mining and information extraction systems applied to the biological domain. The biocurator community, as an active user of biomedical literature, provides a diverse and engaged end user group for text mining tools. Earlier BioCreative challenges involved many text mining teams in developing basic capabilities relevant to biological curation, but they did not address the issues of system usage, insertion into the workflow and adoption by curators. Thus in BioCreative III (BC-III), the InterActive Task (IAT) was introduced to address the utility and usability of text mining tools for real-life biocuration tasks. To support the aims of the IAT in BC-III, involvement of both developers and end users was solicited, and the development of a user interface to address the tasks interactively was requested. Results: A User Advisory Group (UAG) actively participated in the IAT design and assessment. The task focused on gene normalization (identifying gene mentions in the article and linking these genes to standard database identifiers), gene ranking based on the overall importance of each gene mentioned in the article, and gene-oriented document retrieval (identifying full text papers relevant to a selected gene). Six systems participated and all processed and displayed the same set of articles. The articles were selected based on content known to be problematic for curation, such as ambiguity of gene names, coverage of multiple genes and species, or introduction of a new gene name. Members of the UAG curated three articles for training and assessment purposes, and each member was assigned a system to review. A questionnaire related to the interface usability and task performance (as measured by precision and recall) was answered after systems were used to curate articles. Although the limited number of articles analyzed and users involved in the IAT experiment precluded rigorous quantitative analysis of the results, a qualitative analysis provided valuable insight into some of the problems encountered by users when using the systems. The overall assessment indicates that the system usability features appealed to most users, but the system performance was suboptimal (mainly due to low accuracy in gene normalization). Some of the issues included failure of species identification and gene name ambiguity in the gene normalization task leading to an extensive list of gene identifiers to review, which, in some cases, did not contain the relevant genes. The document retrieval suffered from the same shortfalls. The UAG favored achieving high performance (measured by precision and recall), but strongly recommended the addition of features that facilitate the identification of correct gene and its identifier, such as contextual information to assist in disambiguation. Discussion: The IAT was an informative exercise that advanced the dialog between curators and developers and increased the appreciation of challenges faced by each group. A major conclusion was that the intended users should be actively involved in every phase of software development, and this will be strongly encouraged in future tasks. The IAT Task provides the first steps toward the definition of metrics and functional requirements that are necessary for designing a formal evaluation of interactive curation systems in the BioCreative IV challenge. C1 [Arighi, Cecilia N.; Wu, Cathy H.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19716 USA. [Roberts, Phoebe M.; Harrow, Ian] Pfizer Res Technol Ctr, Cambridge, MA USA. [Agarwal, Shashank; Liu, Feifan] Univ Wisconsin, Milwaukee, WI 53201 USA. [Bhattacharya, Sanmitra; Srinivasan, Padmini] Univ Iowa, Dept Comp Sci, Iowa City, IA 52242 USA. [Cesareni, Gianni; Perfetto, Livia] Univ Roma Tor Vergata, Rome, Italy. [Cesareni, Gianni] IRCCS Fdn Santa Lucia, Rome, Italy. [Chatr-aryamontri, Andrew] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH8 9YL, Midlothian, Scotland. [Clematide, Simon; Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, Zurich, Switzerland. [Gaudet, Pascale] Swiss Inst Bioinformat, CALIPHO Grp, Geneva, Switzerland. [Gaudet, Pascale] Northwestern Univ, NIBIC, DictyBase, Chicago, IL 60611 USA. [Giglio, Michelle Gwinn] Univ Maryland, Baltimore, MD 21201 USA. [Huala, Eva; Li, Donghui] Carnegie Inst Sci, TAIR, Washington, DC USA. [Krallinger, Martin] Spanish Natl Canc Res Ctr CNIO, Struct & Computat Biol Grp, Madrid, Spain. [Leser, Ulf; Thomas, Philippe E.] Univ Berlin, D-10099 Berlin, Germany. [Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Maltais, Lois J.] Jackson Lab, MGI, Bar Harbor, ME 04609 USA. [Okazaki, Naoaki; Saetre, Rune] Univ Tokyo, Dept Comp Sci, Tokyo 1138654, Japan. [Saetre, Rune] NTNU, Dept Comp & Informat Sci, Trondheim, Norway. [Salgado, David] Monash Univ, Australian Regenerat Med Inst, Melbourne, Vic 3004, Australia. [Salgado, David] Univ Aix Marseille 2, Dev Biol Inst Marseille Luminy IBDML, Marseille, France. [Toldo, Luca] Merck KGaA, Darmstadt, Germany. [Hirschman, Lynette] Mitre Corp, Informat Technol Ctr, Bedford, MA 01730 USA. RP Arighi, CN (reprint author), Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19716 USA. EM arighi@dbi.udel.edu RI Toldo, Luca/A-3784-2013; SALGADO, David/A-1417-2014; OI Toldo, Luca/0000-0003-2027-5717; Arighi, Cecilia/0000-0002-0803-4817; Rinaldi, Fabio/0000-0001-5718-5462; Huala, Eva/0000-0003-4631-7241 FU NSF [DBI-0850319]; French Association against Myopathies and MyoRes; Swiss National Science Foundation [100014-118396/1, 105315-130558/1]; NITAS/TMS; Text Mining Services; Novartis Pharma AG, Basel, Switzerland; German Federal Ministry of Education and Research [0315417B]; CONSOLIDER [CSD2007-00050]; ENFIN [LSGH-CT-2005-518254]; Eurocancercoms [S-CT-2009- 230548]; NIH/NLM [1G08LM10720-01] FX We would like to thank all members of the User Advisory Group for their active contribution to the IAT task. We also would like to thank Ben Carterette, University of Delaware, and Kevin Cohen, University of Colorado, for reading the manuscript and providing some suggestions about future interface evaluation, and Qinghua Wang from University of Delaware for assisting with manual curation. The BioCreative III workshop was supported under NSF grant DBI-0850319. Team 61 (MyMiner) is funded by the French Association against Myopathies and MyoRes, the first European Network of Excellence dedicated to study normal and aberrant muscle development function and repair. Team 65 (OntoGene) is funded by the Swiss National Science Foundation (grants 100014-118396/1 and 105315-130558/1) and by NITAS/TMS, Text Mining Services, Novartis Pharma AG, Basel, Switzerland. Team 68 (GeneView) is developed as part of the ColoNet project, supported by the German Federal Ministry of Education and Research, grant no 0315417B. Team 78 would like to thank Aditya K. Sehgal for his valuable guidance with this work. Team 93 is a collaborative work with Han-Cheol Cho, Sampo Pyysalo, Tomoko Ohta, and Jun'ichi Tsujii. GNSuite work is supported by Grants-in-Aid for Scientific Research on Priority Areas (MEXT) and for Solution-Oriented Research for Science and Technology (JST), Japan. The CNIO contribution (MK) was funded by CONSOLIDER (CSD2007-00050) ENFIN (LSGH-CT-2005-518254) and Eurocancercoms (SiS-CT-2009- 230548). The University of Delaware contribution (CNA, CHW) was partially supported by NIH/NLM grant 1G08LM10720-01. NR 41 TC 35 Z9 37 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2011 VL 12 SU 8 AR S4 DI 10.1186/1471-2105-12-S8-S4 PG 21 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 940ZX UT WOS:000303932700004 PM 22151968 ER PT J AU Kim, S Wilbur, WJ AF Kim, Sun Wilbur, W. John TI Classifying protein-protein interaction articles using word and syntactic features SO BMC BIOINFORMATICS LA English DT Article ID EXTRACTION; DATABASE; TEXT AB Background: Identifying protein-protein interactions (PPIs) from literature is an important step in mining the function of individual proteins as well as their biological network. Since it is known that PPIs have distinctive patterns in text, machine learning approaches have been successfully applied to mine these patterns. However, the complex nature of PPI description makes the extraction process difficult. Results: Our approach utilizes both word and syntactic features to effectively capture PPI patterns from biomedical literature. The proposed method automatically identifies gene names by a Priority Model, then extracts grammar relations using a dependency parser. A large margin classifier with Huber loss function learns from the extracted features, and unknown articles are predicted using this data-driven model. For the BioCreative III ACT evaluation, our official runs were ranked in top positions by obtaining maximum 89.15% accuracy, 61.42% F1 score, 0.55306 MCC score, and 67.98% AUC iP/R score. Conclusions: Even though problems still remain, utilizing syntactic information for article-level filtering helps improve PPI ranking performance. The proposed system is a revision of previously developed algorithms in our group for the ACT evaluation. Our approach is valuable in showing how to use grammatical relations for PPI article filtering, in particular, with a limited training corpus. While current performance is far from satisfactory as an annotation tool, it is already useful for a PPI article search engine since users are mainly focused on highly-ranked results. C1 [Kim, Sun; Wilbur, W. John] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wilbur, WJ (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM wilbur@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX The authors would like to thank Won Kim and Larry Smith for valuable comments on implementing the proposed method. The authors are supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 32 TC 12 Z9 12 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2011 VL 12 SU 8 AR S9 DI 10.1186/1471-2105-12-S8-S9 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 940ZX UT WOS:000303932700009 PM 22151252 ER PT J AU Krallinger, M Vazquez, M Leitner, F Salgado, D Chatr-aryamontri, A Winter, A Perfetto, L Briganti, L Licata, L Iannuccelli, M Castagnoli, L Cesareni, G Tyers, M Schneider, G Rinaldi, F Leaman, R Gonzalez, G Matos, S Kim, S Wilbur, WJ Rocha, L Shatkay, H Tendulkar, AV Agarwal, S Liu, FF Wang, XL Rak, R Noto, K Elkan, C Lu, ZY Dogan, RI Fontaine, JF Andrade-Navarro, MA Valencia, A AF Krallinger, Martin Vazquez, Miguel Leitner, Florian Salgado, David Chatr-aryamontri, Andrew Winter, Andrew Perfetto, Livia Briganti, Leonardo Licata, Luana Iannuccelli, Marta Castagnoli, Luisa Cesareni, Gianni Tyers, Mike Schneider, Gerold Rinaldi, Fabio Leaman, Robert Gonzalez, Graciela Matos, Sergio Kim, Sun Wilbur, W. John Rocha, Luis Shatkay, Hagit Tendulkar, Ashish V. Agarwal, Shashank Liu, Feifan Wang, Xinglong Rak, Rafal Noto, Keith Elkan, Charles Lu, Zhiyong Dogan, Rezarta Islamaj Fontaine, Jean-Fred Andrade-Navarro, Miguel A. Valencia, Alfonso TI The Protein-Protein Interaction tasks of BioCreative III: classification/ranking of articles and linking bio-ontology concepts to full text SO BMC BIOINFORMATICS LA English DT Article ID BIOLOGICAL LITERATURE; BIOMEDICAL LITERATURE; EXTRACTION; DATABASE; INFORMATION; II.5; ANNOTATION; COMMUNITY; ONTOGENE; RANKING AB Background: Determining usefulness of biomedical text mining systems requires realistic task definition and data selection criteria without artificial constraints, measuring performance aspects that go beyond traditional metrics. The BioCreative III Protein-Protein Interaction (PPI) tasks were motivated by such considerations, trying to address aspects including how the end user would oversee the generated output, for instance by providing ranked results, textual evidence for human interpretation or measuring time savings by using automated systems. Detecting articles describing complex biological events like PPIs was addressed in the Article Classification Task (ACT), where participants were asked to implement tools for detecting PPI-describing abstracts. Therefore the BCIII-ACT corpus was provided, which includes a training, development and test set of over 12,000 PPI relevant and non-relevant PubMed abstracts labeled manually by domain experts and recording also the human classification times. The Interaction Method Task (IMT) went beyond abstracts and required mining for associations between more than 3,500 full text articles and interaction detection method ontology concepts that had been applied to detect the PPIs reported in them. Results: A total of 11 teams participated in at least one of the two PPI tasks (10 in ACT and 8 in the IMT) and a total of 62 persons were involved either as participants or in preparing data sets/evaluating these tasks. Per task, each team was allowed to submit five runs offline and another five online via the BioCreative Meta-Server. From the 52 runs submitted for the ACT, the highest Matthew's Correlation Coefficient (MCC) score measured was 0.55 at an accuracy of 89% and the best AUC iP/R was 68%. Most ACT teams explored machine learning methods, some of them also used lexical resources like MeSH terms, PSI-MI concepts or particular lists of verbs and nouns, some integrated NER approaches. For the IMT, a total of 42 runs were evaluated by comparing systems against manually generated annotations done by curators from the BioGRID and MINT databases. The highest AUC iP/R achieved by any run was 53%, the best MCC score 0.55. In case of competitive systems with an acceptable recall (above 35%) the macro-averaged precision ranged between 50% and 80%, with a maximum F-Score of 55%. Conclusions: The results of the ACT task of BioCreative III indicate that classification of large unbalanced article collections reflecting the real class imbalance is still challenging. Nevertheless, text-mining tools that report ranked lists of relevant articles for manual selection can potentially reduce the time needed to identify half of the relevant articles to less than 1/4 of the time when compared to unranked results. Detecting associations between full text articles and interaction detection method PSI-MI terms (IMT) is more difficult than might be anticipated. This is due to the variability of method term mentions, errors resulting from pre-processing of articles provided as PDF files, and the heterogeneity and different granularity of method term concepts encountered in the ontology. However, combining the sophisticated techniques developed by the participants with supporting evidence strings derived from the articles for human interpretation could result in practical modules for biological annotation workflows. C1 [Krallinger, Martin; Vazquez, Miguel; Leitner, Florian; Valencia, Alfonso] Spanish Natl Canc Res Ctr CNIO, Struct Biol & BioComp Programme, Madrid, Spain. [Salgado, David] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. [Chatr-aryamontri, Andrew; Winter, Andrew; Tyers, Mike] Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland. [Perfetto, Livia; Briganti, Leonardo; Licata, Luana; Iannuccelli, Marta; Castagnoli, Luisa; Cesareni, Gianni] Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy. [Cesareni, Gianni] Fdn Santa Lucia, IRCCS, Rome, Italy. [Schneider, Gerold; Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, Zurich, Switzerland. [Leaman, Robert] Arizona State Univ, Sch Comp Informat & Decis Syst Engn, Tempe, AZ USA. [Gonzalez, Graciela] Arizona State Univ, Dept Biomed Informat, Tempe, AZ USA. [Matos, Sergio] Univ Aveiro, Inst Elect & Telemat Engn Aveiro, P-3810193 Aveiro, Portugal. [Kim, Sun; Wilbur, W. John; Lu, Zhiyong; Dogan, Rezarta Islamaj] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Rocha, Luis] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47408 USA. [Shatkay, Hagit] Univ Delaware, Dept Comp & Informat Sci, Newark, DE 19716 USA. [Tendulkar, Ashish V.] IIT Madras, Dept Comp Sci & Engn, Madras 600036, Tamil Nadu, India. [Agarwal, Shashank; Liu, Feifan] Univ Wisconsin, Milwaukee, WI 53201 USA. [Wang, Xinglong; Rak, Rafal] Univ Manchester, Natl Ctr Text Min, Manchester, Lancs, England. [Wang, Xinglong; Rak, Rafal] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Noto, Keith] Tufts Univ, Dept Comp Sci, Medford, MA 02155 USA. [Elkan, Charles] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. [Fontaine, Jean-Fred; Andrade-Navarro, Miguel A.] Max Delbruck Ctr Mol Med, Computat Biol & Data Min Grp, D-13125 Berlin, Germany. RP Krallinger, M (reprint author), Spanish Natl Canc Res Ctr CNIO, Struct Biol & BioComp Programme, Madrid, Spain. EM mkrallinger@cnio.es RI Andrade, Miguel/B-6565-2008; Matos, Sergio/G-4941-2010; Valencia, Alfonso/I-3127-2015; SALGADO, David/A-1417-2014; OI Gonzalez Hernandez, Graciela/0000-0002-6416-9556; Rocha, Luis/0000-0001-9402-887X; Andrade, Miguel/0000-0001-6650-1711; Matos, Sergio/0000-0003-1941-3983; Valencia, Alfonso/0000-0002-8937-6789; Leitner, Florian/0000-0003-4458-504X; Rinaldi, Fabio/0000-0001-5718-5462 FU project BIO2007 [BIO2007-666855]; project CONSOLIDER [CSD2007-00050]; project ENFIN [LSGH-CT-2005-518254]; Swiss National Science Foundation [100014-118396/1, 105315-130558/1]; NITAS/TMS; Text Mining Services; Novartis Pharma AG; Basel, Switzerland; NIH [NIA P30 AG-19610, GM077402]; Fundacao para a Ciencia e a Tecnologia [PTDC/EIA-CCO/100541/2008]; NIH, National Library of Medicine; National Library of Medicine [5R01LM009836, 5R01LM010125]; UK Biotechnology and Biological Sciences Research Council (BBSRC) [BB/G013160/1]; UK Joint Information Systems Committee (JISC); German Ministry of Education and Research [01GS08170]; Helmholtz Alliance in Systems Biology (Germany); Telethon foundation; AIRC; MyoRes European Network of Excellence; French Association against Myopathies (AFM) FX The work of the CNIO task organizers (MK, MV, FL, AV) was funded by the projects BIO2007 (BIO2007-666855), CONSOLIDER (CSD2007-00050) and ENFIN (LSGH-CT-2005-518254). We would like to thank the following publishers for allowing us to use their articles for this task: Elsevier, Wiley, NPG, Rockefeller University Press, American Society for Biochemistry and Molecular Biology, American Society of Plant Biologists. We would like to thank Reverse Informatics and in particular Parthiban Srinivasan for their collaboration on the ACT. We especially thank the other BioCreative organizers for hosting the evaluation workshop, feedback and coordination. The OntoGene group (GS and FR) is partially supported by the Swiss National Science Foundation (grants 100014-118396/1 and 105315-130558/1) and by NITAS/TMS, Text Mining Services, Novartis Pharma AG, Basel, Switzerland. Additional contributors to their work are: Simon Clematide, Martin Romacker, Therese Vachon. Authors RL and GG (team 69) are supported by The Arizona Alzheimer's Disease Data Management Core under NIH grant NIA P30 AG-19610. The work at University of Aveiro (SM, team 70) was supported by "Fundacao para a Ciencia e a Tecnologia", under the research project PTDC/EIA-CCO/100541/2008. Team 73 (SK and WJW) is supported by the Intramural Research Program of the NIH, National Library of Medicine. Team 89 (SA and FLI) wants to acknowledge the support from the National Library of Medicine, grant numbers 5R01LM009836 to Hong Yu and 5R01LM010125 to Isaac Kohane. The work of team 90 was mainly supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC project BB/G013160/1, Automated Biological Event Extraction from the Literature for Drug Discovery), and the National Centre for Text Mining is supported by the UK Joint Information Systems Committee (JISC). Team 100 (ZL and RID) is grateful to other team members not listed as authors (M. Huang, A. Neveol, and Y. Yang) for their contribution to the tasks. Their work is supported by the Intramural Research Program of the NIH, National Library of Medicine. Team 104's (JFF and MAAN) work was funded within the framework of the Medical Genome Research Programme NGFN-Plus by the German Ministry of Education and Research (reference number: 01GS08170), and by the Helmholtz Alliance in Systems Biology (Germany). GC was supported by the Telethon foundation and AIRC. KN would like to acknowledge funding from NIH R01 grant number GM077402. DS would like to acknowledge the participation in the MyMiner project of Marc Depaule, Elodie Drula and Christophe Marcelle. The MyMiner project was supported by, MyoRes European Network of Excellence dedicated to study normal and aberrant muscle development function and repair and the French Association against Myopathies (AFM). NR 68 TC 50 Z9 50 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2011 VL 12 SU 8 AR S3 DI 10.1186/1471-2105-12-S8-S3 PG 31 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 940ZX UT WOS:000303932700003 PM 22151929 ER PT J AU Lu, ZY Kao, HY Wei, CH Huang, ML Liu, JC Kuo, CJ Hsu, CN Tsai, RTH Dai, HJ Okazaki, N Cho, HC Gerner, M Solt, I Agarwal, S Liu, FF Vishnyakova, D Ruch, P Romacker, M Rinaldi, F Bhattacharya, S Srinivasan, P Liu, HF Torii, M Matos, S Campos, D Verspoor, K Livingston, KM Wilbur, WJ AF Lu, Zhiyong Kao, Hung-Yu Wei, Chih-Hsuan Huang, Minlie Liu, Jingchen Kuo, Cheng-Ju Hsu, Chun-Nan Tsai, Richard Tzong-Han Dai, Hong-Jie Okazaki, Naoaki Cho, Han-Cheol Gerner, Martin Solt, Illes Agarwal, Shashank Liu, Feifan Vishnyakova, Dina Ruch, Patrick Romacker, Martin Rinaldi, Fabio Bhattacharya, Sanmitra Srinivasan, Padmini Liu, Hongfang Torii, Manabu Matos, Sergio Campos, David Verspoor, Karin Livingston, Kevin M. Wilbur, W. John TI The gene normalization task in BioCreative III SO BMC BIOINFORMATICS LA English DT Article ID BIOINFORMATICS; ONTOGENE; PROTEIN; MODELS; NAMES; II.5; TOOL; IB AB Background: We report the Gene Normalization (GN) challenge in BioCreative III where participating teams were asked to return a ranked list of identifiers of the genes detected in full-text articles. For training, 32 fully and 500 partially annotated articles were prepared. A total of 507 articles were selected as the test set. Due to the high annotation cost, it was not feasible to obtain gold-standard human annotations for all test articles. Instead, we developed an Expectation Maximization (EM) algorithm approach for choosing a small number of test articles for manual annotation that were most capable of differentiating team performance. Moreover, the same algorithm was subsequently used for inferring ground truth based solely on team submissions. We report team performance on both gold standard and inferred ground truth using a newly proposed metric called Threshold Average Precision (TAP-k). Results: We received a total of 37 runs from 14 different teams for the task. When evaluated using the gold-standard annotations of the 50 articles, the highest TAP-k scores were 0.3297 (k=5), 0.3538 (k=10), and 0.3535 (k=20), respectively. Higher TAP-k scores of 0.4916 (k=5, 10, 20) were observed when evaluated using the inferred ground truth over the full test set. When combining team results using machine learning, the best composite system achieved TAP-k scores of 0.3707 (k=5), 0.4311 (k=10), and 0.4477 (k=20) on the gold standard, representing improvements of 12.4%, 21.8%, and 26.6% over the best team results, respectively. Conclusions: By using full text and being species non-specific, the GN task in BioCreative III has moved closer to a real literature curation task than similar tasks in the past and presents additional challenges for the text mining community, as revealed in the overall team results. By evaluating teams using the gold standard, we show that the EM algorithm allows team submissions to be differentiated while keeping the manual annotation effort feasible. Using the inferred ground truth we show measures of comparative performance between teams. Finally, by comparing team rankings on gold standard vs. inferred ground truth, we further demonstrate that the inferred ground truth is as effective as the gold standard for detecting good team performance. C1 [Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Kao, Hung-Yu; Wei, Chih-Hsuan] Natl Cheng Kung Univ, Dept Comp Sci & Informat Engn, Tainan 70101, Taiwan. [Huang, Minlie; Liu, Jingchen] Tsinghua Univ, Dept Comp Sci & Technol, Beijing 100084, Peoples R China. [Kuo, Cheng-Ju; Hsu, Chun-Nan; Dai, Hong-Jie] Acad Sinica, Inst Informat Sci, Taipei 115, Taiwan. [Hsu, Chun-Nan] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Tsai, Richard Tzong-Han] Yuan Ze Univ, Dept Comp Sci & Engn, Chungli, Taiwan. [Dai, Hong-Jie] Natl Tsing Hua Univ, Dept Comp Sci, Hsinchu 30043, Taiwan. [Okazaki, Naoaki] Univ Tokyo, Interfac Initiat Informat Studies, Tokyo 1138654, Japan. [Cho, Han-Cheol] Univ Tokyo, Grad Sch Informat Sci & Technol, Tokyo 1138654, Japan. [Gerner, Martin] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England. [Solt, Illes] Budapest Univ Technol & Econ, Dept Telecommun & Media Informat, H-1117 Budapest, Hungary. [Agarwal, Shashank; Liu, Feifan] Univ Wisconsin, Milwaukee, WI 53201 USA. [Vishnyakova, Dina] Univ Geneva, Div Med Informat Sci, BiTem Grp, CH-1211 Geneva 4, Switzerland. [Ruch, Patrick] Univ Appl Sci, Dept Informat Sci, BiTeM Grp, Geneva, Switzerland. [Romacker, Martin] Novartis AG, NITAS TMS, Text Min Serv, Basel, Switzerland. [Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, Zurich, Switzerland. [Bhattacharya, Sanmitra; Srinivasan, Padmini] Univ Iowa, Dept Comp Sci, Iowa City, IA 52242 USA. [Liu, Hongfang] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Torii, Manabu] Georgetown Univ, Med Ctr, Lab Text Intelligence Biomed, Washington, DC 20057 USA. [Matos, Sergio; Campos, David] Univ Aveiro, DETI IEETA, P-3810193 Aveiro, Portugal. [Verspoor, Karin; Livingston, Kevin M.] Univ Colorado, Sch Med, Ctr Computat Pharmacol, Aurora, CO USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov; wilbur@ncbi.nlm.nih.gov RI Dai, Hong-Jie/C-2526-2013; Campos, David/N-2461-2013; Matos, Sergio/G-4941-2010; Verspoor, Karin/G-6034-2016; Vishnyakova, Dina/M-5339-2015; OI Dai, Hong-Jie/0000-0002-1516-7255; Campos, David/0000-0002-3448-2111; Matos, Sergio/0000-0003-1941-3983; Verspoor, Karin/0000-0002-8661-1544; Vishnyakova, Dina/0000-0001-9101-5993; Ruch, Patrick/0000-0002-3374-2962; Torii, Manabu/0000-0002-4825-0696; Rinaldi, Fabio/0000-0001-5718-5462 FU MEXT; (JST), Japan; University of Manchester; Alexander-von-Humboldt Stiftung; National Library of Medicine [5R01LM009836, 5R01LM010125]; European Union [217139]; Swiss National Science Foundation [100014-118396/1, 105315-130558/1]; NITAS/TMS; Text Mining Services; Novartis Pharma AG; Basel, Switzerland; NIH [1-R01-LM009959-01A1, 3T15 LM009451-03S1, 5R01 LM010120-02, 5R01 LM008111-05, 5R01 GM083649-03]; NSF [0845523]; Portuguese Foundation for Science and Technology [PTDC/EIA-CCO/100541/2008] FX The organizers would like to thank Lynette Hirschman for her helpful discussion and feedback on the earlier version of this paper. Zhiyong Lu and W. John Wilbur were supported by the Intramural Research Program of the NIH, National Library of Medicine. For team 93, this was a collaborative work with Rune Saetre, Sampo Pyysalo, Tomoko Ohta, and Jun'ichi Tsujii, supported by Grants-in-Aid for Scientific Research on Priority Areas (MEXT) and for Solution-Oriented Research for Science and Technology (JST), Japan. The work of team 68 was performed in collaboration with Jorg Hakenberg, and was funded by the University of Manchester (for MG) and the Alexander-von-Humboldt Stiftung (for IS). Team 89 would like to thank Zuofeng Li for developing the genetic sequence based gene normalizer and acknowledge the support from the National Library of Medicine, grant numbers 5R01LM009836 to Hong Yu and 5R01LM010125 to Isaac Kohane. The Bibliomics and Text Mining (BiTeM, http://eagl.unige.ch/bitem/) group (Team 80) was supported by the European Union's FP7 (Grant DebugIT # 217139). Additional contributors to the work of Team 80: Julien Gobeill, Emilie Pasche, Douglas Teodoro, Anne-Lise Veuthey and Arnaud Gaudinat. The OntoGene group (Team 65) was partially supported by the Swiss National Science Foundation (grants 100014-118396/1 and 105315-130558/1) and by NITAS/TMS, Text Mining Services, Novartis Pharma AG, Basel, Switzerland. Additional contributors to the work of Team 65: Gerold Schneider, Simon Clematide, and Therese Vachon. Team 97 was supported by NIH 1-R01-LM009959-01A1 and NSF CAREER 0845523. Team 78 would like to thank Aditya K. Sehgal for his valuable guidance with this work. Team 70 was partially supported by the Portuguese Foundation for Science and Technology (research project PTDC/EIA-CCO/100541/2008). Team 65 would like to thank William A. Baumgartner Jr., Kevin Bretonnel Cohen, Helen L. Johnson, Christophe Roeder, Lawrence E. Hunter, and all the members of the Center for Computational Pharmacology at the University of Colorado Denver, supported by NIH grants 3T15 LM009451-03S1 to K. L., 5R01 LM010120-02 to K. V., and 5R01 LM008111-05 and 5R01 GM083649-03 to L. H. All the authors would like to thank all the annotators who produced the gold-standard annotations. NR 45 TC 46 Z9 49 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2011 VL 12 SU 8 AR S2 DI 10.1186/1471-2105-12-S8-S2 PG 19 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 940ZX UT WOS:000303932700002 PM 22151901 ER PT J AU Shin, J Epperson, K Yanjanin, NM Albus, J Borgenheimer, L Bott, N Brennan, E Castellanos, D Cheng, M Clark, M Devany, M Ensslin, C Farivari, N Fernando, S Gabriel, L Gallardo, R Castleman, M Gutierrez, O Herschel, A Hodge, S Horst, A Howard, M James, E Jones, L Kearns, M Kelly, M Kim, C Kiser, K Klazura, G Knoedler, C Kolbus, E Lange, L Lee, J Li, E Lu, W Luttrell, A Ly, E McKeough, K McSorley, B Miller, C Mitchell, S Moon, A Moser, K O'Brien, S Olivieri, P Patzwahl, A Pereira, M Pymento, C Ramelb, E Ramos, B Raya, T Riney, S Roberts, G Robertshaw, M Rudolf, F Rund, S Sansone, S Schwartz, L Shay, R Siu, E Spear, T Tan, C Truong, M Uddin, M VanTrieste, J Veloz, O White, E Porter, FD Haldar, K AF Shin, Jenny Epperson, Katrina Yanjanin, Nicole M. Albus, Jennifer Borgenheimer, Laura Bott, Natalie Brennan, Erin Castellanos, Daniel Cheng, Melissa Clark, Michael Devany, Margaret Ensslin, Courtney Farivari, Nina Fernando, Shanik Gabriel, Lauren Gallardo, Rani Castleman, Moriah Gutierrez, Olimpia Herschel, Allison Hodge, Sarah Horst, Anne Howard, Mary James, Evan Jones, Lindsey Kearns, Mary Kelly, Mary Kim, Christine Kiser, Kinzie Klazura, Gregory Knoedler, Chris Kolbus, Emily Lange, Lauren Lee, Joan Li, Eileena Lu, Wei Luttrell, Andrew Ly, Emily McKeough, Katherine McSorley, Brianna Miller, Catherine Mitchell, Sean Moon, Abbey Moser, Kevin O'Brien, Shane Olivieri, Paula Patzwahl, Aaron Pereira, Marie Pymento, Craig Ramelb, Erin Ramos, Bryce Raya, Teresa Riney, Stephen Roberts, Geoff Robertshaw, Mark Rudolf, Frannie Rund, Samuel Sansone, Stephanie Schwartz, Lindsay Shay, Ryan Siu, Edwin Spear, Timothy Tan, Catherine Marisa Truong Uddin, Mairaj VanTrieste, Jennifer Veloz, Omar White, Elizabeth Porter, Forbes D. Haldar, Kasturi TI Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C SO PLOS ONE LA English DT Article AB Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease. C1 [Shin, Jenny; Epperson, Katrina; Haldar, Kasturi] Univ Notre Dame, Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA. [Yanjanin, Nicole M.; Porter, Forbes D.] NICHD, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD USA. [Albus, Jennifer; Borgenheimer, Laura; Bott, Natalie; Brennan, Erin; Castellanos, Daniel; Cheng, Melissa; Clark, Michael; Devany, Margaret; Ensslin, Courtney; Farivari, Nina; Fernando, Shanik; Gabriel, Lauren; Gallardo, Rani; Castleman, Moriah; Gutierrez, Olimpia; Herschel, Allison; Hodge, Sarah; Horst, Anne; Howard, Mary; James, Evan; Jones, Lindsey; Kearns, Mary; Kelly, Mary; Kim, Christine; Kiser, Kinzie; Klazura, Gregory; Knoedler, Chris; Kolbus, Emily; Lange, Lauren; Lee, Joan; Li, Eileena; Lu, Wei; Luttrell, Andrew; Ly, Emily; McKeough, Katherine; McSorley, Brianna; Miller, Catherine; Mitchell, Sean; Moon, Abbey; Moser, Kevin; O'Brien, Shane; Olivieri, Paula; Patzwahl, Aaron; Pereira, Marie; Pymento, Craig; Ramelb, Erin; Ramos, Bryce; Raya, Teresa; Riney, Stephen; Roberts, Geoff; Robertshaw, Mark; Rudolf, Frannie; Rund, Samuel; Sansone, Stephanie; Schwartz, Lindsay; Shay, Ryan; Siu, Edwin; Spear, Timothy; Tan, Catherine; Marisa Truong; Uddin, Mairaj; VanTrieste, Jennifer; Veloz, Omar; White, Elizabeth] NPC Consortium Community Based Assessment Patient, Cape Town, South Africa. RP Shin, J (reprint author), Univ Notre Dame, Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA. EM khaldar@nd.edu RI Haldar, Kasturi/C-6685-2014; OI Rund, Samuel/0000-0002-1701-7787; Mitchell, Sean/0000-0002-0584-3256 FU University of Notre Dame; NICHD; Office of Rare Diseases; Dana's Angels Research Trust FX The work was supported in part by funds to KH (start-up funds from the University of Notre Dame), to FDP (intramural research program of NICHD and via a Bench to Bedside Grant from the Office of Rare Diseases), and to NY (Ara Parseghian Medical Research Foundation, http://www.parseghian.org/, and Dana's Angels Research Trust, www.DanasAngels.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 6 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 3 PY 2011 VL 6 IS 10 AR e23666 DI 10.1371/journal.pone.0023666 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834EU UT WOS:000295943000001 PM 21984891 ER PT J AU Loeffler, PA Cuneo, MJ Mueller, GA DeRose, EF Gabel, SA London, RE AF Loeffler, Paul A. Cuneo, Matthew J. Mueller, Geoffrey A. DeRose, Eugene F. Gabel, Scott A. London, Robert E. TI Structural studies of the PARP-1 BRCT domain SO BMC STRUCTURAL BIOLOGY LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; DNA-REPAIR; FHA DOMAIN; XRCC1; BINDING; INTERACTS; PROTEIN; CELLS; RECOGNITION; ACTIVATION AB Background: Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the first proteins localized to foci of DNA damage. Upon activation by encountering nicked DNA, the PARP-1 mediated trans-poly(ADP-ribosyl)ation of DNA binding proteins occurs, facilitating access and accumulation of DNA repair factors. PARP-1 also auto (ADP-ribosyl)ates its central BRCT-containing domain forming part of an interaction site for the DNA repair scaffolding protein X-ray cross complementing group 1 protein (XRCC1). The co-localization of XRCC1, as well as bound DNA repair factors, to sites of DNA damage is important for cell survival and genomic integrity. Results: Here we present the solution structure and biophysical characterization of the BRCT domain of rat PARP-1. The PARP-1 BRCT domain has the globular alpha/beta fold characteristic of BRCT domains and has a thermal melting transition of 43.0 degrees C. In contrast to a previous characterization of this domain, we demonstrate that it is monomeric in solution using both gel-filtration chromatography and small-angle X-ray scattering. Additionally, we report that the first BRCT domain of XRCC1 does not interact significantly with the PARP-1 BRCT domain in the absence of ADP-ribosylation. Moreover, none of the interactions with other longer PARP-1 constructs which previously had been demonstrated in a pull-down assay of mammalian cell extracts were detected. Conclusions: The PARP-1 BRCT domain has the conserved BRCT fold that is known to be an important protein: protein interaction module in DNA repair and cell signalling pathways. Data indicating no significant protein: protein interactions between PARP-1 and XRCC1 likely results from the absence of poly(ADP-ribose) in one or both binding partners, and further implicates a poly(ADP-ribose)-dependent mechanism for localization of XRCC1 to sites of DNA damage. C1 [Cuneo, Matthew J.; Mueller, Geoffrey A.; DeRose, Eugene F.; Gabel, Scott A.; London, Robert E.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Loeffler, Paul A.] Sam Houston State Univ, Dept Chem, Huntsville, TX 77340 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov OI Cuneo, Matthew/0000-0002-1475-6656 FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]; National Institutes of Health, NIEHS [HHSN273200700046U]; National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES050111]; Sam Houston State University; Texas State University System; Faculty Development Leave grant FX The authors would like to thank the Drs. Lin Yang and Marc Allaire of the X9 beamline at the National Synchrotron Light Source at Brookhaven National Laboratory. Use of the X9 beamline is supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-98CH10886. E. F. D. is supported by National Institutes of Health, NIEHS, under Delivery Order HHSN273200700046U. This research was supported by Research Project Number Z01-ES050111 to REL in the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health and a Sam Houston State University, Texas State University System, Faculty Development Leave grant to PAL. NR 41 TC 14 Z9 14 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6807 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD OCT 3 PY 2011 VL 11 AR 37 DI 10.1186/1472-6807-11-37 PG 11 WC Biophysics SC Biophysics GA 833XQ UT WOS:000295919000001 PM 21967661 ER PT J AU van Deventer, HE Miller, WG Myers, GL Sakurabayashi, I Bachmann, LM Caudill, SP Dziekonski, A Edwards, S Kimberly, MM Korzun, WJ Leary, ET Nakajima, K Nakamura, M Shamburek, RD Vetrovec, GW Warnick, GR Remaley, AT AF van Deventer, Hendrick E. Miller, W. Greg Myers, Gary L. Sakurabayashi, Ikunosuke Bachmann, Lorin M. Caudill, Samuel P. Dziekonski, Andrzej Edwards, Selvin Kimberly, Mary M. Korzun, William J. Leary, Elizabeth T. Nakajima, Katsuyuki Nakamura, Masakazu Shamburek, Robert D. Vetrovec, George W. Warnick, G. Russell Remaley, Alan T. TI Non-HDL cholesterol shows improved accuracy for cardiovascular risk score classification compared to direct or calculated ldl cholesterol in a dyslipidemic population SO ACTA BIOQUIMICA CLINICA LATINOAMERICANA LA Spanish DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; APOLIPOPROTEIN-A-I; VASCULAR-DISEASE; ARTERY DISEASE; LIPID MEASURES; PLASMA; EVENTS; WOMEN; STANDARDIZATION AB Backgound: Our objective was to evaluate the accuracy of cardiovascular disease (CVD) risk score classification by direct LDL cholesterol (dLDL-C), calculated LDL cholesterol (cLDL-C), and non-HDL cholesterol (non-HDL-C) compared to classification by reference measurement procedures (RMPs) performed at the CDC. Methods: We examined 175 individuals, including 138 with CVD or conditions that may affect LDL-C measurement. dLDL-C measurements were performed using Denka, Kyowa, Sekisui, Serotec, Sysmex, UMA, and Wako reagents. cLDL-C was calculated by the Friedewald equation, using each manufacturer's direct HDL-C assay measurements, and total cholesterol and triglyceride measurements by Roche and Siemens (Advia) assays, respectively. Results: For participants with triglycerides <2.26 mmol/L (<200 mg/dL), the overall misclassification rate for the CVD risk score ranged from 5% to 17% for cLDL-C methods and 8% to 26% for dLDL-C methods when compared to the RMP. Only Wako dLDL-C had fewer misclassifications than its corresponding cLDL-C method (8% vs 17%; P < 0.05). Non-HDL-C assays misclassified fewer patients than dLDL-C for 4 of 8 methods (P < 0.05). For participants with triglycerides < 2.26 mmol/L (200 mg/dL) and < 4.52 mmol/L (< 400 mg/dL), dLDL-C methods, in general, performed better than cLDL-C methods, and non-HDL-C methods showed better correspondence to the RMP for CVD risk score than either dLDL-C or cLDL-C methods. Conclusions: Except for hypertriglyceridemic individuals, 7 of 8 dLDL-C methods failed to show improved CVD risk score classification over the corresponding cLDL-C methods. Non-HDL-C showed overall the best concordance with the RMP for CVD risk score classification of both normal and hypertriglyceridemic individuals. C1 [Remaley, Alan T.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Miller, W. Greg; Bachmann, Lorin M.; Dziekonski, Andrzej; Korzun, William J.; Vetrovec, George W.] Virginia Commonwealth Univ, Richmond, VA USA. [Myers, Gary L.; Caudill, Samuel P.; Edwards, Selvin; Kimberly, Mary M.] Ctr Dis Control Prevent, Atlanta, GA USA. [Sakurabayashi, Ikunosuke] Jichi Med Univ, Shimotsuke, Tochigi, Japan. [Leary, Elizabeth T.] Pacific Biomarkers & Pacific Biometr Res Fdn, Seattle, WA USA. [Nakajima, Katsuyuki] Otsuka Pharmaceut Co Ltd, Tokyo, Japan. [Nakamura, Masakazu] Osaka Med Ctr Hlth Sci & Promot, Osaka, Japan. [Warnick, G. Russell] Hlth Diagnost Lab, Richmond, VA USA. RP Remaley, AT (reprint author), NIH, Dept Lab Med, Bldg 10,Room 2C-433,10 Ctr Dr,MSC 1508, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov NR 37 TC 0 Z9 0 U1 1 U2 3 PU FEDERACION BIOQUIMICA PROVINCIA BUENOS AIRES PI LA PLATA, BUENOS AIRES PA CALLE 6, NO. 1344, 1900 LA PLATA, BUENOS AIRES, ARGENTINA SN 0325-2957 J9 ACTA BIOQUIM CLIN L JI Acta Bioquim. Clin. Latinoam. PD OCT-DEC PY 2011 VL 45 IS 4 BP 773 EP 784 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 975KY UT WOS:000306511400036 ER PT J AU Middeldorp, CM de Moor, MHM McGrath, LM Gordon, SD Blackwood, DH Costa, PT Terracciano, A Krueger, RF de Geus, EJC Nyholt, DR Tanaka, T Esko, T Madden, PAF Derringer, J Amin, N Willemsen, G Hottenga, JJ Distel, MA Uda, M Sanna, S Spinhoven, P Hartman, CA Ripke, S Sullivan, PF Realo, A Allik, J Heath, AC Pergadia, ML Agrawal, A Lin, P Grucza, RA Widen, E Cousminer, DL Eriksson, JG Palotie, A Barnett, JH Lee, PH Luciano, M Tenesa, A Davies, G Lopez, LM Hansell, NK Medland, SE Ferrucci, L Schlessinger, D Montgomery, GW Wright, MJ Aulchenko, YS Janssens, ACJW Oostra, BA Metspalu, A Abecasis, GR Deary, IJ Raikkonen, K Bierut, LJ Martin, NG Wray, NR van Duijn, CM Smoller, JW Penninx, BWJH Boomsma, DI AF Middeldorp, C. M. de Moor, M. H. M. McGrath, L. M. Gordon, S. D. Blackwood, D. H. Costa, P. T. Terracciano, A. Krueger, R. F. de Geus, E. J. C. Nyholt, D. R. Tanaka, T. Esko, T. Madden, P. A. F. Derringer, J. Amin, N. Willemsen, G. Hottenga, J-J Distel, M. A. Uda, M. Sanna, S. Spinhoven, P. Hartman, C. A. Ripke, S. Sullivan, P. F. Realo, A. Allik, J. Heath, A. C. Pergadia, M. L. Agrawal, A. Lin, P. Grucza, R. A. Widen, E. Cousminer, D. L. Eriksson, J. G. Palotie, A. Barnett, J. H. Lee, P. H. Luciano, M. Tenesa, A. Davies, G. Lopez, L. M. Hansell, N. K. Medland, S. E. Ferrucci, L. Schlessinger, D. Montgomery, G. W. Wright, M. J. Aulchenko, Y. S. Janssens, A. C. J. W. Oostra, B. A. Metspalu, A. Abecasis, G. R. Deary, I. J. Raikkonen, K. Bierut, L. J. Martin, N. G. Wray, N. R. van Duijn, C. M. Smoller, J. W. Penninx, B. W. J. H. Boomsma, D. I. TI The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depression ID GENOTYPE IMPUTATION; ANXIETY DISORDERS; 5-FACTOR MODEL; TWIN; POPULATION; HERITABILITY; METAANALYSIS; SAMPLE; SCHIZOPHRENIA; EPIDEMIOLOGY AB The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N = 8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N = 6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, similar to 0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other. Translational Psychiatry (2011) 1, e50; doi:10.1038/tp.2011.45; published online 18 October 2011 C1 [Middeldorp, C. M.; de Moor, M. H. M.; de Geus, E. J. C.; Willemsen, G.; Hottenga, J-J; Distel, M. A.; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Middeldorp, C. M.; de Moor, M. H. M.; de Geus, E. J. C.; Penninx, B. W. J. H.; Boomsma, D. I.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Middeldorp, C. M.] Univ Amsterdam, Acad Med Ctr, Dept Child & Adolescent Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Middeldorp, C. M.] GGZ inGeest VU Med Ctr, Dept Child & Adolescent Psychiat, Amsterdam, Netherlands. [McGrath, L. M.; Ripke, S.; Barnett, J. H.; Lee, P. H.; Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Human Genet Res, Boston, MA 02114 USA. [McGrath, L. M.; Ripke, S.; Barnett, J. H.; Lee, P. H.; Smoller, J. W.] Massachusetts Gen Hosp, Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Gordon, S. D.; Nyholt, D. R.; Hansell, N. K.; Medland, S. E.; Montgomery, G. W.; Wright, M. J.; Martin, N. G.; Wray, N. R.] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. [Blackwood, D. H.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Costa, P. T.; Terracciano, A.; Tanaka, T.; Ferrucci, L.; Schlessinger, D.] NIA, NIH, Baltimore, MD 21224 USA. [Krueger, R. F.; Derringer, J.] Univ Minnesota, Dept Psychol, Baltimore, MD USA. [Esko, T.; Metspalu, A.] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Esko, T.; Metspalu, A.] Estonian Bioctr, Tartu, Estonia. [Esko, T.; Metspalu, A.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Madden, P. A. F.; Heath, A. C.; Pergadia, M. L.; Agrawal, A.; Lin, P.; Grucza, R. A.; Bierut, L. J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Amin, N.; Aulchenko, Y. S.; Janssens, A. C. J. W.; van Duijn, C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Distel, M. A.; Penninx, B. W. J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Uda, M.; Sanna, S.] Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Spinhoven, P.; Penninx, B. W. J. H.] Leiden Univ, Dept Clin Psychol, Leiden, Netherlands. [Spinhoven, P.; Penninx, B. W. J. H.] Leiden Univ, Dept Psychiat, Leiden, Netherlands. [Hartman, C. A.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Ripke, S.; Palotie, A.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Realo, A.; Allik, J.] Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. [Widen, E.; Cousminer, D. L.; Palotie, A.] Univ Helsinki, FIMM, Helsinki, Finland. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Vasa Cent Hosp, Vaasa, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, A.] Univ Cent Hosp, Helsinki, Finland. [Barnett, J. H.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Luciano, M.; Davies, G.; Lopez, L. M.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Tenesa, A.] Western Gen Hosp, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Oostra, B. A.] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Abecasis, G. R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Raikkonen, K.] Univ Helsinki, Dept Psychol, SF-00100 Helsinki, Finland. [Penninx, B. W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. RP Middeldorp, CM (reprint author), Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM cm.middeldorp@psy.vu.nl RI Lopez, Lorna/F-7265-2010; Montgomery, Grant/B-7148-2008; Hansell, Narelle/A-4553-2016; Deary, Ian/C-6297-2009; Nyholt, Dale/C-8384-2013; terracciano, antonio/B-1884-2008; Aulchenko, Yurii/M-8270-2013; Lin, P/G-7702-2014; Medland, Sarah/C-7630-2013; Wray, Naomi/C-8639-2015; Allik, Juri/D-5609-2009; de Geus, Eco/M-9318-2015; Wright, Margaret/A-4560-2016; Realo, Anu/M-9524-2016; Luciano, Michelle/F-7277-2010; OI Montgomery, Grant/0000-0002-4140-8139; Hansell, Narelle/0000-0002-8229-9741; Aulchenko, Yurii/0000-0002-7899-1575; Medland, Sarah/0000-0003-1382-380X; Wray, Naomi/0000-0001-7421-3357; Allik, Juri/0000-0002-8358-4747; de Geus, Eco/0000-0001-6022-2666; Wright, Margaret/0000-0001-7133-4970; Luciano, Michelle/0000-0003-0935-7682; Eriksson, Johan/0000-0002-2516-2060; Middeldorp, Christel/0000-0002-6218-0428; Raikkonen, Katri/0000-0003-3124-3470 FU Wellcome Trust [076113, 89061/Z/09/Z, 089062/Z/09/Z]; Netherlands Scientific Organization Centre for Medical Systems Biology (NWO Genomics) [904-61-090, 904-61-193, 480-04-004, 400-05-717, 912-100-20]; Neuroscience Campus Amsterdam (NCA); EMGO+ Institute; European Union [EU/WLRT-2001-01254]; ZonMW [10-000-1002]; NIMH [RO1 MH059160, R01 MH-079799]; NESDA; NTR; NWO-SPI [56-464-1419]; Netherlands Organization for Scientific Research (NWO) (ZonMW) [31160008, VENI-016-115-035, 916-76-125]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613608]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health (NIH) [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951]; National Health and Medical Research Council (NHMRC); Australian Research Council; Netherlands Organization for Scientific Research (NWO) [480-05-003]; Erasmus MC; Netherlands Genomics Initiative (NGI); NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; NIH [AA13320, AA13321, DA12854, HHSN268200782096C, AA07728, AA07580, AA11998]; NIH from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U10AA008401]; National Institute on Drug Abuse (NIDA); NIH from the National Cancer Institute [P01CA89392]; NIH, National Institute on Aging [NO1-AG-1-2109]; Academy of Finland [120315, 129287, 1129457, 1216965, 120386, 125876]; European Science Foundation (EuroSTRESS); Signe and Ane Gyllenberg foundation; Research Into Ageing; Help the Aged/Age Concern (The Disconnected Mind); Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC); cross-council Lifelong Health and Wellbeing Initiative; eDIKT initiative; ECOGENE [205419]; Estonian Government [SF0180142s08]; EU; Estonian Ministry of Science and Education [SF0180029s08]; Parke-Davis Exchange Fellowship; [201413 ENGAGE]; [212111 BBMRI] FX This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the WTCCC data is available from http://www.wtccc.org.uk. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. NESDA/NTR: Funding support was provided by the Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, 912-100-20) Centre for Medical Systems Biology (NWO Genomics), the Neuroscience Campus Amsterdam (NCA) and the EMGO+ Institute; the European Union (EU/WLRT-2001-01254), ZonMW (Geestkracht program, 10-000-1002), NIMH (RO1 MH059160) and matching funds from participating institutes in NESDA and NTR. The NTR controls in MDD2000+ were genotyped in the Genomics platform (certified service provider (CSPro(R)) for Illumina) at the LIFE and BRAIN Center, Bonn (funded by NWO-SPI 56-464-1419). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the NWO (480-05-003). MHM de Moor and CM Middeldorp are financially supported by the Netherlands Organization for Scientific Research (NWO) (ZonMW Addiction program, grant 31160008, VENI-016-115-035 and VENI grant 916-76-125). MDD2000+/QIMR: Funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675,496739, 552485, 552498, 613608), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951). A portion of the genotyping on which this study was based (Illumina 370K scans on 4300 individuals) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). GW Montgomery is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. NRWray and DR Nyholt are supported by the Australian Research Council Future Fellowship Scheme. The ERF study was supported by grants from The Netherlands Organization for Scientific Research (NWO), Erasmus MC and the Netherlands Genomics Initiative (NGI)-sponsored Center of Medical Systems Biology (CMSB). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963).; Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The Collaborative Study on the Genetics of Alcoholism (COGA) Principal Investigators: B Porjesz, V Hesselbrock, H Edenberg, L Bierut, includes 10 different centers: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr., T Foroud); University of Iowa (S Kuperman, J Kramer); SUNY Downstate (B Porjesz); Washington University in St Louis (L Bierut, A Goate, J Rice, K Bucholz); University of California at San Diego (M Schuckit); Rutgers University (J Tischfield); Southwest Foundation (L Almasy), Howard University (R Taylor) and Virginia Commonwealth University (D Dick). A Parsian and M Reilly are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Lead investigators directing data collection are Laura Bierut, Naomi Breslau, Dorothy Hatsukami and Eric Johnson. We thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. In memory of Theodore Reich, founding Principal Investigator of COGEND, we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. COGEND is supported by the NIH grant P01CA89392 from the National Cancer Institute. SardiNIA: We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. Funding was provided by the National Institute on Aging, NIH contract NO1-AG-1-2109 to the SardiNIA ('ProgeNIA') team. HBCS: We acknowledge financial support from the Academy of Finland (grant no. 120315 and 129287 to EW, 1129457 and 1216965 to KR, 120386 and 125876 to JGE), the European Science Foundation (EuroSTRESS), the Wellcome Trust (grant no. 89061/Z/09/Z and 089062/Z/09/Z) and the Signe and Ane Gyllenberg foundation. NAG/IRPG: This study is supported by NIH grants DA12854 (to PAFM), AA07728, AA07580, AA11998, AA13320 and AA13321 (to ACH); and grants from the Australian National Health and Medical Research Council; MLP is supported by DA019951. LBC36: We thank David Liewald and Paul Redmond for technical assistance; the study Secretary Paula Davies; Alan Gow, Michelle Taylor, Janie Corley, Caroline Brett and Caroline Cameron for data collection and data entry; nurses and staff at the Wellcome Trust Clinical Research Facility, where subjects were tested and at the genotyping was performed; staff at the Lothian Health Board and staff at the SCRE Centre, University of Glasgow. The research was supported by a program grant from Research Into Ageing.; The research continues with program grants from Help the Aged/Age Concern (The Disconnected Mind). GWAS funding awarded by the Biotechnology and Biological Sciences Research Council (BBSRC) to IJD and AT. ML is a Royal Society of Edinburgh/Lloyds TSB Foundation for Scotland Personal Research Fellow. The study was conducted within the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, supported by the (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative. This work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). The ECDF is partially supported by the eDIKT initiative (http://www.edikt.org.uk). BLSA: We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. We thank Robert McCrae. EGPUT: AM and TE received support from FP7 grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (no. 205419, EBC)). AM and TE also received targeted financing from Estonian Government SF0180142s08 and by EU through the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. The genotyping of the Estonian Genome Project samples was performed in Estonian Biocentre Genotyping Core Facility, AM and TE thank Mari Nelis and Viljo Soo for their contributions. A Realo and J Allik are supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08). STEP-BD: JH Barnett was funded by the Parke-Davis Exchange Fellowship. JW Smoller and LM McGrath were supported in part by NIMH grant R01 MH-079799 (Dr Smoller, PI). NR 62 TC 26 Z9 27 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2011 VL 1 AR e50 DI 10.1038/tp.2011.45 PG 8 WC Psychiatry SC Psychiatry GA 971PM UT WOS:000306216300007 PM 22833196 ER PT J AU Terracciano, A Esko, T Sutin, AR de Moor, MHM Meirelles, O Zhu, G Tanaka, T Giegling, I Nutile, T Realo, A Allik, J Hansell, NK Wright, MJ Montgomery, GW Willemsen, G Hottenga, JJ Friedl, M Ruggiero, D Sorice, R Sanna, S Cannas, A Raikkonen, K Widen, E Palotie, A Eriksson, JG Cucca, F Krueger, RF Lahti, J Luciano, M Smoller, JW van Duijn, CM Abecasis, GR Boomsma, DI Ciullo, M Costa, PT Ferrucci, L Martin, NG Metspalu, A Rujescu, D Schlessinger, D Uda, M AF Terracciano, A. Esko, T. Sutin, A. R. de Moor, M. H. M. Meirelles, O. Zhu, G. Tanaka, T. Giegling, I. Nutile, T. Realo, A. Allik, J. Hansell, N. K. Wright, M. J. Montgomery, G. W. Willemsen, G. Hottenga, J-J Friedl, M. Ruggiero, D. Sorice, R. Sanna, S. Cannas, A. Raikkonen, K. Widen, E. Palotie, A. Eriksson, J. G. Cucca, F. Krueger, R. F. Lahti, J. Luciano, M. Smoller, J. W. van Duijn, C. M. Abecasis, G. R. Boomsma, D. I. Ciullo, M. Costa, P. T., Jr. Ferrucci, L. Martin, N. G. Metspalu, A. Rujescu, D. Schlessinger, D. Uda, M. TI Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE catenin cadherin-associated protein alpha 2 (CTNNA2); excitement-seeking; genome-wide association (GWA); impulsivity; sensation-seeking ID ALPHA-N-CATENIN; NETHERLANDS TWIN REGISTER; SENSATION SEEKING; PERSONALITY-TRAITS; BIPOLAR DISORDER; 5-FACTOR MODEL; IMPULSIVITY; RISK; GENE; SCHIZOPHRENIA AB The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N = 7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P = 2 x 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed a-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N = 5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders. Translational Psychiatry (2011) 1, e49; doi:10.1038/tp.2011.42; published online 18 October 2011 C1 [Terracciano, A.; Sutin, A. R.; Meirelles, O.; Costa, P. T., Jr.; Ferrucci, L.; Schlessinger, D.] NIA, NIH, US Dept HHS, Baltimore, MD 21224 USA. [Esko, T.; Realo, A.; Allik, J.; Metspalu, A.] Univ Tartu, EE-50090 Tartu, Estonia. [Esko, T.; Metspalu, A.] Estonian Bioctr, Tartu, Estonia. [de Moor, M. H. M.; Willemsen, G.; Hottenga, J-J; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Zhu, G.; Hansell, N. K.; Wright, M. J.; Montgomery, G. W.; Martin, N. G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Giegling, I.; Friedl, M.; Rujescu, D.] Univ Munich, Dept Psychiat, D-8000 Munich, Germany. [Nutile, T.; Ruggiero, D.; Sorice, R.; Ciullo, M.] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. [Sanna, S.; Cannas, A.; Cucca, F.; Uda, M.] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Raikkonen, K.; Lahti, J.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Widen, E.; Palotie, A.] Univ Helsinki, FIMM, Helsinki, Finland. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Krueger, R. F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Luciano, M.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Human Genet Res, Boston, MA 02114 USA. [Smoller, J. W.] Massachusetts Gen Hosp, Neurodev Genet Unit, Boston, MA 02114 USA. [van Duijn, C. M.] ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands. [Abecasis, G. R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Terracciano, A (reprint author), NIA, NIH, US Dept HHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Terraccianoa@mail.nih.gov RI Wright, Margaret/A-4560-2016; ruggiero, daniela/K-5638-2016; Realo, Anu/M-9524-2016; Luciano, Michelle/F-7277-2010; terracciano, antonio/B-1884-2008; Allik, Juri/D-5609-2009; Montgomery, Grant/B-7148-2008; Hansell, Narelle/A-4553-2016; OI Wright, Margaret/0000-0001-7133-4970; ruggiero, daniela/0000-0003-3898-7827; Luciano, Michelle/0000-0003-0935-7682; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Costa, Paul/0000-0003-4375-1712; NUTILE, TERESA/0000-0001-7062-8352; Allik, Juri/0000-0002-8358-4747; Montgomery, Grant/0000-0002-4140-8139; Hansell, Narelle/0000-0002-8229-9741; Lahti, Jari/0000-0002-4310-5297; Martin, Nicholas/0000-0003-4069-8020 FU NIH, National Institute on Aging; Estonian Ministry of Science and Education [SF0180029s08]; European Social Fund [3-8.2/60]; Estonian Government [SF0180142s08]; European Union; Beyond Blue; Borderline Personality Disorder Research Foundation; National Health and Medical Research Council [389891]; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; [201413]; [212111]; [245536] FX We thank study subjects for their participation as well as everybody involved in each of the participating studies. EGCUT authors want to acknowledge EGCUT personnel, especially Merli Hass, Viljo Soo and Mari Nelis. EGCUT data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. Cilento authors acknowledge Dr Maria Enza Amendola for the test administration and thank the personnel working in the organization of the study in the villages. QIMR thanks study participants and acknowledges Nathan Gillespie for discussion on study design related to NEO collection; Marisa Grimmer, Romana Leisser and Kim Eldridge for overseeing data collection; Anjali Henders, Megan Campbell, Lisa Bowdler, Steven Crooks and staff of the Molecular Epidemiology Laboratory for sample processing and preparation; and Harry Beeby, David Smyth and Daniel Park for IT support. We acknowledge Drs Dale R Nyholt and Scott Gordon for their substantial efforts involving the QC and preparation of the GWA data sets and Dr Sarah Medland for undertaking the imputation of the GWAS data and subsequent preparation for analyses. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Anu Realo and Juri Allik were supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08) and by a Primus Grant (3-8.2/60) from the European Social Fund. TE and AM received support from FP7 Grants (201413, 212111, 245536). TE and AM also received targeted financing from Estonian Government SF0180142s08 and from the European Union through the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. QIMR received support from Beyond Blue and the Borderline Personality Disorder Research Foundation. Genotyping was funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891). Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation and Emil Aaltonen Foundation. NR 72 TC 20 Z9 20 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2011 VL 1 AR e49 DI 10.1038/tp.2011.42 PG 8 WC Psychiatry SC Psychiatry GA 971PM UT WOS:000306216300006 PM 22833195 ER PT J AU Morgan, DL Nyska, A Harbo, SJ Grumbein, SL Dill, JA Roycroft, JH Kissling, GE Cesta, MF AF Morgan, Daniel L. Nyska, Abraham Harbo, Sam Jens Grumbein, Sondra L. Dill, Jeffrey A. Roycroft, Joseph H. Kissling, Grace E. Cesta, Mark F. TI Multisite Carcinogenicity and Respiratory Toxicity of Inhaled 1-Bromopropane in Rats and Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE 1-bromopropane; n-propyl bromide; inhalation; carcinogenesis; Splendore Hoeppli; rats; mice ID SPLENDORE-HOEPPLI PHENOMENON; LAYER DEPLETING SOLVENTS; INHALATION EXPOSURE; BOTRYOMYCOSIS; TESTS; GLUTATHIONE AB Two-year 1-bromopropane (1-BP) inhalation studies were conducted because of the potential for widespread exposure, the lack of chronic toxicity and carcinogenicity data, and the known carcinogenicity of structurally related compounds. Male and female F344/N rats and B6C3F1/N mice were exposed by inhalation to 0, 62.5 (mice only), 125, 250, or 500 (rats only) ppm 1-BP for 6 hr/day, 5 days/week for 105 weeks. Exposure of male and female rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma of the epididymis was statistically significantly increased at 500 ppm, but the biological significance of this common lesion is unclear. Incidences of pancreatic islet adenoma in male rats were significantly increased at all concentrations relative to concurrent controls but were within the historical control range for inhalation studies. There was no evidence of carcinogenic activity of 1-BP in male B6C3F1 mice; however, significantly increased incidences of alveolar/bronchiolar neoplasms of the lung were present in female mice. Exposure to 1-BP also resulted in increased incidences of nonneoplastic lesions in the nose of rats and mice, the larynx of rats and male mice, the trachea of female rats and male and female mice, and the lungs of mice. Inflammatory lesions with Splendore Hoeppli (S-H) material were present primarily in the nose and skin of exposed male and female rats, indicating that 1-BP caused immunosuppression. C1 [Morgan, Daniel L.; Roycroft, Joseph H.; Kissling, Grace E.; Cesta, Mark F.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Nyska, Abraham] Tel Aviv Univ, Timrat & Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Harbo, Sam Jens; Grumbein, Sondra L.; Dill, Jeffrey A.] Battelle Toxicol NW, Richland, WA USA. RP Morgan, DL (reprint author), NIEHS, Natl Toxicol Program, Mail Drop IF-00,POB 12233, Res Triangle Pk, NC 27709 USA. EM morgan3@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences (NIEHS) FX This research was carried out under the auspices of the National Toxicology Program and supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS). The authors wish to thank Drs. Cunny and Dixon for critical review of this article. The statements, opinions, and conclusions contained herein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH, or U.S. government. NR 39 TC 3 Z9 5 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2011 VL 39 IS 6 BP 938 EP 948 DI 10.1177/0192623311416374 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA 961IO UT WOS:000305458300004 PM 21859883 ER PT J AU Duma, D Fernandes, D Bonini, MG Stadler, K Mason, RP Assreuy, J AF Duma, Danielle Fernandes, Daniel Bonini, Marcelo G. Stadler, Krisztian Mason, Ronald P. Assreuy, Jamil TI NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Nitric oxide; Sepsis; NOS-1; Skeletal muscle; Vascular hyporesponsiveness ID NITRIC-OXIDE SYNTHASE; RAT SMALL-INTESTINE; IN-OVINE SEPSIS; SKELETAL-MUSCLE; SEPTIC SHOCK; ENDOTOXIN-SHOCK; NEURONAL NOS; L-ARGININE; KAPPA-B; INHIBITION AB Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1(-/-)mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1(-/)-mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1. (C) 2011 Elsevier B.V. All rights reserved. C1 [Assreuy, Jamil] Univ Fed Santa Catarina, Dept Pharmacol, BR-88040900 Florianopolis, SC, Brazil. [Duma, Danielle] Natl Inst Environm Hlth Sci, Lab Signal Transduct, Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. [Bonini, Marcelo G.] Univ Illinois, Coll Med, Cardiol Sect, Chicago, IL USA. [Bonini, Marcelo G.] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL USA. [Stadler, Krisztian] Louisiana State Univ, Pennington Biomed Res Ctr, Oxidat Stress & Dis Lab, Baton Rouge, LA 70808 USA. RP Assreuy, J (reprint author), Univ Fed Santa Catarina, Dept Pharmacol, Block D CCB,Campus Trindade, BR-88040900 Florianopolis, SC, Brazil. EM assreuy@farmaco.ufsc.br RI Fernandes, Daniel/B-7147-2012 OI Fernandes, Daniel/0000-0002-8935-4176 FU CNPq; PRONEX; CAPES; FAPESC (Brazil); National Institute of Environmental Health Sciences/NIH (USA) FX We gratefully acknowledge the technical assistance of Adriane S. Madeira. We thank Dr. J. B. Calixto (Universidade Federal de Santa Catarina, Brazil) for the use of some of his equipment. Cristalia Pharmaceutical Industries (Sao Paulo, SP, Brazil) is gratefully acknowledged for the gift of heparin. This work was supported by CNPq, PRONEX, CAPES and FAPESC (Brazil) and the intramural research program of the National Institute of Environmental Health Sciences/NIH (USA). The authors declare no conflict of interest. NR 49 TC 8 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD OCT 1 PY 2011 VL 668 IS 1-2 BP 285 EP 292 DI 10.1016/j.ejphar.2011.05.065 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 929GA UT WOS:000303048100037 PM 21651902 ER PT J AU Wang, Q Li, DR Zhang, W Tang, BJ Li, QDQT Li, L AF Wang, Qi Li, Danrong Zhang, Wei Tang, Bujian Li, Qingdi Quentin Li, Li TI Evaluation of proteomics-identified CCL18 and CXCL1 as circulating tumor markers for differential diagnosis between ovarian carcinomas and benign pelvic masses SO INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS LA English DT Article DE Ovarian cancer; Benign pelvic masses; Diagnosis; Biomarkers; CCL18; CXCL1; Serum proteomics; Protein expression ID ACTIVATION-REGULATED CHEMOKINE; COLONY-STIMULATING FACTOR; MELANOCYTE TRANSFORMATION; HEPATOCELLULAR-CARCINOMA; CANCER BIOMARKERS; SERUM BIOMARKERS; PROTEIN; EXPRESSION; PATTERN; PROGRESSION AB A lack of sensitive and specific tumor markers for early diagnosis and treatment is a major cause for the high mortality rate of ovarian cancer. The purpose of this study was to identify potential proteomics-based biomarkers useful for the differential diagnosis between ovarian cancer and benign pelvic masses. Serum samples from 41 patients with ovarian cancer, 32 patients with benign pelvic masses, and 41 healthy female blood donors were examined, and proteomic profiling of the samples was assessed by surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy (MS). A confirmatory study was also conducted with serum specimens from 58 patients with ovarian carcinoma, 37 patients with benign pelvic masses, and 48 healthy women. A classification tree was established using Biomarker Pattern Software. Six differentially expressed proteins (APP, CA 125, CCL18, CXCL1, IL-8, and ITIH4) were separated by high-performance liquid chromatography and identified by matrix-assisted laser desorption/ionization (MALDI)-MS/MS and database searches. Two of the proteins overexpressed in ovarian cancer patients, chemokine CC2 motif ligand 18 (CCL18) and chemokine CXC motif ligand 1 (CXCL1), were automatically selected in a multivariate predictive model. These two protein biomarkers were then validated and evaluated by enzyme-linked immunosorbent assay (ELISA) in 535 serum specimens (130 ovarian cancer, 64 benign ovarian masses, 36 lung cancer, 60 gastric cancer, 55 nasopharyngeal carcinoma, 48 hepatocellular carcinoma, and 142 healthy women). The combined use of CCL18 and CXCL1 as biomarkers for ovarian cancer had a sensitivity of 92% and a specificity of 97%. The multivariate ELISA analysis of the two putative markers in combination with CA 125 resulted in a sensitivity of 99% for healthy women and 94% for benign pelvic masses, and a specificity of 92% for both groups; these values were significantly higher than those obtained with CA 125 alone (p<0.05). We conclude that serum CCL18 and CXCL1 are potentially useful as novel circulating tumor markers for the differential diagnosis between ovarian cancer and benign ovarian masses. C1 [Wang, Qi; Li, Danrong; Zhang, Wei; Tang, Bujian; Li, Li] Guangxi Med Univ, Canc Hosp, Dept Gynecol Oncol, Nanning 530021, Guangxi, Peoples R China. [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. RP Li, L (reprint author), Guangxi Med Univ, Canc Hosp, Nanning 530021, GX, Peoples R China. EM liquenti@mail.nih.gov; lili_temp@hotmail.com FU Provincial Research Project Funding of Guangxi, China [GSR 9817101] FX This study was supported by a grant from the Provincial Research Project Funding of Guangxi, China (No. GSR 9817101). NR 44 TC 15 Z9 21 U1 0 U2 5 PU WICHTIG EDITORE PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 0393-6155 J9 INT J BIOL MARKER JI Int. J. Biol. Markers PD OCT-DEC PY 2011 VL 26 IS 4 BP 262 EP 273 DI 10.5301/JBM.2011.8616 PG 12 WC Biotechnology & Applied Microbiology; Oncology SC Biotechnology & Applied Microbiology; Oncology GA 927BU UT WOS:000302882700009 PM 21928244 ER PT J AU Kratochwil, C Lopez-Benitez, R Mier, W Haufe, S Isermann, B Kauczor, HU Choyke, PL Haberkorn, U Giesel, FL AF Kratochwil, Clemens Lopez-Benitez, Ruben Mier, Walter Haufe, Sabine Isermann, Berend Kauczor, Hans-Ulrich Choyke, Peter L. Haberkorn, Uwe Giesel, Frederik L. TI Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases SO ENDOCRINE-RELATED CANCER LA English DT Article ID RECEPTOR RADIONUCLIDE THERAPY; Y-90-LABELED SOMATOSTATIN ANALOGS; TUMORS; COMBINATION; DOSIMETRY; TOXICITY AB Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled Ga-68-DOTA(0)-D-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic beta emitters Y-90 and Lu-177. (90) Y- and/or Lu-177-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using In-111-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of Y-90-/Lu-177-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach. Endocrine-Related Cancer (2011) 18 595-602 C1 [Kratochwil, Clemens; Mier, Walter; Haufe, Sabine; Haberkorn, Uwe; Giesel, Frederik L.] Univ Heidelberg Hosp, Dept Nucl Med, INF 400, D-69120 Heidelberg, Germany. [Lopez-Benitez, Ruben; Kauczor, Hans-Ulrich] Univ Heidelberg Hosp, Dept Diagnost & Intervent Radiol, D-69120 Heidelberg, Germany. [Isermann, Berend] Univ Heidelberg Hosp, Dept Endocrinol, D-69120 Heidelberg, Germany. [Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Kratochwil, C (reprint author), Univ Heidelberg Hosp, Dept Nucl Med, INF 400, D-69120 Heidelberg, Germany. EM clemens.kratochwil@med.uni-heidelberg.de NR 18 TC 21 Z9 22 U1 1 U2 8 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD OCT PY 2011 VL 18 IS 5 BP 595 EP 602 DI 10.1530/ERC-11-0144 PG 8 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 918HD UT WOS:000302239000010 PM 21791571 ER PT J AU Chakkera, HA Weil, EJ Swanson, CM Dueck, AC Heilman, RL Reddy, KS Hamawi, K Khamash, H Moss, AA Mulligan, DC Katariya, N Knowler, WC AF Chakkera, Harini A. Weil, E. Jennifer Swanson, Christine M. Dueck, Amylou C. Heilman, Raymond L. Reddy, Kunam S. Hamawi, Khaled Khamash, Hasan Moss, Adyr A. Mulligan, David C. Katariya, Nitin Knowler, William C. TI Pretransplant Risk Score for New-Onset Diabetes After Kidney Transplantation SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; PREVENTION PROGRAM; MELLITUS; METFORMIN; HYPERGLYCEMIA; RECIPIENTS AB OBJECTIVE-New-onset diabetes after kidney transplantation (NODAT) has adverse clinical and economic implications. A risk score for NODAT could help identify research subjects for intervention studies. RESEARCH DESIGN AND METHODS-We conducted a single-center retrospective cohort study using pretransplant clinical and laboratory measurements to construct a risk score for NODAT. NODAT was defined by hemoglobin A(1c) (HbA(1c)) >= 6.5%, fasting serum glucose >= 126 mg/dL, or prescribed therapy for diabetes within 1 year posuransplant. Three multivariate logistic regression models were constructed: 1) standard model, with both continuous and discrete variables; 2) dichotomous model, with continuous variables dichotomized at clinically relevant cut points; and 3) summary score defined as the suns of the points accrued using the terms from the dichotomous model. RESULTS-A total or 31.6 subjects had seven pretransplant variables with P < 0.10 in univariate logistic regression analyses (age, planned corticosteroid therapy posttransplant, prescription for gout medicine, BMI, fasting glucose and triglycerides, and family history of type 2 diabetes) that were selected for multivariate models. Areas under receiver operating curves for all three models were similar (0.72, 0.71, and 0.70). A simple risk score calculated as the sum of points from the seven variables performed as well as the other two models in identifying risk of NODAT. CONCLUSIONS-A risk score computed from seven simple pretransplant variables can identify risk of NODAT. C1 [Chakkera, Harini A.; Heilman, Raymond L.; Hamawi, Khaled; Khamash, Hasan] Mayo Clin, Div Nephrol, Scottsdale, AZ USA. [Chakkera, Harini A.; Heilman, Raymond L.; Hamawi, Khaled; Khamash, Hasan] Mayo Clin, Div Transplantat, Scottsdale, AZ USA. [Weil, E. Jennifer; Knowler, William C.] NIDDK, NIH, Phoenix, AZ USA. [Swanson, Christine M.] Mayo Clin, Div Endocrinol, Scottsdale, AZ USA. [Dueck, Amylou C.] Mayo Clin, Div Biostat, Scottsdale, AZ USA. [Reddy, Kunam S.; Moss, Adyr A.; Mulligan, David C.; Katariya, Nitin] Mayo Clin, Div Surg, Scottsdale, AZ USA. RP Chakkera, HA (reprint author), Mayo Clin, Div Nephrol, Scottsdale, AZ USA. EM chakkera.harini@mayo.edu FU National Center for Research Resources (NCRR) [1-KL2-RR-024151]; National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases FX This work was funded by National Center for Research Resources (NCRR) Grant 1-KL2-RR-024151, a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. Information on NCRR is available at Imp://www.ncrr.nih.gov/. Additionally, this research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 14 TC 26 Z9 26 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 OCT PY 2011 VL 34 IS 10 BP 2141 EP 2145 DI 10.2337/dell-0752 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 910AG UT WOS:000301609000001 PM 21949218 ER PT J AU Unick, JL Beavers, D Jakicic, JM Kitabchi, AE Knowler, WC Wadden, TA Wing, RR AF Unick, Jessica L. Beavers, Daniel Jakicic, John M. Kitabchi, Abbas E. Knowler, William C. Wadden, Thomas A. Wing, Rena R. CA Look AHEAD Res Grp TI Effectiveness of Lifestyle Interventions for Individuals With Severe Obesity and Type 2 Diabetes SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; WEIGHT-LOSS; PHYSICAL-ACTIVITY; ADULTS; OVERWEIGHT; EXERCISE; OUTCOMES; TRIAL; WOMEN AB OBJECTIVE-Rates of severe obesity (BMI 40 kg/m(2)) are on the rise, and effective treatment options are needed. We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were severely obese compared with overweight (BMI 25 to <30 kg/m(2)), class I (BMI 30 to <35 kg/m(2)), and class II (BMI 35 to <40 kg/m(2)) obese participants. RESEARCH DESIGN AND METHODS-Participants in the Action for Health in Diabetes (Look AHEAD) trial were randomly assigned to ILI or diabetes support and education (DSE). DSE participants received a less intense educational intervention, whereas ILI participants received an intensive behavioral treatment to increase physical activity (PA) and reduce caloric intake. This article focuses on the 2,503 ILI participants (age 58.6 +/- 6.8 years). RESULTS-At 1 year, severely obese participants in the ILI group lost 9.04 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (-7.43 +/- 5.6%) and comparable to class I (-8.72 +/- 6.4%) and class II obese (-8.64 +/- 7.4%) participants. All BMI groups had comparable improvements in fitness, PA, LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA(1c) at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43). CONCLUSIONS-Severely obese participants in the ILI group had similar adherence, percentage of weight loss, and improvement in CVD risk compared with less obese participants. Behavioral weight loss programs should be considered an effective option for this population. C1 [Unick, Jessica L.; Wing, Rena R.] Miriam Hosp, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [Unick, Jessica L.; Wing, Rena R.] Brown Med Sch, Providence, RI USA. [Beavers, Daniel] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Activ, Phys Activ & Weight Management Res Ctr, Pittsburgh, PA USA. [Kitabchi, Abbas E.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Wadden, Thomas A.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Unick, JL (reprint author), Miriam Hosp, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. EM junick@lifespan.org RI Beavers, Daniel/G-5338-2016 FU Department of Health and Human Services, National Institutes of Health [DK-57136, DK-57149, DK-56990, DK-57177, DK-57171, DK-57151, DK-57182, DK-57131, DK-57002, DK-57078, DK-57154, DK-57178, DK-57219, DK-57008, DK-57135, DK-56992]; National Institute of Diabetes and Digestive and Kidney Diseases; The Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Johns Hopkins-University of Maryland Diabetes Research and Training Center [P60DK079637]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056 44]; National Institutes of Health [DK-046204]; University of Washington/VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Banter General Clinical Research Center [M01RR01346]; Google; BodyMedia, Inc. FX This study was supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health: DK-57136, DK-57149, DK-56990, DK-57177, DK-57171, DK-57151, DK-57182, DK-57131, DK-57002, DK-57078, DK-57154, DK-57178, DK-57219, DK-57008, DK-57135, and DK-56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; and the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (IHS) provided personnel, medical oversight, and use of facilities. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Johns Hopkins-University of Maryland Diabetes Research and Training Center (P60DK079637); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (M01RR000056 44) and National Institutes of Health grant (DK-046204); and the University of Washington/VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Banter General Clinical Research Center (M01RR01346). The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the IHS or other funding sources.; The following organizations have committed to make major contributions to Look AHEAD: Federal Express, Health Management Resources, Johnson & Johnson, LifeScan, Optifast-Novartis Nutrition, Roche Pharmaceuticals, Ross Product Division of Abbott Laboratories, Slim-Fast. Foods Company, and Unilever. J.M.J. is on the Scientific Advisory Board for Free & Clear, has received an honorarium from Jenny Craig for a research presentation, and is the principal investigator on research grants awarded to the University of Pittsburgh from Google and BodyMedia, Inc. T.A.W. is the principal investigator on a grant awarded to the University of Pennsylvania for Nutrisystem and also serves on an advisory board for Novo Nordisk. No other potential conflicts of interest relevant to this article were reported. NR 27 TC 73 Z9 76 U1 1 U2 23 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 OCT PY 2011 VL 34 IS 10 BP 2152 EP 2157 DI 10.2337/dc11-0874 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 910AG UT WOS:000301609000003 PM 21836103 ER PT J AU Smith, CA Hetzel, S Dalrymple, P Keselman, A AF Smith, Catherine Arnott Hetzel, Scott Dalrymple, Prudence Keselman, Alla TI Beyond Readability: Investigating Coherence of Clinical Text for Consumers SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Health literacy; comprehension; vocabulary; patients; language tests; retention (psychology) ID PATIENT EDUCATION MATERIALS; IMPROVE INSTRUCTIONAL TEXT; MEDICAL RECORDS; HEALTH LITERACY; CANCER-PATIENTS; ACCESS; COMPREHENSION; PRACTITIONER; CONSULTANTS; KNOWLEDGE AB Background: A basic tenet of consumer health informatics is that understandable health resources empower the public. Text comprehension holds great promise for helping to characterize consumer problems in understanding health texts. The need for efficient ways to assess consumer-oriented health texts and the availability of computationally supported tools led us to explore the effect of various text characteristics on readers' understanding of health texts, as well as to develop novel approaches to assessing these characteristics. Objective: The goal of this study was to compare the impact of two different approaches to enhancing readability, and three interventions, on individuals' comprehension of short, complex passages of health text. Methods: Participants were 80 university staff, faculty, or students. Each participant was asked to "retell" the content of two health texts: one a clinical trial in the domain of diabetes mellitus, and the other typical Visit Notes. These texts were transformed for the intervention arms of the study. Two interventions provided terminology support via (1) standard dictionary or (2) contextualized vocabulary definitions. The third intervention provided coherence improvement. We assessed participants' comprehension of the clinical texts through propositional analysis, an open-ended questionnaire, and analysis of the number of errors made. Results: For the clinical trial text, the effect of text condition was not significant in any of the comparisons, suggesting no differences in recall, despite the varying levels of support (P = .84). For the Visit Note, however, the difference in the median total propositions recalled between the Coherent and the (Original + Dictionary) conditions was significant (P = .04). This suggests that participants in the Coherent condition recalled more of the original Visit Notes content than did participants in the Original and the Dictionary conditions combined. However, no difference was seen between (Original + Dictionary) and Vocabulary (P = .36) nor Coherent and Vocabulary (P = .62). No statistically significant effect of any document transformation was found either in the open-ended questionnaire (clinical trial: P = .86, Visit Note: P = .20) or in the error rate (clinical trial: P = .47, Visit Note: P = .25). However, post hoc power analysis suggested that increasing the sample size by approximately 6 participants per condition would result in a significant difference for the Visit Note, but not for the clinical trial text. Conclusions: Statistically, the results of this study attest that improving coherence has a small effect on consumer comprehension of clinical text, but the task is extremely labor intensive and not scalable. Further research is needed using texts from more diverse clinical domains and more heterogeneous participants, including actual patients. Since comprehensibility of clinical text appears difficult to automate, informatics support tools may most productively support the health care professionals tasked with making clinical information understandable to patients. C1 [Smith, Catherine Arnott] Univ Wisconsin, Sch Lib & Informat Studies, Madison, WI 53706 USA. [Hetzel, Scott] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Dalrymple, Prudence] Drexel Univ, Inst Healthcare Informat, Coll Informat Sci & Technol, Philadelphia, PA 19104 USA. [Keselman, Alla] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD USA. RP Smith, CA (reprint author), Univ Wisconsin, Sch Lib & Informat Studies, 600 N Pk St, Madison, WI 53706 USA. EM casmith24@wisc.edu FU NIDDK [7R01DK075837]; National Library of Medicine FX The authors gratefully acknowledge the helpful assistance of Hyeoneui Kim, RN, MPH, PhD, during the development of the various text conditions, and Qing Zeng-Treitler, PhD; funding support by NIDDK 7R01DK075837; and the Intramural Research Program of the National Library of Medicine. NR 45 TC 5 Z9 5 U1 1 U2 6 PU JOURNAL MEDICAL INTERNET RESEARCH PI TORONTO PA TORONTO GENERAL HOSPITAL, R FRASER ELLIOTT BLDG, 4TH FL, R 4S435, 190 ELIZABETH ST, TORONTO, ON M5G 2C4, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD OCT-DEC PY 2011 VL 13 IS 4 AR e104 DI 10.2196/jmir.1842 PG 16 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 879EU UT WOS:000299313300029 PM 22138127 ER PT J AU Kamal, N Khangura, S Zhao, XC Marciano, B Simpson, J Kuhns, D Gallin, J Malech, H Holland, S Heller, T AF Kamal, Natasha Khangura, Sajneet Zhao, Xiongce Marciano, Beatriz Simpson, Jennifer Kuhns, Douglas Gallin, John Malech, Harry Holland, Steven Heller, Theo TI The Gastrointestinal Manifestations of Chronic Granulomatous Disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Kamal, Natasha; Khangura, Sajneet; Zhao, Xiongce; Marciano, Beatriz; Simpson, Jennifer; Gallin, John; Malech, Harry; Holland, Steven; Heller, Theo] Univ MD, NIH, Bethesda, MD USA. [Kuhns, Douglas] NCI, SAIC Frederick Inc, Frederick, MD 21701 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 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1268 BP S482 EP S482 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002112 ER PT J AU Khangura, S Kamal, N Zhao, XC Marciano, B Simpson, J Kuhns, D Gallin, J Malech, H Holland, S Heller, T AF Khangura, Sajneet Kamal, Natasha Zhao, Xiongce Marciano, Beatriz Simpson, Jennifer Kuhns, Douglas Gallin, John Malech, Harry Holland, Steven Heller, Theo TI Endoscopic Features of Gastrointestinal Disease in Chronic Granulomatous Disease: A Distinct Entity SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Khangura, Sajneet; Kamal, Natasha; Zhao, Xiongce; Marciano, Beatriz; Simpson, Jennifer; Gallin, John; Malech, Harry; Holland, Steven; Heller, Theo] Univ MD, NIH, Bethesda, MD USA. [Kuhns, Douglas] NCI, SAIC Frederick Inc, Frederick, MD 21701 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 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1267 BP S482 EP S482 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002111 ER PT J AU Gupta, N Stopfer, M AF Gupta, Nitin Stopfer, Mark TI Insect olfactory coding and memory at multiple timescales SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID EVOKED NEURAL OSCILLATIONS; HONEYBEE ANTENNAL LOBE; MUSHROOM BODY; TRANSIENT DYNAMICS; TERM-MEMORY; DEPENDENT PLASTICITY; ODOR REPRESENTATIONS; CORRELATED ACTIVITY; NETWORK DYNAMICS; DROSOPHILA AB Insects can learn, allowing them great flexibility for locating seasonal food sources and avoiding wily predators. Because insects are relatively simple and accessible to manipulation, they provide good experimental preparations for exploring mechanisms underlying sensory coding and memory. Here we review how the intertwining of memory with computation enables the coding, decoding, and storage of sensory experience at various stages of the insect olfactory system. Individual parts of this system are capable of multiplexing memories at different timescales, and conversely, memory on a given timescale can be distributed across different parts of the circuit. Our sampling of the olfactory system emphasizes the diversity of memories, and the importance of understanding these memories in the context of computations performed by different parts of a sensory system. C1 [Gupta, Nitin; Stopfer, Mark] NICHD, NIH, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NICHD, NIH, Bldg 35,35 Lincoln Dr,Rm 3A-102,Msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov OI Gupta, Nitin/0000-0002-8408-3848 FU NICHD-NIH FX We thank Stopfer lab members for helpful discussions, and NICHD-NIH for intramural funding. NR 57 TC 4 Z9 4 U1 1 U2 18 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 EI 1873-6882 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD OCT PY 2011 VL 21 IS 5 BP 768 EP 773 DI 10.1016/j.conb.2011.05.005 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 862VE UT WOS:000298121400015 PM 21632235 ER PT J AU Caron, WP Clewell, H Dedrick, R Ramanathan, RK Davis, WL Yu, N Tonda, M Schellens, JH Beijnen, JH Zamboni, WC AF Caron, Whitney P. Clewell, Harvey Dedrick, Robert Ramanathan, Ramesh K. Davis, Whitney L. Yu, Ning Tonda, Margaret Schellens, Jan H. Beijnen, Jos H. Zamboni, William C. TI Allometric scaling of pegylated liposomal anticancer drugs SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Allometric; Dedrick Plot; Pegylated liposomes; Anticancer drugs; Preclinical; Mononuclear phagocyte system (MPS) ID CKD-602 S-CKD602; HEMOLYTIC-ANEMIA; SOLID TUMORS; PHARMACOKINETICS; DELIVERY; PLASMA; AGENTS; DOXORUBICIN; PRINCIPLES; CLEARANCE AB Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil (R)), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil (R), and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil (R), and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed. C1 [Caron, Whitney P.; Davis, Whitney L.; Zamboni, William C.] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Clewell, Harvey] Hamner Inst Hlth Sci, Durham, NC USA. [Dedrick, Robert] NIH, US Dept Hlth Educ & Welf, Publ Hlth Serv, Bethesda, MD 20892 USA. [Ramanathan, Ramesh K.] Univ Pittsburgh Canc Inst, Mol Therapeut & Drug Discovery Program, Pittsburgh, PA USA. [Yu, Ning; Tonda, Margaret] ALZA Corp, Mountain View, CA USA. [Schellens, Jan H.; Beijnen, Jos H.] Netherlands Canc Inst, Dept Clin Pharmacol, Amsterdam, Netherlands. [Zamboni, William C.] Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Zamboni, William C.] Univ N Carolina, UNC Inst Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Zamboni, William C.] Univ N Carolina, UNC Ctr Canc Nanotechnol Excellence, Chapel Hill, NC USA. [Zamboni, William C.] Univ N Carolina, N Carolina Med Innovat Network, Chapel Hill, NC USA. RP Zamboni, WC (reprint author), Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, 120 Mason Farm Rd,Suite 1013,CB 7361, Chapel Hill, NC 27599 USA. EM zamboni@email.unc.edu NR 46 TC 14 Z9 14 U1 1 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2011 VL 38 IS 5 BP 653 EP 669 DI 10.1007/s10928-011-9213-5 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 890VB UT WOS:000300172600008 PM 21863380 ER PT J AU Michaelides, M Thanos, PK Volkow, ND Wang, GJ AF Michaelides, Michael Thanos, Panayotis K. Volkow, Nora D. Wang, Gene-Jack TI Functional Neuroimaging in Obesity SO PSYCHIATRIC ANNALS LA English DT Article ID GASTRIC STIMULATION; BRAIN ACTIVATION; FOOD STIMULATION; BODY-MASS; DOPAMINE; ASSOCIATION; DISORDER; SURGERY; POPULATION; DISTENSION C1 [Michaelides, Michael; Thanos, Panayotis K.; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Michaelides, Michael] Mt Sinai Sch Med, Dept Pharmacol, New York, NY USA. [Michaelides, Michael] Mt Sinai Sch Med, Dept Syst Therapeut, New York, NY USA. [Thanos, Panayotis K.; Volkow, Nora D.] Natl Inst Alcohol Abuse & Alcoholism, Lab Neuroimaging, Bethesda, MD USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Neurosci, Stony Brook, NY 11794 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. [Wang, Gene-Jack] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Wang, GJ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM gjwang@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 NR 35 TC 4 Z9 6 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD OCT PY 2011 VL 41 IS 10 BP 496 EP 500 DI 10.3928/00485713-20110921-09 PG 5 WC Psychiatry SC Psychiatry GA 885YP UT WOS:000299817700009 ER PT J AU Bumb, A Sarkar, SK Wu, XFS Brechbiel, MW Neuman, KC AF Bumb, Ambika Sarkar, Susanta K. Wu, Xufeng S. Brechbiel, Martin W. Neuman, Keir C. TI Quantitative characterization of fluorophores in multi-component nanoprobes by single-molecule fluorescence SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID SILICA NANOPARTICLES; CANCER-THERAPY; SPECTROSCOPY; PROTEINS; NUMBER; DYES AB Multi-modal nanoparticles incorporating fluorophores are increasingly being used for medical applications. The number of fluorophores incorporated into the nanoparticles during synthesis is stochastic, leaving some nanoparticles devoid of fluorophores. Determining the number, the brightness and the photostability of the fluorophores incorporated, and the percentage of labeled nanoparticles (labeling efficiency) remains challenging. We have determined the aforementioned quantities for two synthesized multi-modal nanoparticles by exploiting the photobleaching of fluorophores at the single-molecule level using a total internal reflection fluorescence microscope. Labeling efficiency was determined by fitting the distribution of incorporated fluorophores with a statistical model and verified by independent experiments. (C) 2011 Optical Society of America C1 [Bumb, Ambika; Brechbiel, Martin W.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Sarkar, Susanta K.; Neuman, Keir C.] NHLBI, Lab Mol Biophys, Bethesda, MD 20892 USA. [Wu, Xufeng S.] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Bumb, A (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10,Room 1B53, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Institutes of Health (NCI NHLBI) FX We would like to acknowledge Dr. Grzegorz Piszczek (Biophysics Facility, NHLBI) for help with the fluorescence lifetime experiments. This research was supported by the Intramural Research Program of the National Institutes of Health (NCI & NHLBI). NR 24 TC 8 Z9 9 U1 2 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD OCT 1 PY 2011 VL 2 IS 10 BP 2761 EP 2769 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886FN UT WOS:000299838800003 PM 22025982 ER PT J AU Tchebakova, NM Parfenova, EI Lysanova, GI Soja, AJ AF Tchebakova, N. M. Parfenova, E. I. Lysanova, G. I. Soja, A. J. TI Agroclimatic potential across central Siberia in an altered twenty-first century SO ENVIRONMENTAL RESEARCH LETTERS LA English DT Article DE climate warming; central Siberia; agriculture; crop range and production AB Humans have traditionally cultivated steppe and forest-steppe on fertile soils for agriculture. Forests are predicted to shift northwards in a warmer climate and are likely to be replaced by forest-steppe and steppe ecosystems. We analyzed potential climate change impacts on agriculture in south-central Siberia believing that agriculture in traditionally cold Siberia may benefit from warming. Simple models determining crop range and regression models determining crop yields were constructed and applied to climate change scenarios for various time frames: pre-1960, 1960-90 and 1990-2010 using historic data and data taken from 2020 and 2080 HadCM3 B1 and A2 scenarios. From 50 to 85% of central Siberia is predicted to be climatically suitable for agriculture by the end of the century, and only soil potential would limit crop advance and expansion to the north. Crop production could increase twofold. Future Siberian climatic resources could provide the potential for a great variety of crops to grow that previously did not exist on these lands. Traditional Siberian crops could gradually shift as far as 500 km northwards (about 50-70 km/decade) within suitable soil conditions, and new crops nonexistent today may be introduced in the dry south that would necessitate irrigation. Agriculture in central Siberia would likely benefit from climate warming. Adaptation measures would sustain and promote food security in a warmer Siberia. C1 [Tchebakova, N. M.; Parfenova, E. I.] Russian Acad Sci, Siberian Branch, VN Sukachev Inst Forest, Krasnoyarsk 660036, Russia. [Lysanova, G. I.] Russian Acad Sci, Siberian Branch, Inst Geog, Irkutsk, Russia. [Soja, A. J.] NASA, Langley Res Ctr, NIA, Hampton, VA 23681 USA. RP Tchebakova, NM (reprint author), Russian Acad Sci, Siberian Branch, VN Sukachev Inst Forest, Krasnoyarsk 660036, Russia. EM ncheby@forest.akadem.ru; lyeti@ksc.krasn.ru; lysanova@irigs.irk.ru; Amber.J.Soja@nasa.gov FU NASA [NNH09ZDA001N-IDS]; Russian Foundation for Basic Research [10-05-00941] FX We would like to recognize the Northern Eurasian Earth Science Partnership Initiative (NEESPI) and the NASA Land Cover Land Use Change (LCLUC) program for providing the background that made this work possible. We are greatly appreciative of the current support for this work provided by the NASA InterDisciplinary Science grant NNH09ZDA001N-IDS and the Russian Foundation for Basic Research grant 10-05-00941. We thank our two anonymous reviewers for their very helpful comments. NR 38 TC 11 Z9 12 U1 1 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1748-9326 J9 ENVIRON RES LETT JI Environ. Res. Lett. PD OCT-DEC PY 2011 VL 6 IS 4 AR 045207 DI 10.1088/1748-9326/6/4/045207 PG 11 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA 870MX UT WOS:000298674700045 ER PT J AU Robertson, K Kumwenda, J Supparatpinyo, K Jiang, JH Evans, S Campbell, TB Price, RW Murphy, R Hall, C Marra, CM Marcus, C Berzins, B Masih, R Santos, B Silva, MT Kumarasamy, N Walawander, A Nair, A Tripathy, S Kanyama, C Hosseinipour, M Montano, S La Rosa, A Amod, F Sanne, I Firnhaber, C Hakim, J Brouwers, P AF Robertson, Kevin Kumwenda, Johnstone Supparatpinyo, Khuanchai Jiang, Jeanne H. Evans, Scott Campbell, Thomas B. Price, Richard W. Murphy, Robert Hall, Colin Marra, Christina M. Marcus, Cheryl Berzins, Baiba Masih, Reena Santos, Breno Silva, Marcus T. Kumarasamy, N. Walawander, Ann Nair, Apsara Tripathy, Srikanth Kanyama, Cecilia Hosseinipour, Mina Montano, Silvia La Rosa, Alberto Amod, Farida Sanne, Ian Firnhaber, Cindy Hakim, James Brouwers, Pim CA Aids Clinical Trials Grp TI A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE HIV; Resource-limited; Cognitive impairment; CNS; Neuropsychological examination ID AIDS DEMENTIA COMPLEX; VIRUS-ASSOCIATED DEMENTIA; COGNITIVE IMPAIRMENT; CLINICAL-TRIALS; RISK-FACTORS; HIV; NEUROPATHY; DISORDERS; INFECTION; DISEASE AB Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naive individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p<0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naive individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance. C1 [Robertson, Kevin] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Supparatpinyo, Khuanchai] Chiang Mai Univ, Chiang Mai 50000, Thailand. [Jiang, Jeanne H.; Evans, Scott] Harvard Univ, Boston, MA 02115 USA. [Campbell, Thomas B.] Univ Colorado Denver, Aurora, CO USA. [Price, Richard W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Murphy, Robert; Berzins, Baiba] Northwestern Univ, Chicago, IL 60611 USA. [Marra, Christina M.] Univ Washington, Seattle, WA 98195 USA. [Masih, Reena] Social & Sci Syst Inc, Silver Spring, MD USA. [Walawander, Ann; Nair, Apsara] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Brouwers, Pim] NIMH, Bethesda, MD 20892 USA. [Silva, Marcus T.] Fiocruz MS, BR-21045900 Rio De Janeiro, Brazil. RP Robertson, K (reprint author), Univ N Carolina, Dept Neurol, 2128 Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. EM kevinr@neurology.unc.edu OI Murphy, Robert/0000-0003-3936-2052 FU National Institute of Mental Health; AIDS Clinical Trials Group (ACTG); National Institute of Allergy and Infectious Diseases (NIAID) [U01AI068636]; General Clinical Research Center (GCRC); National Center for Research Resources; SDAC [AI-068634]; CTU [AI69476, 5U01AI069426-03, AI069432, AI069518, BRS-ACURE-Q-08-00173-TOOI-OOO, AI069463, BRS-ACURE-Q-07-00143 T006, AI069399, AACTG.27.5199.06, 5 U01 AI069401, 5U01AI069417-03, U01A1069518, 5U01 AI069438-03] FX The project described was supported by the National Institute of Mental Health, and the AIDS Clinical Trials Group (ACTG) funded by The National Institute of Allergy and Infectious Diseases (NIAID) Award Number U01AI068636, General Clinical Research Center (GCRC) funded by the National Center for Research Resources, and SDAC Grant Number AI-068634. The content is solely the responsibility of the above authors and does not necessarily represent the official views of the NIAID or the National Institutes of Health (NIH). The authors were supported by the following grants: Deise Vieira and Marcus Tulius T. Silva, IPEC-FIOCRUZ (Site 12101) CTU Grant no. AI69476; Umesh Lalloo and Rosie Mngqibisa, Durban Adult HIV CRS (Site 11201) CTU Grant no. 5U01AI069426-03; Nagalingeshwaran Kumarasamy and Jabin Sharma, YRGCARE Medical Centre (Site 11701) CTU Grant no. AI069432; Virginia M. Kayoyo and Franklin D. Kilembe, Franklin Kilembe University of North Carolina Project, Kamuzu Central Hospital, Lilongwe (Site 12001) CTU Grant no. AI069518; Mauleen Waison and Rachel Mahachi-Parirenyatwa CRS (Site 30313) CTU Grant no. BRS-ACURE-Q-08-00173-TOOI-OOO; Cynthia Firnhaber and Daphne S. Radebe, Wits HIV Clinical Research Site (Helen Joseph Hosp) (Site 11101) CTU Grant no. AI069463; BRS-ACURE-Q-07-00143 T006; Thira Sirisanthana and Daralak Tavornprasit, Research Institute for Health Sciences, Chiang Mai University (Site 11501) CTU Grant no. AI069399; AACTG.27.5199.06; Maria Siliprandi and Renata Londero, Hospital Nossa Senhora da Conceicao CRS (Site 12201) CTU Grant no. 5 U01 AI069401; Anjali A. Joglekar and Srikanth Prasad Tripathy, NARI Pune CRS (Site 11601) CTU Grant no. 5U01AI069417-03; Ben Kalonga and Henry Chamba, College of Medicine, Johns Hopkins Project (Site 30301) CTU Grant no. U01A1069518; Carlos Mosquera and Rosa Infante, INMENSA-Lince CRS (Site 11302) CTU Grant no. 5U01 AI069438-03; BRS-ACURE-Q-07-00141-T001-001; Juan Carlos Hurtado and Alberto La Rosa, Asociacion Civil Impacta Salud y Educacion (Site 11301) CTU Grant no. AI069438; BRS-ACURE-Q-08-00007-T-002; Manisha V. Ghate and Madhura Nene, NARI-NIV Clinic (Site 11603) CTU Grant no. 5U01AI069417-03; Dr. Raman Gnagakhedkar and Usha Katti, Dr. Kotnis Dispensary, NARI (Site 11602) CTU Grant no. 5U01AI069417-03.; R.W. Price is involved in an investigator-initiated grant funding for Merck and honorarium for a lecture for Abbott Laboratories. NR 31 TC 14 Z9 14 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2011 VL 17 IS 5 BP 438 EP 447 DI 10.1007/s13365-011-0044-3 PG 10 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 876QG UT WOS:000299122000004 PM 21786076 ER PT J AU Kelada, SNP Wilson, MS Tavarez, U Kubalanza, K Borate, B Whitehead, GS Maruoka, S Roy, MG Olive, M Carpenter, DE Brass, DM Wynn, TA Cook, DN Evans, CM Schwartz, DA Collins, FS AF Kelada, Samir N. P. Wilson, Mark S. Tavarez, Urraca Kubalanza, Kari Borate, Bhavesh Whitehead, Greg S. Maruoka, Shuichiro Roy, Michelle G. Olive, Michelle Carpenter, Danielle E. Brass, David M. Wynn, Thomas A. Cook, Donald N. Evans, Christopher M. Schwartz, David A. Collins, Francis S. TI Strain-Dependent Genomic Factors Affect Allergen-Induced Airway Hyperresponsiveness in Mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asthma; airway hyperresponsiveness; inflammation; house dust mite; Der p 1 ID ASTHMA-LIKE RESPONSES; MURINE MODEL; DEFICIENT MICE; RECEPTOR; ANTIGEN; EOSINOPHILS; EXPRESSION; DISEASE; CELLS; LUNG AB Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the strain-dependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1-challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein-coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain-dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-protein-coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation. C1 [Kelada, Samir N. P.; Tavarez, Urraca; Kubalanza, Kari; Borate, Bhavesh; Olive, Michelle; Carpenter, Danielle E.; Collins, Francis S.] NHGRI, Mol Genet Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Wilson, Mark S.; Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Whitehead, Greg S.; Maruoka, Shuichiro; Cook, Donald N.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Roy, Michelle G.; Evans, Christopher M.] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA. [Brass, David M.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Schwartz, David A.] Natl Jewish Hlth, Denver, CO USA. [Schwartz, David A.] Univ Colorado, Dept Med, Denver, CO USA. RP Collins, FS (reprint author), NHGRI, Mol Genet Sect, Genome Technol Branch, NIH, Bldg 1,Room 126, Bethesda, MD 20892 USA. EM collinsf@od.nih.gov RI Wynn, Thomas/C-2797-2011 FU National Human Genome Research Institute at the National Institutes of Health; Wallace and Graham; Brayton and Purcell; Weitz and Luxemberg; Waters and Kraus; National Human Genome Research Institute; National Institute of Environmental Health Sciences; NIH [R01 HL080396]; [10GRNT4200070] FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health (F.S.C.).; D.A.S. received expert witness fees from Wallace and Graham, Brayton and Purcell, Weitz and Luxemberg, and Waters and Kraus, and is a full-time employee of National Jewish Health. The rest of the authors have no financial relationship with a commercial entity that has an interest in the subject of this manuscript.; The authors thank Shelley Hoogstraten-Miller for significant training and input on the murine model, Abdel Elkahloun for microarray support, and Michael Erdos for substantial advice during the course of data generation and analysis. We would like to acknowledge the professional skills and advice of Dr. Christian A. Combs and Daniela Malide (Light Microscopy Core Facility, National Heart, Lung and Blood Institute, National Institutes of Health) regarding microscopy-related experiments performed in this paper. This work was supported by the intramural research programs of the National Human Genome Research Institute and the National Institute of Environmental Health Sciences, and by R01 HL080396 (NIH) and 10GRNT4200070 (Am. Heart Assoc.) to C. Evans. NR 44 TC 23 Z9 24 U1 1 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD OCT PY 2011 VL 45 IS 4 BP 817 EP 824 DI 10.1165/rcmb.2010-0315OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 884BX UT WOS:000299681000019 PM 21378263 ER PT J AU Kumar, A Bishier, MP Naito, Y Sharma, A Solimene, U Jain, S Yadav, H Minelli, E Tomella, C Marotta, F AF Kumar, A. Bishier, M. P. Naito, Y. Sharma, A. Solimene, U. Jain, S. Yadav, H. Minelli, E. Tomella, C. Marotta, F. TI PROTECTIVE EFFECT OF AN ORAL NATURAL PHYTONUTRIENT IN RECURRENT VULVOVAGINAL CANDIDIASIS: A 12-MONTH STUDY SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS LA English DT Article DE recurrent vulvovaginal candidiasis; itraconazole; antifungal phytonutrient ID SPECTRUM ANTIBIOTICS; FLUCONAZOLE; THERAPY; SUSCEPTIBILITY; ANETHOLE; SAPONINS; ALBICANS; FUNGAL; WOMEN; GUT AB The aim of the present study is to assess the clinical efficacy of a phytocompound with antimicotic properties (K-712, with the following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30% concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC) as compared to an azole drug during a 12-month period: 6 months of treatment followed by 6 months of observation. This prospective randomized study involved 82 women (19-61 years) with complaints of abnormal vaginal discharge and with a history of at least four proven episodes of RVVC in the previous 12 months. Patients were divided into two groups of treatment of 41 patients each and were given: A) Itraconazole 200 mg orally daily for 4 days, then 200 mg once weekly for 6 months or B) 1 tablet twice a day of a K-712 for 4 weeks and then for the first 2 weeks of each month for a total of 6 months. Both groups were then followed-up for further 6 months. Each treatment schedule was well tolerated with only 4 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste). Itraconazole reached an earlier symptomatic relief during the first two weeks of observation as compared with K-712 (p<0.05) but both treatments enabled a comparable benefit during the entire treatment study period, afterwards with comparable symptom/sign score (itraconazole vs K-712: 9 vs 11). At 6-month observation, mycological cure was reached by 83% in the itraconazole group and in 78% of the K-712-treated patients. During the further 6-month observation period without treatment, the itraconazole group showed significantly more relapses (65.7 vs 34.2 in K-712, p<0.05) and at the end of the whole 12-month study period the mycological cure was significantly higher in the K-712-treated patients (65.8.% vs 34.3%, p<0.05). There was a non- significant trend increase of less drug-susceptible species in the itraconazole group. From these preliminary data it would appear that a natural antifungal phytocompound proves to be as good as itraconazole in the maintenance treatment of RVVC. Moreover, this approach seems to maintain a higher mycological success rate afterwards by reducing the number of relapses and probably of the growth of azole-resistant species. C1 [Kumar, A.] Chaudhary Charan Singh Univ, Dept Microbiol, Meerut, Uttar Pradesh, India. [Bishier, M. P.; Naito, Y.; Sharma, A.] Immunol Res Inst & Clin, Nagoya, Aichi, Japan. [Solimene, U.; Minelli, E.] Univ Milan, WHO Ctr Biotechnol & Tradit Med, I-20122 Milan, Italy. [Jain, S.; Yadav, H.] NIDDK, NIH, Bethesda, MD USA. [Tomella, C.; Marotta, F.] ReGenera Res Grp Intervent Aging, Milan, Italy. RP Marotta, F (reprint author), Piazza Firenze 12, I-20154 Milan, Italy. EM fmarchimede@libero.it NR 23 TC 2 Z9 2 U1 1 U2 2 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0393-974X J9 J BIOL REG HOMEOS AG JI J. Biol. Regul. Homeost. Agents PD OCT-DEC PY 2011 VL 25 IS 4 BP 543 EP 551 PG 9 WC Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology SC Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology GA 876XQ UT WOS:000299141500006 PM 22217987 ER PT J AU Olney, C Hansen, L Vickman, A Reibman, S Wood, FB Siegel, E AF Olney, Cynthia Hansen, Lucille Vickman, Ann Reibman, Sara Wood, Frederick B. Siegel, Elliot TI Long-term outcomes of the !VIVA! Peer Tutor Project: use of MedlinePlus by former peer tutors and the adults they taught SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID HISPANIC OUTREACH C1 [Olney, Cynthia] CO Evaluat Consulting, Roswell, GA 30076 USA. [Hansen, Lucille; Vickman, Ann; Reibman, Sara] S Texas Independent Sch Dist, Mercedes, TX 78570 USA. [Wood, Frederick B.] Natl Lib Med, Off Hlth Informat Programs Dev, Bethesda, MD 20894 USA. [Siegel, Elliot] Elliot Siegel Consulting, Bluffton, SC 29910 USA. RP Olney, C (reprint author), CO Evaluat Consulting, POB 767671, Roswell, GA 30076 USA. EM olneyc@coevaluation.com; lucy.hansen@stisd.net; ann.vickman@stisd.net; sara.reibman@stisd.net; fredwood@mail.nih.gov; siegel@nlm.nih.gov FU NLM NIH HHS [N01-LM-6-3505] NR 14 TC 0 Z9 0 U1 1 U2 11 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2011 VL 99 IS 4 BP 317 EP 320 DI 10.3163/1536-5050.99.4.012 PG 4 WC Information Science & Library Science SC Information Science & Library Science GA 862IN UT WOS:000298084400012 PM 22022228 ER PT J AU Linkous, AG Yazlovitskaya, EM AF Linkous, Amanda G. Yazlovitskaya, Eugenia M. TI Angiogenesis in Glioblastoma Multiforme: Navigating the Maze SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Angiogenesis; anti-angiogenic agents; drug resistance; glioblastoma multiforme (GBM); signal transduction; targeted drug therapy; tumor vascularization ID ENDOTHELIAL GROWTH-FACTOR; HIGH-GRADE GLIOMA; TUMOR ANGIOGENESIS; STEM-CELLS; PHASE-II; TISSUE FACTOR; THERAPEUTIC IMPLICATIONS; PERIVASCULAR NICHE; PROLONGS SURVIVAL; KINASE INHIBITOR AB Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. In aggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. In an attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. Although several angiogenesis inhibitors have produced enhanced clinical benefits in GBM, many of these pharmacologic agents result in transitory initial response phases followed by evasive tumor resistance. Thus, a significant need exists for the discovery of novel and effective anti-angiogenic therapies. The development of new molecular-targeted therapeutic strategies is often complicated by the complexity of angiogenic signal transduction. Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenic factors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatory mechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This review presents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancements in targeted anti-angiogenic drug therapy. C1 [Yazlovitskaya, Eugenia M.] Vanderbilt Univ, Med Ctr, Div Nephrol, Dept Med, Nashville, TN 37232 USA. [Linkous, Amanda G.] NIH, Neurooncol Branch, Bethesda, MD 20892 USA. [Yazlovitskaya, Eugenia M.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. RP Yazlovitskaya, EM (reprint author), Vanderbilt Univ, Med Ctr, Div Nephrol, Dept Med, C3210 Med Ctr N 1161,21st Ave S, Nashville, TN 37232 USA. EM eugenia.yazlovitskaya@vanderbilt.edu NR 61 TC 9 Z9 10 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD OCT PY 2011 VL 11 IS 8 BP 712 EP 718 PG 7 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 861YU UT WOS:000298057800004 PM 21707499 ER PT J AU Sun, JH Nguyen, T Murphy, E AF Sun, Junhui Tiffany Nguyen Murphy, Elizabeth TI ISCHEMIC PRECONDITIONING ACTIVATES CAVEOLAE-MEDIATED ENOS SIGNALLING AND ELICITS CARDIOPROTECTION THROUGH S-NITROSYLATION OF THE SUBSARCOLEMMAL MITOCHONDRIA SO HEART LA English DT Meeting Abstract CT 22nd Great Wall International Congress of Cardiology/Asia Pacific Heart Congress (GWICC and APHF) CY OCT 13-16, 2011 CL China Int Conf Ctr Sci & Technol (CICCST), Beijing, PEOPLES R CHINA SP Chinese Med Soc Cardiovasc Dis (CMSCD), Comm Cardio-Cerebral Vasc Dis GSC & CHRS, Chinese Coll Cardiovasc Phys (CCCP) HO China Int Conf Ctr Sci & Technol (CICCST) C1 [Sun, Junhui; Tiffany Nguyen; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD USA. RI Sun, Junhui/C-3499-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD OCT PY 2011 VL 97 SU 3 BP A59 EP A59 DI 10.1136/heartjnl-2011-300867.172 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 866AV UT WOS:000298352900172 ER PT J AU Chen, F Wang, Q Wang, S Zhang, WD Xu, WL AF Chen, Feng Wang, Qing Wang, Song Zhang, Weidong Xu, Wenli TI Object tracking via appearance modeling and sparse representation SO IMAGE AND VISION COMPUTING LA English DT Article DE Target variation; Online appearance modeling; Sparse representation; Bayesian inference ID VISUAL TRACKING AB This paper proposes a robust tracking method by the combination of appearance modeling and sparse representation. In this method, the appearance of an object is modeled by multiple linear subspaces. Then within the sparse representation framework, we construct a similarity measure to evaluate the distance between a target candidate and the learned appearance model. Finally, tracking is achieved by Bayesian inference, in which a particle filter is used to estimate the target state sequentially over time. With the tracking result, the learned appearance model will be updated adaptively. The combination of appearance modeling and sparse representation makes our tracking algorithm robust to most of possible target variations due to illumination changes, pose changes, deformations and occlusions. Theoretic analysis and experiments compared with state-of-the-art methods demonstrate the effectivity of the proposed algorithm. (C) 2011 Elsevier B.V. All rights reserved. C1 [Chen, Feng; Wang, Qing; Xu, Wenli] Tsinghua Univ, Dept Automat, Tsinghua Natl Lab Informat Sci & Technol, Beijing 100084, Peoples R China. [Wang, Song] Univ S Carolina, Dept Comp Sci & Engn, Columbia, SC 29208 USA. [Zhang, Weidong] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Chen, F (reprint author), Tsinghua Univ, Dept Automat, Tsinghua Natl Lab Informat Sci & Technol, Beijing 100084, Peoples R China. EM chenfeng@mail.tsinghua.edu.cn; qing-wang07@mails.tsinghua.edu.cn RI Chen, Feng/K-4179-2012 FU National Natural Science Foundation of China [60772050, 61071131]; No.2 Important National Science and Technology Specific Projects [2009ZX02001]; United Technologies Research Center (UTRC) FX This work was supported by National Natural Science Foundation of China (Project no. 60772050 and Project no. 61071131), No.2 Important National Science and Technology Specific Projects (Project no. 2009ZX02001) and United Technologies Research Center (UTRC). NR 23 TC 25 Z9 38 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0262-8856 J9 IMAGE VISION COMPUT JI Image Vis. Comput. PD OCT PY 2011 VL 29 IS 11 BP 787 EP 796 DI 10.1016/j.imavis.2011.08.006 PG 10 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering; Computer Science, Theory & Methods; Engineering, Electrical & Electronic; Optics SC Computer Science; Engineering; Optics GA 864EE UT WOS:000298219000007 ER PT J AU Tang, ZH Yu, Y Qiu, WH Zhang, J Yang, XP AF Tang, Zhaohui Yu, Yan Qiu, Wenhong Zhang, Jian Yang, Xiangping TI Up-regulation of Tim-3 Expression Contributes to Development of Burn-induced T Cell Immune Suppression in Mice SO JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY-MEDICAL SCIENCES LA English DT Article DE T cell immunoglobulin and mucin domain 3; T cells; burn injury; immune suppression ID CD1D-RESTRICTED NKT CELLS; THERMAL-INJURY; PROGRAMMED DEATH-1; VIRUS-INFECTION; PD-1; ACTIVATION; RESPONSES; PATHWAYS; TRAUMA; IMMUNOSUPPRESSION AB T cell immunoglobulin and mucin domain 3 (Tim-3) is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3(+) T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4(+) and CD8(+) T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-gamma and TNF-alpha, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3(+) T cells subsets were more prone to spontaneous apoptosis than Tim-3(-) T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression. C1 [Tang, Zhaohui; Zhang, Jian] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Trauma Surg, Wuhan 430030, Peoples R China. [Yu, Yan] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Cardiol, Wuhan 430030, Peoples R China. [Qiu, Wenhong] Jianghan Univ, Coll Med, Dept Immunol, Wuhan 430056, Peoples R China. [Yang, Xiangping] NIAMS, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Tang, ZH (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Trauma Surg, Wuhan 430030, Peoples R China. EM tangzh45@hotmail.com FU National Natural Science Foundation of China [30700799, 81172803]; Ministry of Education of China [20070487119]; Natural Science Foundation of Hubei Province [2007AD A201] FX This project was supported by grants from National Natural Science Foundation of China (No. 30700799, 81172803), Doctoral Fund of Ministry of Education of China (No. 20070487119) and Natural Science Foundation of Hubei Province (No. 2007AD A201). NR 41 TC 2 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1672-0733 J9 J HUAZHONG U SCI-MED JI J. Huazhong Univ. Sci. Tech.-Med. PD OCT PY 2011 VL 31 IS 5 BP 642 EP 651 DI 10.1007/s11596-011-0575-0 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 864HT UT WOS:000298230000010 PM 22038354 ER PT J AU Carlson, BA Yoo, MH Conrad, M Gladyshev, VN Hatfield, DL Park, JM AF Carlson, Bradley A. Yoo, Min-Hyuk Conrad, Marcus Gladyshev, Vadim N. Hatfield, Dolph L. Park, Jin Mo TI Protein kinase-regulated expression and immune function of thioredoxin reductase 1 in mouse macrophages SO MOLECULAR IMMUNOLOGY LA English DT Article DE Thioredoxin reductase; Macrophage; Lipopolysaccharide; VSIG4; Selenoprotein ID NF-KAPPA-B; GENE-EXPRESSION; SELENOPROTEINS; SELENOCYSTEINE; ACTIVATION; APOPTOSIS; RESPONSES; SELENIUM; MICE AB Macrophages exposed to lipopolysaccharide (LPS) exhibit radical changes in mRNA and protein profiles. This shift in gene expression is geared not only to activate immune effector and regulatory mechanisms, but also to adjust the immune cell's metabolism to new physiological demands. However, it remains largely unknown whether immune function and metabolic state are mutually regulatory and, if so, how they are mechanistically interrelated in macrophages. Selenium, a dietary trace element exerting pleiotropic effects on immune homeostasis, and selenium-containing proteins (selenoproteins) may play a role in such coordination. We examined the incorporation of radiolabeled selenium into protein during LPS stimulation, and identified thioredoxin reductase 1 (TR1) as the only LPS-inducible selenoprotein in macrophages. TR1 induction occurred at the transcriptional level and depended on the intracellular signaling pathways mediated by p38 MAP kinase and I kappa B kinase. Macrophage-specific ablation of TR1 in mice resulted in a drastic decrease in the expression of VSIG4, a B7 family protein known to suppress T cell activation. These results reveal TR1 as both a regulator and a regulated target in the macrophage gene expression network, and suggest a link between selenium metabolism and immune signaling. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Carlson, Bradley A.; Yoo, Min-Hyuk; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Conrad, Marcus] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany. [Conrad, Marcus] DZNE German Ctr Neurodegenerat Dis, Munich, Germany. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov; jmpark@cbrc2.mgh.harvard.edu RI Gladyshev, Vadim/A-9894-2013; OI Conrad, Marcus/0000-0003-1140-5612 FU National Institutes of Health (NIH), National Cancer Institute (NCI); Center for Cancer Research; NCI; NIH [AI074957, GM065204] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research, and in addition, a specific grant from the Office of Dietary Supplements, NCI, NIH, and NIH grants AI074957 (J.M.P.) and GM065204 (V.N.G.). NR 22 TC 2 Z9 2 U1 0 U2 1 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 OCT-NOV PY 2011 VL 49 IS 1-2 BP 311 EP 316 DI 10.1016/j.molimm.2011.09.001 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 862TU UT WOS:000298117800036 PM 21943784 ER PT J AU Hassan, SS Romero, R Vidyadhari, D Fusey, S Baxter, JK Khandelwal, M Vijayaraghavan, J Trivedi, Y Soma-Pillay, P Sambarey, P Dayal, A Potapov, V O'brien, J Astakhov, V Yuzko, O Kinzler, W Dattel, B Sehdev, H Mazheika, L Manchulenko, D Gervasi, MT Sullivan, L Conde-Agudelo, A Phillips, JA Creasy, GW AF Hassan, S. S. Romero, R. Vidyadhari, D. Fusey, S. Baxter, J. K. Khandelwal, M. Vijayaraghavan, J. Trivedi, Y. Soma-Pillay, P. Sambarey, P. Dayal, A. Potapov, V. O'brien, J. Astakhov, V. Yuzko, O. Kinzler, W. Dattel, B. Sehdev, H. Mazheika, L. Manchulenko, D. Gervasi, M. T. Sullivan, L. Conde-Agudelo, A. Phillips, J. A. Creasy, G. W. CA PREGNANT Trial TI Vaginal Progesterone Reduces the Rate of Preterm Birth in Women With a Sonographic Short Cervix: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB A number of interventions have been studied to prevent preterm birth and the perinatal morbidity and mortality associated with delivery of premature infants. Prevention strategies investigated include progesterone administration, cervical cerclage, and insertion of a pessary. A midtrimester sonographic short cervix is a strong predictor of preterm delivery. In a previous randomized clinical trial, vaginal progesterone capsule was found to reduce the rate of preterm delivery at <34 weeks of gestation in women with a short cervix, but it was not associated with a significant improvement in neonatal outcome. This multicenter, randomized, placebo-controlled, double-blind trial was designed to determine the efficacy and safety of vaginal progesterone gel in reducing the rate of preterm birth and associated neonatal complications in women with a midtrimester sonographic short cervix. Participants were asymptomatic women with a singleton gestation and short cervical length (10-20 mm) between 19 + 0 and 23 + 6 weeks of gestation. A total of 465 women were randomized to receive vaginal progesterone gel or placebo; 7 patients were lost to follow-up. In the final analysis, 235 women received vaginal progesterone gel and 223 received placebo. Treatment was initiated at 20 to 23 + 6 weeks of gestation and continued until 36 + 6 weeks, rupture of membranes, or delivery, whichever occurred first. The primary study end point was preterm birth before 33 weeks' gestation. The trial was conducted according to intent-to-treat. In unadjusted analysis, women who received vaginal progesterone gel had a significantly lower rate of preterm birth before 33 weeks of gestation compared with the placebo (8.9% [n = 21] vs. 16.1% [ n = 36]); the relative risk (RR) was 0.55, with a 95% confidence interval (CI) of 0.33 to 0.92; P = 0.02. After adjustment for covariables using multivariable logistic regression, the effect remained significant (adjusted RR, 0.52; 95% CI, 0.31-0.91; P = 0.02). Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks (5.1% vs. 10.3%; RR, 0.50; 95% CI, 0.25-0.97; P = 0.04) and 35 weeks' gestation (14.5% vs. 23.3%; RR, 0.62; 95% CI, 0.42-0.92; P = 0.02), respiratory distress syndrome (3.0% vs. 7.6%; RR, 0.39; 95% CI, 0.17-0.92; P = 0.03), any neonatal morbidity or mortality event (7.7% vs. 13.5%; RR, 0.57; 95% CI, 0.33-0.99; P = 0.04), and birth weight <1500 g (6.4% vs. 13.6%; RR, 0.47; 95% CI, 0.26-0.85; P = 0.01). Adverse events were comparable between the 2 groups. These findings indicate that administration of vaginal progesterone gel to women with a midtrimester short cervix is associated with a substantial reduction in the rate of preterm delivery before 33 weeks' gestation and improved neonatal outcomes. C1 [Hassan, S. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit Med Ctr, Hutzel Womens Hosp, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. MediCiti Inst Med Serv, Dept Obstet & Gynecol, Hyderabad, Andhra Pradesh, India. Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. Cooper Univ Hosp, Dept Obstet & Gynecol, Camden, NJ USA. Shri Ramchandra Med Coll & Hosp, Dept Obstet & Gynecol, Madras, Tamil Nadu, India. Sheth LG Hosp, Dept Gynecol, Ahmadabad, Gujarat, India. Steve Biko Acad Hosp, Dept Obstet & Gynaecol, Pretoria, South Africa. BJ Med Coll & Sassoon Gen Hosp, Dept Obstet & Gynecol, Pune, Maharashtra, India. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. Municipal Estab City Matern Hosp 1, Dnepropetrovsk State Med Acad, Dept Obstet & Gynecol, Dnepropetrovsk, Ukraine. Cent Baptist Hosp, Perinatal Diagnost Ctr, Lexington, KY USA. Univ Kentucky, Dept Obstet & Gynecol, Lexington, KY USA. M Gorky Donetsk Natl Med Univ, Dept Obstet & Gynecol, Municipal Hosp Cent City Clin Hosp 6, Donetsk, Ukraine. PL Shupik Natl Acad Postgrad Educ, Pechersk Reg Antenatal Out Patients Clin 1, Dept Obstet & Gynecol 1, Ukrainian State Inst Human Reproductol, Kiev, Ukraine. Winthrop Univ Hosp, Clin Trials Ctr, Mineola, NY 11501 USA. Eastern Virginia Med Sch, Dept Obstet & Gynecol, Norfolk, VA 23501 USA. Univ Penn Hlth Syst, Penn Hosp, Philadelphia, PA USA. Publ Hlth Serv Estab Minsk First City Clin, Minsk, Byelarus. Day Hosp Municipal Hlth Care Estab City Matern Ho, Dept Antenatal, Chernovtsy, Ukraine. Azienda Osped Padova, UO Ostetricia Ginecol, Padua, Italy. Boston Univ, Sch Publ Hlth, Boston, MA USA. Stat Solutions Inc, Elfand, NC USA. Columbia Labs Inc, Livingston, NJ USA. RP Hassan, SS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. OI Creasy, George/0000-0002-6645-4238 NR 2 TC 0 Z9 0 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD OCT PY 2011 VL 66 IS 10 BP 609 EP 611 DI 10.1097/OGX.0b013e31823d8a9e PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 863EQ UT WOS:000298146000007 ER PT J AU Reidy, M Masison, DC AF Reidy, Michael Masison, Daniel C. TI Modulation and elimination of yeast prions by protein chaperones and co-chaperones SO PRION LA English DT Review DE prion; amyloid; chaperone; yeast; Hsp70; Hsp40; Hsp104 ID BETA-SHEET STRUCTURE; NUCLEOTIDE EXCHANGE FACTOR; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; HSP104 CHAPERONE; ANTAGONISTIC INTERACTIONS; SUP35 POLYMERS; HSP70; PROPAGATION; URE3 AB The yeast system has provided considerable insight into the biology of amyloid and prions. Here we focus on how alterations in abundance or function of protein chaperones and co-chaperones affect propagation of yeast prions. In spite of a considerable amount of information, a clear understanding of the molecular mechanisms underlying these effects remains wanting. C1 [Reidy, Michael; Masison, Daniel C.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov OI Reidy, Michael/0000-0002-9290-7595 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank NIH colleagues for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 57 TC 20 Z9 20 U1 2 U2 17 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD OCT-DEC PY 2011 VL 5 IS 4 SI SI BP 245 EP 249 DI 10.4161/pri.5.4.17749 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873YN UT WOS:000298922100003 PM 22052352 ER PT J AU Wickner, RB Edskes, HK Bateman, D Kelly, AC Gorkovskiy, A AF Wickner, Reed B. Edskes, Herman K. Bateman, David Kelly, Amy C. Gorkovskiy, Anton TI The yeast prions [PSI+] and [URE3] are molecular degenerative diseases SO PRION LA English DT Review DE [URE3]; [PSI+]; prion; Sup35p; Ure2p ID TERMINATION FACTOR ERF3; 2-MU-M CIRCLE PLASMID; HET-S PRION; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; SEXUAL TRANSMISSION; SPECIES BARRIER; SUP35 PROTEIN; SELFISH DNA; INCOMPATIBILITY AB The yeast prions [URE3] and [PSI] are not found in wild strains, suggesting they are not an advantage. Prion-forming ability is not conserved, even within Saccharomyces, suggesting it is a disease. Prion domains have non-prion functions, explaining some conservation of sequence. However, in spite of the sequence being constrained in evolution by these non-prion functions, the prion domains vary more rapidly than the remainder of the molecule, and these changes produce a transmission barrier, suggesting that these changes were selected to block prion infection. Yeast prions [PSI] and [URE3] induce a cellular stress response (Hsp104 and Hsp70 induction), suggesting the cells are not happy about being infected. Recently, we showed that the array of [PSI] and [URE3] prions includes a majority of lethal or very toxic variants, a result not expected if either prion were an adaptive cellular response to stress. C1 [Wickner, Reed B.; Edskes, Herman K.; Bateman, David; Kelly, Amy C.; Gorkovskiy, Anton] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Gorkovskiy, Anton/J-8930-2016 OI Gorkovskiy, Anton/0000-0003-4811-2282 FU National Institute of Diabetes Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes Digestive and Kidney Diseases. NR 48 TC 24 Z9 25 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD OCT-DEC PY 2011 VL 5 IS 4 SI SI BP 258 EP 262 DI 10.4161/pri.5.4.17748 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873YN UT WOS:000298922100005 PM 22052353 ER PT J AU Evans, ML Schmidt, JC Ilbert, M Doyle, SM Quan, S Bardwell, JCA Jakob, U Wickner, S Chapman, MR AF Evans, Margery L. Schmidt, Jens C. Ilbert, Marianne Doyle, Shannon M. Quan, Shu Bardwell, James C. A. Jakob, Ursula Wickner, Sue Chapman, Matthew R. TI E-coli chaperones DnaK, Hsp33 and Spy inhibit bacterial functional amyloid assembly SO PRION LA English DT Article DE chaperone; curli; functional amyloid; CsgA; DnaK; Hsp33; Spy ID THIN AGGREGATIVE FIMBRIAE; DEPENDENT REACTION CYCLE; REDOX-SWITCH DOMAIN; HEAT-SHOCK-PROTEIN; SALMONELLA-ENTERITIDIS; CURLI FIBERS; SACCHAROMYCES-CEREVISIAE; STREPTOMYCES-COELICOLOR; FIBRONECTIN-BINDING; ALZHEIMERS-DISEASE AB Amyloid formation is an ordered aggregation process, where beta-sheet rich polymers are assembled from unstructured or partially folded monomers. We examined how two Escherichia coli cytosolic chaperones, DnaK and Hsp33, and a more recently characterized periplasmic chaperone, Spy, modulate the aggregation of a functional amyloid protein, CsgA. We found that DnaK, the Hsp70 homolog in E. coli, and Hsp33, a redox-regulated holdase, potently inhibited CsgA amyloidogenesis. The Hsp33 anti-amyloidogenesis activity was oxidation dependent, as oxidized Hsp33 was significantly more efficient than reduced Hsp33 at preventing CsgA aggregation. When soluble CsgA was seeded with preformed amyloid fibers, neither Hsp33 nor DnaK were able to efficiently prevent soluble CsgA from adopting the amyloid conformation. Moreover, both DnaK and Hsp33 increased the time that CsgA was reactive with the amyloid oligomer conformation-specific A11 antibody. Since CsgA must also pass through the periplasm during secretion, we assessed the ability of the periplasmic chaperone Spy to inhibit CsgA polymerization. Like DnaK and Hsp33, Spy also inhibited CsgA polymerization in vitro. Overexpression of Spy resulted in increased chaperone activity in periplasmic extracts and in reduced curli biogenesis in vivo. We propose that DnaK, Hsp33 and Spy exert their effects during the nucleation stages of CsgA fibrillation. Thus, both housekeeping and stress induced cytosolic and periplasmic chaperones may be involved in discouraging premature CsgA interactions during curli biogenesis. C1 [Evans, Margery L.; Schmidt, Jens C.; Ilbert, Marianne; Quan, Shu; Bardwell, James C. A.; Jakob, Ursula; Chapman, Matthew R.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Doyle, Shannon M.; Wickner, Sue] NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Chapman, MR (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. EM chapmanm@umich.edu RI Quan, Shu/O-4562-2015 OI Quan, Shu/0000-0002-6672-4947 FU NIH [RO1 A1073847, GM065318]; NIH NRSA [T32 GM008353]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We would like to thank the members of the Chapman lab for helpful discussions and review of this manuscript. This work was supported by NIH grants RO1 A1073847 and GM065318, by NIH NRSA T32 GM008353 and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 86 TC 11 Z9 11 U1 2 U2 13 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 J9 PRION JI Prion PD OCT-DEC PY 2011 VL 5 IS 4 SI SI BP 323 EP 334 DI 10.4161/pri.5.4.18555 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873YN UT WOS:000298922100015 PM 22156728 ER PT J AU Larson, DR AF Larson, Daniel R. TI What do expression dynamics tell us about the mechanism of transcription? SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID STOCHASTIC GENE-EXPRESSION; REAL-TIME ANALYSIS; IN-VIVO; GLUCOCORTICOID-RECEPTOR; MESSENGER-RNA; LIVING CELLS; ORDERED RECRUITMENT; MAMMALIAN-CELLS; RAPID EXCHANGE; PROMOTER AB Single-cell microscopy studies have the potential to provide an unprecedented view of gene expression with exquisite spatial and temporal sensitivity. However, there is a challenge to connect the holistic cellular view with a reductionist biochemical view. In particular, experimental efforts to characterize the in vivo regulation of transcription have focused primarily on measurements of the dynamics of transcription factors and chromatin modifying factors. Such measurements have elucidated the transient nature of many nuclear interactions. In the past few years, experimental approaches have emerged that allow for interrogation of the output of transcription at the single-molecule, single-cell level. Here, I summarize the experimental results and models that aim to provide an integrated view of transcriptional regulation. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Larson, DR (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM dan.larson@nih.gov RI Larson, Daniel/B-9829-2008 OI Larson, Daniel/0000-0001-9253-3055 FU NIH, National Cancer Institute, Center for Cancer Research FX Thanks to A Coulon, Y Dalal, I Golding, and K Willis for critical reading of the manuscript. D Suter, I Golding, and C Harper kindly provided original images for Figure 1. DRL is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 78 TC 38 Z9 39 U1 1 U2 23 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD OCT PY 2011 VL 21 IS 5 BP 591 EP 599 DI 10.1016/j.gde.2011.07.010 PG 9 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 860RO UT WOS:000297965600011 PM 21862317 ER PT J AU Geng, XJ Gu, H Shin, WY Ross, TJ Yang, YH AF Geng, Xiujuan Gu, Hong Shin, Wanyong Ross, Thomas J. Yang, Yihong TI Unbiased Group-Wise Image Registration: Applications in Brain Fiber Tract Atlas Construction and Functional Connectivity Analysis SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Group-wise image registration; DTI; Fractional anisotropy; Fiber tract; Resting-state fMRI ID DIFFUSION TENSOR; MRI; ECHO AB We propose an unbiased implicit-reference group-wise (IRG) image registration method and demonstrate its applications in the construction of a brain white matter fiber tract atlas and the analysis of resting-state functional MRI (fMRI) connectivity. Most image registration techniques pair-wise align images to a selected reference image and group analyses are performed in the reference space, which may produce bias. The proposed method jointly estimates transformations, with an elastic deformation model, registering all images to an implicit reference corresponding to the group average. The unbiased registration is applied to build a fiber tract atlas by registering a group of diffusion tensor images. Compared to reference-based registration, the IRG registration improves the fiber track overlap within the group. After applying the method in the fMRI connectivity analysis, results suggest a general improvement in functional connectivity maps at a group level in terms of larger cluster size and higher average t-scores. C1 [Geng, Xiujuan; Gu, Hong; Shin, Wanyong; Ross, Thomas J.; Yang, Yihong] NIDA, Neuroimaging Res Branch, Baltimore, MD USA. RP Geng, XJ (reprint author), NIDA, Neuroimaging Res Branch, Baltimore, MD USA. EM gengx@nida.nih.gov RI Geng, Xiujuan/I-3852-2012; Ross, Thomas/B-7469-2008 OI Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse (NIDA), National Institute of Health (NIH) FX This work was supported in part by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institute of Health (NIH). NR 28 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 J9 J MED SYST JI J. Med. Syst. PD OCT PY 2011 VL 35 IS 5 SI SI BP 921 EP 928 DI 10.1007/s10916-010-9509-9 PG 8 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 859DZ UT WOS:000297856600022 PM 20703687 ER PT J AU Mattai, A Miller, R Weisinger, B Greenstein, D Bakalar, J Tossell, J David, C Wassermann, EM Rapoport, J Gogtay, N AF Mattai, Anand Miller, Rachel Weisinger, Brian Greenstein, Deanna Bakalar, Jennifer Tossell, Julia David, Christopher Wassermann, Eric M. Rapoport, Judith Gogtay, Nitin TI Tolerability of transcranial direct current stimulation in childhood-onset schizophrenia SO BRAIN STIMULATION LA English DT Article DE dorsolateral prefrontal cortex; transcranial direct current stimulation; childhood-onset schizophrenia ID HUMAN MOTOR CORTEX; NONINVASIVE CORTICAL STIMULATION; EXCITABILITY CHANGES; PARKINSONS-DISEASE; EVOKED-POTENTIALS; BRAIN-STIMULATION; REPEATED SESSIONS; HEALTHY-SUBJECTS; WORKING-MEMORY; DC STIMULATION AB Background In recent years, transcranial direct current stimulation (tDCS) has been used to study and treat many neuropsychiatric conditions. However, information regarding its tolerability in the pediatric population is lacking. Objective This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population. Methods Twelve participants with COS completed this inpatient study. Participants were assigned to one of two groups: bilateral anodal dorsolateral prefrontal cortex (DLPFC) stimulation (n = 8) or bilateral cathodal superior temporal gyrus (STG) stimulation (n = 5). Patients received either 2 mA of active treatment or sham treatment (with possibility of open active treatment) for 20 minutes, for a total of 10 sessions (2 weeks). Results tDCS was well tolerated in the COS population with no serious adverse events occurring during the study. Conclusions This is the first study to demonstrate that a 20-minute duration of 2 mA of bilateral anodal and bilateral cathodal DC polarization to the DLPFC and STG was well tolerated in a pediatric population. Published by Elsevier Inc. C1 [Mattai, Anand; Miller, Rachel; Weisinger, Brian; Greenstein, Deanna; Bakalar, Jennifer; Tossell, Julia; David, Christopher; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Wassermann, Eric M.] NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. RP Mattai, A (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM mattaia@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 FU Intramural NIH HHS [Z99 MH999999] NR 38 TC 45 Z9 45 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD OCT PY 2011 VL 4 IS 4 BP 275 EP 280 DI 10.1016/j.brs.2011.01.001 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 855MP UT WOS:000297568800012 PM 22032743 ER PT J AU Doppalapudi, RS Riccio, ES Davis, Z Menda, S Du, NN Green, CE Kapetanovic, IM AF Doppalapudi, R. S. Riccio, E. S. Davis, Z. Menda, S. Du, N. N. Green, C. E. Kapetanovic, I. M. TI Genotoxicity of Chemopreventive Agents. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Doppalapudi, R. S.; Riccio, E. S.; Davis, Z.; Menda, S.; Du, N. N.; Green, C. E.] SRI Int, Menlo Pk, CA 94025 USA. [Kapetanovic, I. M.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S71 EP S71 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800239 ER PT J AU Euling, SY White, L Ovacik, AM Makris, SL Sen, B Androulakis, IP Hester, S Gaido, KW Kim, AS Benson, R Wilson, VS Keshava, C Keshava, N Foster, PM Gray, LE Chiu, WA Thompson, C AF Euling, S. Y. White, L. Ovacik, A. M. Makris, S. L. Sen, B. Androulakis, I. P. Hester, S. Gaido, K. W. Kim, A. S. Benson, R. Wilson, V. S. Keshava, C. Keshava, N. Foster, P. M. Gray, Jr. L. E. Chiu, W. A. Thompson, C. TI An Approach to Using Toxicogenomic Data in Risk Assessment: Dibutyl Phthalate Case Study. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Euling, S. Y.; Makris, S. L.; Chiu, W. A.] US EPA, NCEA, Washington, DC 20460 USA. [Hester, S.; Wilson, V. S.; Keshava, C.; Keshava, N.; Gray, Jr. L. E.] US EPA, Res Triangle Pk, NC 27711 USA. [White, L.; Sen, B.; Foster, P. M.] NIEHS, Res Triangle Pk, NC 27709 USA. [Ovacik, A. M.; Androulakis, I. P.] Rutgers State Univ, UMDNJ, ebCTC, Piscataway, NJ USA. [Gaido, K. W.] US FDA, Rockville, MD 20857 USA. [Kim, A. S.] Allergan Pharmaceut Inc, Irvine, CA USA. [Benson, R.] US EPA, Denver, CO USA. [Thompson, C.] ToxStrategies Inc, Katy, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S16 EP S16 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800016 ER PT J AU Hobbs, CA Chhabra, RS Recio, L Winters, J Shepard, K Allen, P Streicker, M Witt, KL AF Hobbs, C. A. Chhabra, R. S. Recio, L. Winters, J. Shepard, K. Allen, P. Streicker, M. Witt, K. L. TI Genotoxicity of Styrene-Acrylonitrile Trimer in Brain, Liver, and Blood Cells of Weanling F344 Rats. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Hobbs, C. A.; Recio, L.; Winters, J.; Shepard, K.; Allen, P.] ILS Inc, Genet & Mol Toxicol Div, Res Triangle Pk, NC USA. [Streicker, M.] ILS Inc, Investigat Toxicol Div, Res Triangle Pk, NC USA. [Chhabra, R. S.; Witt, K. L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S72 EP S72 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800241 ER PT J AU Kasiviswanathan, R Gustafson, M Copeland, W Meyer, J AF Kasiviswanathan, R. Gustafson, M. Copeland, W. Meyer, J. TI Human Mitochondrial DNA Polymerase gamma Exhibits Potential for Bypass and Mutagenesis at UV-Induced Cyclobutane Thymine Dimers. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Gustafson, M.; Meyer, J.] Duke Univ, Durham, NC USA. [Kasiviswanathan, R.; Copeland, W.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S48 EP S48 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800144 ER PT J AU Momot, D John, K Poirier, MC Olivero, OA AF Momot, D. John, K. Poirier, M. C. Olivero, O. A. TI Zidovudine (AZT)-Induced Genotoxicity in DNA Repair-Deficient Human Fibroblasts. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Momot, D.; John, K.; Poirier, M. C.; Olivero, O. A.] NCI, Bethesda, MD 20892 USA. [Momot, D.] Temple Univ, Philadelphia, PA 19122 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S44 EP S44 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800130 ER PT J AU Myatt, GJ Bower, D Cross, K Crump, M Miller, S Saiakhov, R Tice, RR AF Myatt, G. J. Bower, D. Cross, K. Crump, M. Miller, S. Saiakhov, R. Tice, R. R. TI Providing a Single Point of Access to Genetic Toxicity Models and Data SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Myatt, G. J.; Bower, D.; Cross, K.; Crump, M.; Miller, S.] Leadscope Inc, Columbus, OH USA. [Tice, R. R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Saiakhov, R.] MultiCASE Inc, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S76 EP S76 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800259 ER PT J AU Nguyen, PG Liu, YM Poirier, MC AF Nguyen, P. G. Liu, Y. M. Poirier, M. C. TI Toxicity of Anti-HIV Drugs and the Use of Tempol As a Therapeutic Agent. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Nguyen, P. G.; Liu, Y. M.; Poirier, M. C.] NIH, Bethesda, MD 20892 USA. [Nguyen, P. G.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S74 EP S74 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800248 ER PT J AU Swartz, CD Lentz, C Baldetti, C Garibaldi, P Recio, L Witt, KL AF Swartz, C. D. Lentz, C. Baldetti, C. Garibaldi, P. Recio, L. Witt, K. L. TI Mutagenicity of AIDS Therapeutics in a Bacterial Reverse Mutation Assay. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Swartz, C. D.; Lentz, C.; Baldetti, C.; Garibaldi, P.; Recio, L.] Integrated Syst Lab, Res Triangle Pk, NC USA. [Witt, K. L.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S70 EP S70 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800235 ER PT J AU Witt, KL AF Witt, K. L. TI The US Tox21 Effort: Current Status. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Witt, K. L.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S35 EP S35 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800092 ER PT J AU Conley, B Jessup, J Lively, T Williams, M AF Conley, B. Jessup, J. Lively, T. Williams, M. TI Clinical Assay Development Program SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 5th European-Organisation-for-Research-and-Treatment-of-Cancer (EORTC)/National-Cancer-Institute (NCI)/American-Society-of-Clinical-Oncology (ASCO) Annual Meeting on Molecular Markers in Cancer CY OCT 27-29, 2011 CL Brussels, BELGIUM SP European Org Res & Treatment Canc (EORTC), Natl Canc Inst (NCI), Amer Soc Clin Oncol (ASCO) C1 [Conley, B.; Jessup, J.; Lively, T.; Williams, M.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2011 VL 47 SU 4 BP S15 EP S15 PG 1 WC Oncology SC Oncology GA 853UT UT WOS:000297451900055 ER PT J AU Jacobs, P AF Jacobs, P. TI Translating molecular imaging agents into phase 3 trials SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 5th European-Organisation-for-Research-and-Treatment-of-Cancer (EORTC)/National-Cancer-Institute (NCI)/American-Society-of-Clinical-Oncology (ASCO) Annual Meeting on Molecular Markers in Cancer CY OCT 27-29, 2011 CL Brussels, BELGIUM SP European Org Res & Treatment Canc (EORTC), Natl Canc Inst (NCI), Amer Soc Clin Oncol (ASCO) C1 [Jacobs, P.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2011 VL 47 SU 4 BP S2 EP S3 PG 2 WC Oncology SC Oncology GA 853UT UT WOS:000297451900009 ER PT J AU McShane, LM AF McShane, L. M. TI Requirements for prospective use of omics-based tests in NCl-sponsored trials SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 5th European-Organisation-for-Research-and-Treatment-of-Cancer (EORTC)/National-Cancer-Institute (NCI)/American-Society-of-Clinical-Oncology (ASCO) Annual Meeting on Molecular Markers in Cancer CY OCT 27-29, 2011 CL Brussels, BELGIUM SP European Org Res & Treatment Canc (EORTC), Natl Canc Inst (NCI), Amer Soc Clin Oncol (ASCO) C1 [McShane, L. M.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2011 VL 47 SU 4 BP S4 EP S4 PG 1 WC Oncology SC Oncology GA 853UT UT WOS:000297451900014 ER PT J AU Shankar, L AF Shankar, L. TI Functional activity versus clinical predictivity SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 5th European-Organisation-for-Research-and-Treatment-of-Cancer (EORTC)/National-Cancer-Institute (NCI)/American-Society-of-Clinical-Oncology (ASCO) Annual Meeting on Molecular Markers in Cancer CY OCT 27-29, 2011 CL Brussels, BELGIUM SP European Org Res & Treatment Canc (EORTC), Natl Canc Inst (NCI), Amer Soc Clin Oncol (ASCO) C1 [Shankar, L.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2011 VL 47 SU 4 BP S5 EP S5 PG 1 WC Oncology SC Oncology GA 853UT UT WOS:000297451900019 ER PT J AU Wei, W Li, X Zhou, QF Shung, KK Chen, ZP AF Wei, Wei Li, Xiang Zhou, Qifa Shung, K. Kirk Chen, Zhongping TI Integrated ultrasound and photoacoustic probe for co-registered intravascular imaging SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE ultrasound; photoacoustic imaging; endoscopic imaging ID OPTICAL COHERENCE TOMOGRAPHY; ATHEROSCLEROSIS; MICROSCOPY; PLAQUE AB We report on the synergy of an integrated ultrasound (US) and photoacoustic (PA) probe system for intravascular imaging. The combined dual-modality probe is based on a 39 MHz ring-shaped US transducer which detects both US echoes and laser-generated PA signals. By combining optical fiber, US transducer, and micromirror, we can obtain intravascular cross-sectional B-scan images by internal illumination of the sample. The performance of the probe is evaluated in a phantom study. Moreover, the coaxially designed probe also provides co-registered US and PA images of a normal rabbit aorta, which demonstrates the imaging ability of the dual-functional system, implying future clinical applications. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3631798] C1 [Wei, Wei; Chen, Zhongping] Univ Calif Irvine, Beckman Laser Inst & Med Clin, Dept Biomed Engn, Irvine, CA 92612 USA. [Wei, Wei] Wuhan Univ, Dept Phys, Wuhan 430072, Peoples R China. [Wei, Wei] Minist Educ, Key Lab Acoust & Photon Mat & Devices, Wuhan 430072, Peoples R China. [Li, Xiang; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Li, Xiang; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Chen, ZP (reprint author), Univ Calif Irvine, Beckman Laser Inst & Med Clin, Dept Biomed Engn, Irvine, CA 92612 USA. EM qifazhou@usc.edu; z2chen@uci.edu FU NIH [EB-00293, EB-10090, RR-01192, P41-EB2182]; U.S. Air Force Office of Scientific Research [FA9550-08-1-0384]; China Scholarship Council (CSC) FX We would like to thank Ms. Hongrui Li for preparing the tissue. This work is based on the research supported by the NIH (Grant Nos. EB-00293, EB-10090, RR-01192, and P41-EB2182) and the U.S. Air Force Office of Scientific Research, Medical Free-Electron Laser Program Grant No. FA9550-08-1-0384. Wei Wei is supported in part by the China Scholarship Council (CSC) and works as a joint Ph.D. student at the Beckman Laser Institute and Medical Clinic, University of California, Irvine. NR 29 TC 22 Z9 23 U1 0 U2 13 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2011 VL 16 IS 10 AR 106001 DI 10.1117/1.3631798 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 853ZV UT WOS:000297465200008 PM 22029348 ER PT J AU Wang, L Xiong, YM Bosselut, R AF Wang, Lie Xiong, Yumei Bosselut, Remy TI Maintaining CD4-CD8 lineage integrity in T cells: Where plasticity serves versatility SO SEMINARS IN IMMUNOLOGY LA English DT Review DE T cell differentiation; CD4-CD8 commitment; T cells; Transcriptional control; Epigenetic control ID RUNX TRANSCRIPTION FACTORS; DIFFERENTIATION IN-VIVO; HELPER TYPE-1 CELLS; LONG NONCODING RNA; LYMPHOCYTE DEVELOPMENT; POSITIVE SELECTION; GENE-EXPRESSION; CD4 EXPRESSION; THYMOCYTE DIFFERENTIATION; MOLECULAR-MECHANISMS AB The divergence of the two alpha beta T cell subsets defined by the mutually exclusive expression of CD4 and CD8 glycoproteins is an important event during the intrathymic differentiation of T lymphocytes. This reviews briefly summarizes the mechanisms that promote commitment to the CD4 or CD8 lineage in the thymus, and discusses the transcription factor circuits and epigenetic mechanisms that concur to maintain lineage integrity in post-thymic cells and yet allow effector cell differentiation. Published by Elsevier Ltd. C1 [Wang, Lie; Xiong, Yumei; Bosselut, Remy] NCI, Lab Immune Cell Biol, CCR, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, CCR, NIH, Bldg 37,Room 3015,37 Convent Dr, Bethesda, MD 20892 USA. EM remy@helix.nih.gov FU National Cancer Institute, Center for Cancer Research, NIH FX We thank Yasmine Belkaid, Avinash Bhandoola and Jinfang Zhu for stimulating discussions and Melanie Vacchio for reading the manuscript. Research work in the authors' laboratory is supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 94 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD OCT PY 2011 VL 23 IS 5 BP 360 EP 367 DI 10.1016/j.smim.2011.08.008 PG 8 WC Immunology SC Immunology GA 853SZ UT WOS:000297447300007 PM 21963088 ER PT J AU Smith, SA Williams, ZR Ratchford, JN Newsome, SD Farrell, SK Farrell, JAD Gifford, A Miller, NR van Zijl, PCM Calabresi, PA Reich, DS AF Smith, S. A. Williams, Z. R. Ratchford, J. N. Newsome, S. D. Farrell, S. K. Farrell, J. A. D. Gifford, A. Miller, N. R. van Zijl, P. C. M. Calabresi, P. A. Reich, D. S. TI Diffusion Tensor Imaging of the Optic Nerve in Multiple Sclerosis: Association with Retinal Damage and Visual Disability SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID PRINCIPAL EIGENVECTOR MEASUREMENTS; MAGNETIZATION-TRANSFER; FRACTIONAL ANISOTROPY; MEAN DIFFUSIVITY; NEURITIS; MRI; DTI; REPRODUCIBILITY; DYSFUNCTION; RESOLUTION AB BACKGROUND AND PURPOSE: There is a well-known relationship between MS and damage to the optic nerve, but advanced, quantitative MR imaging methods have not been applied to large cohorts. Our objective was to determine whether a short imaging protocol (<10 minutes), implemented with standard hardware, could detect abnormal water diffusion in the optic nerves of patients with MS. MATERIALS AND METHODS: We examined water diffusion in human optic nerves via DTI in the largest MS cohort reported to date (104 individuals, including 38 optic nerves previously affected by optic neuritis). We also assessed whether such abnormalities are associated with loss of visual acuity (both high and low contrast) and damage to the retinal nerve fiber layer (assessed via optical coherence tomography). RESULTS: The most abnormal diffusion was found in the optic nerves of patients with SPMS, especially in optic nerves previously affected by optic neuritis (19% drop in FA). DTI abnormalities correlated with both retinal nerve fiber layer thinning (correlation coefficient, 0.41) and loss of visual acuity, particularly at high contrast and in nerves previously affected by optic neuritis (correlation coefficient, 0.54). However, diffusion abnormalities were overall less pronounced than retinal nerve fiber layer thinning. CONCLUSIONS: DTI is sensitive to optic nerve damage in patients with MS, but a short imaging sequence added to standard clinical protocols may not be the most reliable indicator of optic nerve damage. C1 [Smith, S. A.] Vanderbilt Univ, Dept Radiol & Radiol Sci, Inst Imaging Sci, Nashville, TN 37232 USA. [Smith, S. A.; Farrell, J. A. D.; van Zijl, P. C. M.; Reich, D. S.] Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Smith, S. A.; Farrell, J. A. D.; van Zijl, P. C. M.] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD USA. [Williams, Z. R.; Miller, N. R.] Wilmer Eye Inst, Baltimore, MD 21287 USA. [Ratchford, J. N.; Newsome, S. D.; Farrell, S. K.; Calabresi, P. A.; Reich, D. S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Gifford, A.] Johns Hopkins Univ, Dept Neurogenet, Baltimore, MD USA. [Reich, D. S.] NINDS, NIH, Bethesda, MD 20892 USA. RP Smith, SA (reprint author), Vanderbilt Univ, Dept Radiol & Radiol Sci, Inst Imaging Sci, 1161 21st Ave S,MCN AAA3111, Nashville, TN 37232 USA. EM seth.smith@vanderbilt.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU National Multiple Sclerosis Society [TR3760A3]; National Institutes of Health [K01EB009120, K99NS064098, P41RR015241]; National Institutes of Health, National Institute of Neurological Disorders and Stroke; EMD Serono; Novartis; University of California, Los Angeles; Philips Healthcare; Heidelberg Engineering; Biogen-Idec; Teva; Bayer; Serono; Genentech; Vertex FX This study was supported by the National Multiple Sclerosis Society (grant TR3760A3), the National Institutes of Health (grants K01EB009120, K99NS064098, and P41RR015241, and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke), and an unrestricted grant from EMD Serono to support data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.; John N. Ratchford: Research Support (including provision of equipment or materials): Novartis, University of California, Los Angeles. Details: I receive salary support in my function as the site PI for 2 clinical trials funded by Novartis and 1 funded by UCLA. Consultant: Sun Pharamceuticals. Derails: Consulted on design of a clinical trial. Ownership Interest: Merck & Co, Inc. Details: Stockholder. Scott D. Newsome: Consultant: Biogen Idec. Details: Attended Advisory Board meeting and has given dinner talks. Peter van Zijl: Research Support (including provision of equipment or materials): Philips Healthcare. Details: Grant for research support. Speaker Bureau: Philips Healthcare. Details: Fees for lecturing. Peter A. Calabresi: Research Support (including provision of equipment or materials): Heidelberg Engineering, Biogen-Idec, Teva, Bayer, Serono, Genentech, Vertex, and Novartis. Details: Heidelberg provided an OCT scanner to our clinic as a loaner. The one used in this paper was from their competitor, Zeiss. All other affiliations are for clinical trials in MS or basic science lab projects unrelated to topic of this paper. Consultant: Biogen-Idec, Teva, Novonordisk, Serono, and Novartis. Details: For MS research projects unrelated to this paper. NR 39 TC 17 Z9 18 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2011 VL 32 IS 9 BP 1662 EP 1668 DI 10.3174/ajnr.A2574 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 849RL UT WOS:000297142700018 PM 21799043 ER PT J AU Alba, MI Guthrie, LC Ward, MM AF Alba, Maria I. Guthrie, Lori C. Ward, Michael M. TI Sensitivity and Specificity of the American College of Rheumatology and Europe League Against Rheumatism Response Criteria in Rheumatoid Arthritis for Changes Important to Patients: Is An ACR20 Meaningful? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Alba, Maria I.; Guthrie, Lori C.; Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 136 BP S49 EP S49 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500137 ER PT J AU Bethi, S Dasgupta, A Weisman, MH Learch, TJ Gensler, LS Davis, JC Reveille, JD Ward, MM AF Bethi, Siddharth Dasgupta, Abhijit Weisman, Michael H. Learch, Thomas J. Gensler, Lianne S. Davis, John C. Reveille, John D. Ward, Michael M. TI Associations Between Axial and Peripheral Signs of Ankylosing Spondylitis and the Acute Phase Response: A Prospective Longitudinal Study in 411 Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Bethi, Siddharth; Dasgupta, Abhijit; Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Learch, Thomas J.] Cedars Sinai, Los Angeles, CA USA. [Gensler, Lianne S.] UCSF, San Francisco, CA USA. [Davis, John C.] Genentech Inc, San Francisco, CA USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 518 BP S199 EP S200 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500518 ER PT J AU Dema, B Hasni, SA Jiang, C Hardwick, DF Charles, N Illei, GG Rivera, J AF Dema, Barbara Hasni, Sarfaraz A. Jiang, Chao Hardwick, Donna F. Charles, Nicolas Illei, Gabor G. Rivera, Juan TI Auto-Reactive IgEs and Basophils in Systemic Lupus Erythematosus. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Dema, Barbara; Jiang, Chao; Rivera, Juan] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD USA. [Charles, Nicolas] Inst Natl Sante & Res Med, Paris, France. [Illei, Gabor G.] NIDCR NIH 10 1N110, Bethesda, MD USA. [Hardwick, Donna F.] NIH MSC 1616, Bethesda, MD USA. RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 662 BP S257 EP S258 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500658 ER PT J AU Dillon, SP Kao, L Kaufman, KM Ice, JA Omdal, R Mariette, X Witte, T Illei, GG Rischmueller, M Nordmark, G Jonsson, R Herlenius, MW Vyse, TJ Brennan, MT Rybicki, BA Ng, WF Segal, BM Rhodus, NL Merrill, JT Montgomery, CG Lessard, CJ Harley, JB Moser, KL Gaffney, PM Scofield, RH AF Dillon, Skyler P. Kao, Lydia Kaufman, Kenneth M. Ice, John A. Omdal, Roald Mariette, Xavier Witte, Torsten Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Jonsson, Roland Herlenius, Marie Wahren Vyse, Timothy J. Brennan, Michael T. Rybicki, Benjamin A. Ng, Wan-Fai Segal, Barbara M. Rhodus, Nelson L. Merrill, Joan T. Montgomery, Courtney G. Lessard, Christopher J. Harley, John B. Moser, Kathy L. Gaffney, Patrick M. Scofield, R. Hal TI Triple X Syndrome (47,XXX) Increases the Risk and Accelerates the Onset of Systemic Lupus Erythematosus and Sjogren's Syndrome: Support for a Gene-Dose Effect From the X Chromosome SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Dillon, Skyler P.; Kao, Lydia] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Mariette, Xavier] Univ Paris 11, Le Kremlin Bicetre, France. [Witte, Torsten] Hannover Med Sch, Hannover, Germany. [Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Herlenius, Marie Wahren] CMM L8204 Karolinska Hosp, Stockholm, Sweden. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Rybicki, Benjamin A.] Henry Ford Hlth Syst, Detroit, MI USA. [Ng, Wan-Fai] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Moser, Kathy L.; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK USA. RI Witte, Torsten/B-5783-2016 NR 0 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 643 BP S251 EP S251 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500639 ER PT J AU Engel, OHG Sanchez, C Dvir-Ginzberg, M Gagarina, V Lee, EJ Zaal, KJ McBurney, M Hall, DJ AF Engel, Odile H. Gabay Sanchez, Christelle Dvir-Ginzberg, Mona Gagarina, Viktoria Lee, Eun Jin Zaal, Kristien J. McBurney, Michael Hall, David J. TI Sirt1 Deficient Mice Exhibit An Altered Cartilage Phenotype SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Engel, Odile H. Gabay; Gagarina, Viktoria; Lee, Eun Jin; Zaal, Kristien J.; Hall, David J.] NIH, Bethesda, MD 20892 USA. [Sanchez, Christelle] Bone & Cartilage Res Unit, Liege, Belgium. [Dvir-Ginzberg, Mona] Hebrew Univ Hadassah Ein Kerem, Jerusalem, Israel. [McBurney, Michael] Ottawa Hosp, Ottawa, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1795 BP S702 EP S702 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502181 ER PT J AU Eudy, A Vines, AI Poole, C Parks, CG AF Eudy, Amanda Vines, Anissa I. Poole, Charles Parks, Christine G. CA Carolina Lupus Study Investigators TI Everyday Stress, C-Reactive Protein, and Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Eudy, Amanda; Vines, Anissa I.; Poole, Charles] Univ N Carolina, Chapel Hill, NC USA. [Parks, Christine G.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1857 BP S724 EP S724 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502243 ER PT J AU Fert, I Cagnard, N Glatigny, S Letourneur, F Jacques, S Krause, L Colbert, RA Chiocchia, G Breban, MA AF Fert, Ingrid Cagnard, Nicolas Glatigny, Simon Letourneur, Franck Jacques, Sebastien Krause, Luiza Colbert, Robert A. Chiocchia, Gilles Breban, Maxime A. TI A Reverse Interferon-gamma Signature Is Shared by CD103+CD4+Dendritic Cells From HLA-B27 Transgenic Rat and Macrophages From Ankylosing Spondylitis Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Fert, Ingrid; Cagnard, Nicolas; Glatigny, Simon; Letourneur, Franck; Jacques, Sebastien; Krause, Luiza; Chiocchia, Gilles] Inst Cochin Genet Mol, F-75014 Paris, France. [Colbert, Robert A.] NIAMS NIH, Bethesda, MD USA. [Breban, Maxime A.] Hop Ambroise Pare, Boulogne, France. RI chiocchia, gilles/F-6287-2013 OI chiocchia, gilles/0000-0001-9973-0940 NR 0 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1701 BP S666 EP S667 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502086 ER PT J AU Fike, A Kline, K Martinez, J Gourley, MF AF Fike, Alice Kline, Katherine Martinez, Jorel Gourley, Mark F. TI "Lo Que Me Diga El Doctor": Patient Reported Interpersonal Processes of Care in An Urban Rheumatology Clinic. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Kline, Katherine] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1574 BP S614 EP S615 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501768 ER PT J AU Gallo, A Tandon, M Jang, SI Ong, HL Ambudkar, I Illei, GG Alevizos, I AF Gallo, Alessia Tandon, Mayank Jang, Shyh-Ing Ong, Hwei Ling Ambudkar, Indu Illei, Gabor G. Alevizos, Ilias TI Functional Delivery of EBV-Mir-BART13 by exosomes in Human Salivary Gland Cells Affects Calcium Signaling SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Illei, Gabor G.] NIDCR, NIH 10 1N110, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 775 BP S304 EP S304 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500771 ER PT J AU Gallo, A Tandon, M Illei, GG Alevizos, I AF Gallo, Alessia Tandon, Mayank Illei, Gabor G. Alevizos, Ilias TI The Majority of Micrornas in Serum and Saliva Is Concentrated in Exosomes SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 497 BP S190 EP S190 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500497 ER PT J AU Gilliam, BE Ombrello, AK Burlingame, RW Pepmueller, PH Moore, TL AF Gilliam, Brooke E. Ombrello, Amanda K. Burlingame, Rufus W. Pepmueller, Peri H. Moore, Terry L. TI Evaluation of An Autoantibody Profile in Pediatric- and Adolescent-Onset Systemic Lupus Erythematosus and Their Association with Disease-Associated Manifestations. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Gilliam, Brooke E.; Pepmueller, Peri H.; Moore, Terry L.] St Louis Univ, St Louis, MO 63103 USA. [Ombrello, Amanda K.] NIH, Bethesda, MD 20892 USA. [Burlingame, Rufus W.] INOVA Diagnost Inc, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 302 BP S113 EP S113 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500302 ER PT J AU Goldsmith, DP Barron, KS Ombrello, AK Lembo, R Stone, D Jones, A Neal, DCC Kastner, DL AF Goldsmith, Donald P. Barron, Karyl S. Ombrello, Amanda K. Lembo, Robert Stone, Deborah Jones, Anne Neal, Dawn C. Chapelle Kastner, Daniel L. TI Anakinra for the Treatment of Hyper-IgD with Periodic Fever Syndrome in Children SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Goldsmith, Donald P.] Drexel Univ, Coll Med, St Christophers Hosp Child, Philadelphia, PA 19104 USA. [Barron, Karyl S.] NIAID, NIH, Bethesda, MD 20892 USA. [Jones, Anne] NIAMS, NIH, Bethesda, MD USA. [Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2028 BP S790 EP S790 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502414 ER PT J AU Habal, N Chen, YQ Jordan, C Liu, Y Neal, DCC Stone, D Garcia, D Plass, N Cowen, E Lee, CC Lowes, M Goldbach-Mansky, RT AF Habal, Nadia Chen, Yongqing Jordan, Catherine Liu, Yin Neal, Dawn C. Chapelle Stone, Deborah Garcia, Damaris Plass, Nicole Cowen, Edward Lee, Chyi-chia Lowes, Michelle Goldbach-Mansky, Raphaela T. TI Pathogenesis Study of Infantile-Onset, Severe Pustular Psoriasis Reveals a De Novo Mutation in CARD14 Causing Psoriasis Which Responds Clinically to IL-12/23 Blocking Treatment with Ustekinumab. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Habal, Nadia] NIH NIAMS, Bethesda, MD USA. [Stone, Deborah; Garcia, Damaris] NIAMS, Off Clin Director, Translat Autoinflammatory Dis Sect, Bethesda, MD USA. [Jordan, Catherine] Washington Univ, Div Human Genet, St Louis, MO USA. [Neal, Dawn C. Chapelle; Cowen, Edward; Lee, Chyi-chia] NIAMS NIH, Bethesda, MD USA. [Plass, Nicole] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lowes, Michelle] Rockefeller Univ, Lab Investigat Dermatol, New York, NY 10021 USA. NR 0 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 310 BP S116 EP S116 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500310 ER PT J AU Hashkes, PJ Spalding, SJ Giannini, EH Huang, B Park, G Barron, KS Weisman, MH Pashinian, N Reiff, A Samuels, J Wright, DA Kastner, DL Lovell, DJ AF Hashkes, Philip J. Spalding, Steven J. Giannini, Edward H. Huang, Bin Park, Grace Barron, Karyl S. Weisman, Michael H. Pashinian, Noune Reiff, Andreas Samuels, Jonathan Wright, Dowain A. Kastner, Daniel L. Lovell, Daniel J. TI Rilonacept (Interleukin-1 Trap) for Treatment of Colchicine Resistant Familial Mediterranean Fever: A Randomized, Multicenter Double-Blinded, Alternating Treatment Phase II Trial. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Hashkes, Philip J.] Shaare Zedek Med Ctr, Cleveland Clin, Jerusalem, Israel. [Spalding, Steven J.] Cleveland Clin, Cleveland, OH 44106 USA. [Giannini, Edward H.] PRCSG Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Huang, Bin; Lovell, Daniel J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Park, Grace; Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Barron, Karyl S.] NIAID, NIH, Bethesda, MD 20892 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Reiff, Andreas] PRSCG, Los Angeles, CA USA. [Samuels, Jonathan] NYU, Hosp Joint Dis, New York, NY USA. [Wright, Dowain A.] Childrens Hosp Cent Cal, Madera, CA USA. RI Huang, bin/G-2468-2014 NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2445 BP S952 EP S952 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503016 ER PT J AU Hasni, SA Dema, B Hardwick, DF Souto-Adeva, G Jiang, C Rivera, J Illei, GG AF Hasni, Sarfaraz A. Dema, Barbara Hardwick, Donna F. Souto-Adeva, Gema Jiang, Chao Rivera, Juan Illei, Gabor G. TI Elevated IgE Anti-Ds-DNA Levels Are Associated with Serological Disease Activity in Patients with SLE: Potential for a New Treatment Target. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Dema, Barbara; Rivera, Juan] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD USA. [Hardwick, Donna F.] NIH MSC 1616, Bethesda, MD USA. [Souto-Adeva, Gema; Illei, Gabor G.] NIDCR NIH 10 1N110, Bethesda, MD USA. [Jiang, Chao] NIAMS, Immunogenet Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 664 BP S258 EP S258 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500660 ER PT J AU Holzinger, D Austermann, J Lohse, P Aksentijevich, I Holland, S Gattorno, M Rodriguez-Gallego, C Fessatou, S Isidor, B Tokio, S Bernstein, J Sampson, B Sunderkoetter, C Foell, D Roth, J AF Holzinger, Dirk Austermann, Judith Lohse, Peter Aksentijevich, Ivona Holland, Steven Gattorno, Marco Rodriguez-Gallego, Carlos Fessatou, S. Isidor, Bertrand Tokio, S. Bernstein, Jon Sampson, Barry Sunderkoetter, Cord Foell, Dirk Roth, Johannes TI A Novel Mutation in the PSTPIP1 Gene is Associated with An Autoinflammatory Disease Distinct From Classical Pyogenic Arthritis, Pyoderma Gangrenosum and Acne Syndrome. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Holzinger, Dirk; Austermann, Judith; Roth, Johannes] Univ Munster, Munster, Germany. [Lohse, Peter] Univ Munich, Munich, Germany. [Aksentijevich, Ivona] NHGRI, NIH, Bethesda, MD 20892 USA. [Holland, Steven] NIAID, NIH, Bethesda, MD 20892 USA. [Gattorno, Marco] G Gaslini Inst Children, Genoa, Italy. [Rodriguez-Gallego, Carlos] Dr Negrin Univ Hosp, Las Palmas Gran Canaria, Spain. [Fessatou, S.] Attikon Hosp, Athens, Greece. [Isidor, Bertrand] Ctr Hosp Univ, Nantes, France. [Tokio, S.] Nagoya City Univ, Tokyo, Japan. [Bernstein, Jon] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Sampson, Barry] Charing Cross Hosp, London, England. RI Isidor, Bertrand/L-2435-2015 OI Isidor, Bertrand/0000-0001-6480-126X NR 0 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 306 BP S115 EP S115 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500306 ER PT J AU Jesus, AA Fujihira, E Watase, MG Terreri, MT Hilario, MO Carneiro-Sampaio, M Len, C Oliveira, SK Rodrigues, MC Pereira, RMR Bica, BE Silva, NA Cavalcanti, A Marini, R Sztajnbok, F Quintero, MV Ferriani, VP Moraes-Vasconcelos, D Oliveira, JB Silva, CA AF Jesus, Adriana A. Fujihira, Erika Watase, Mariana G. Terreri, Maria Teresa Hilario, Maria Odete Carneiro-Sampaio, Magda Len, Claudio Oliveira, Sheila K. Rodrigues, Marta C. Pereira, Rosa M. R. Bica, Blanca E. Silva, Nilzio A. Cavalcanti, Andre Marini, Roberto Sztajnbok, Flavio Quintero, Maria V. Ferriani, Virginia P. Moraes-Vasconcelos, Dewton Oliveira, Joao B. Silva, Clovis A. TI Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Jesus, Adriana A.; Hilario, Maria Odete] Univ Sao Paulo FMUSP, Fac Med, Inst Crianca, Sao Paulo, Brazil. [Fujihira, Erika; Watase, Mariana G.; Moraes-Vasconcelos, Dewton] FMUSP, Lab Invest Med Dermatol & Imunodeficiencias LIM 5, Sao Paulo, Brazil. [Terreri, Maria Teresa; Hilario, Maria Odete; Len, Claudio] Univ Fed Sao Paulo UNIFESP, Sao Paulo, Brazil. [Oliveira, Sheila K.; Rodrigues, Marta C.] Univ Fed Rio de Janeiro UFRJ, IPPMG, Rio De Janeiro, Brazil. [Pereira, Rosa M. R.] FMUSP, Disciplina Reumatol, Sao Paulo, Brazil. [Bica, Blanca E.] UFRJ, Disciplina Reumatol, Rio De Janeiro, Brazil. [Silva, Nilzio A.] Univ Fed Goias, Fac Med, Goiania, Go, Brazil. [Cavalcanti, Andre] Univ Fed Pernambuco, Recife, PE, Brazil. [Marini, Roberto] Univ Estadual Campinas, Sao Paulo, Brazil. [Sztajnbok, Flavio] Univ Estado Rio de Janeiro, BR-20550011 Rio De Janeiro, Brazil. [Quintero, Maria V.] Santa Casa Misericordia Belo Horizonte, Belo Horizonte, MG, Brazil. [Ferriani, Virginia P.] FMUSP Ribeirao Preto, Ribeirao Preto, Brazil. [Oliveira, Joao B.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Silva, Clovis A.] Univ Sao Paulo, Fac Med, Hosp Clin, Inst Crianca, Sao Paulo, Brazil. RI Moraes-Vasconcelos, Dewton/G-2209-2012; Ferriani, Virginia/E-2209-2012; Marini, Roberto/D-3279-2013; Oliveira, Sheila/F-5213-2016 OI Oliveira, Sheila/0000-0002-2426-716X NR 0 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 304 BP S114 EP S114 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500304 ER PT J AU Joshi, RK Reveille, JD Brown, MA Weisman, MH Ward, MM Gensler, LS Wordsworth, BP Evans, DM Assassi, S AF Joshi, Reeti K. Reveille, John D. Brown, Matthew A. Weisman, Michael H. Ward, Michael M. Gensler, Lianne S. Wordsworth, B. Paul Evans, David M. Assassi, Shervin TI Is There a Higher Genetic Load of Susceptibility Loci in Familial Ankylosing Spondylitis? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Joshi, Reeti K.] Washington Univ, St Louis, MO USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Brown, Matthew A.] Wellcome Trust Ctr, Headington, Oxon, England. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, Michael M.] NIAMS, NIH, IRP, Bethesda, MD USA. [Gensler, Lianne S.] UCSF, San Francisco, CA USA. [Assassi, Shervin] Univ Texas Hlth Sci, Houston, TX USA. RI Evans, David/H-6325-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 153 BP S56 EP S56 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500154 ER PT J AU Kirino, Y Bertsias, G Ombrello, MJ Ustek, D Satorius, C Le, J Mizuki, N Ishigatsubo, Y Seyahi, E Sacli, FS Gul, A Kastner, DL Remmers, E AF Kirino, Yohei Bertsias, George Ombrello, Michael J. Ustek, Duran Satorius, Colleen Le, Julie Mizuki, Nobuhisa Ishigatsubo, Yoshiaki Seyahi, Emire Sacli, F. Sevgi Gul, Ahmet Kastner, Daniel L. Remmers, Elaine TI Genome-Wide Analysis of Imputed Genotypes Identifies Chemokine Receptor-1 CCR1) As a Novel Candidate Risk Locus in Behcet's Disease. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Kirino, Yohei; Bertsias, George; Ombrello, Michael J.; Satorius, Colleen; Le, Julie; Kastner, Daniel L.; Remmers, Elaine] NHGRI, NIH, Bethesda, MD 20892 USA. [Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey. [Mizuki, Nobuhisa; Ishigatsubo, Yoshiaki] Yokohama City Univ, Grad Sch Med, Yokohama, Kanagawa 232, Japan. [Seyahi, Emire; Sacli, F. Sevgi] Istanbul Univ, Cerrahpasa Med Fac, Istanbul, Turkey. NR 0 TC 1 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2431 BP S946 EP S946 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503002 ER PT J AU Kontzias, A Chen, YQ Plass, N Garcia, D Joyal, E Wesley, R Goldbach-Mansky, RT AF Kontzias, Apostolos Chen, Yongqing Plass, Nicole Garcia, Damaris Joyal, Elizabeth Wesley, Robert Goldbach-Mansky, Raphaela T. TI Comparative Cytokine Analysis Across a Spectrum of Genetically and/or Clinically Defined Auto-Inflammatory Syndromes SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Kontzias, Apostolos; Chen, Yongqing; Plass, Nicole; Garcia, Damaris; Joyal, Elizabeth; Wesley, Robert; Goldbach-Mansky, Raphaela T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 60 BP S21 EP S21 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500061 ER PT J AU Layh-Schmitt, G Yang, E Colbert, RA AF Layh-Schmitt, Gerlinde Yang, Eva Colbert, Robert A. TI Evidence That HLA-B27-Induced Endoplasmic Reticulum (ER) Stress Produces Pro- and Anti-Osteoclastogenic Cytokines in Rats with Spondyloarthritis-Like Disease SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Layh-Schmitt, Gerlinde; Yang, Eva; Colbert, Robert A.] NIAMS NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1703 BP S667 EP S667 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502089 ER PT J AU Lessard, CJ Adrianto, I Ice, JA Kelly, JA Jonsson, R Illei, GG Rischmueller, M Nordmark, G Mariette, X Miceli-Richard, C Herlenius, MW Witte, T Brennan, MT Omdal, R Gaffney, PM Lessard, JA Ng, WF Rhodus, NL Segal, BM Scofield, RH James, JA Anaya, JM Harley, JB Montgomery, C Moser, KL AF Lessard, Christopher J. Adrianto, Indra Ice, John A. Kelly, Jennifer A. Jonsson, Roland Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Mariette, Xavier Miceli-Richard, Corinne Herlenius, Marie Wahren Witte, Torsten Brennan, Michael T. Omdal, Roald Gaffney, Patrick M. Lessard, James A. Ng, Wan-Fai Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal James, Judith A. Anaya, Juan-Manuel Harley, John B. Montgomery, Courtney Moser, Kathy L. TI Large-Scale, High-Density Genotyping Performed by the Sjogren's Genetics Network Using the ImmunoChip Identifies PRKRA as a Novel Sjogren's Syndrome Susceptibility Locus and Confirms Associations with IRF5, BLK and MHC SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Gaffney, Patrick M.; Moser, Kathy L.] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Illei, Gabor G.] NIDCR, NIH 10 1N110, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Mariette, Xavier; Miceli-Richard, Corinne] Bicetre Univ Hosp, Le Kremlin Bicetre, France. [Herlenius, Marie Wahren] Karolinska Inst, Stockholm, Sweden. [Witte, Torsten] Hannover Med Sch, Hannover, Germany. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Lessard, James A.] Valley Bone& Joint Clin, Grand Forks, ND USA. [Ng, Wan-Fai] Newcastle Univ, Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Anaya, Juan-Manuel] Univ Rosario Corp Invest Biol, Bogota, Colombia. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RI Adrianto, Indra/D-4214-2013; Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016 OI Adrianto, Indra/0000-0002-9973-3057; Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 773 BP S303 EP S304 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500769 ER PT J AU Lessard, CJ Ice, JA Adrianto, I Kelly, JA Jonsson, R Illei, GG Rischmueller, M Nordmark, G Mariette, X Miceli-Richard, C Herlenius, MW Witte, T Brennan, MT Omdal, R Vyse, TJ Lessard, JA Ng, WF Rhodus, NL Segal, BM Scofield, RH Anaya, JM Harley, JB Montgomery, CG Moser, KL AF Lessard, Christopher J. Ice, John A. Adrianto, Indra Kelly, Jennifer A. Jonsson, Roland Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Mariette, Xavier Miceli-Richard, Corinne Herlenius, Marie Wahren Witte, Torsten Brennan, Michael T. Omdal, Roald Vyse, Timothy J. Lessard, James A. Ng, Wan-Fai Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal Anaya, Juan-Manuel Harley, John B. Montgomery, Courtney G. Moser, Kathy L. CA Benjamin A Rybicki ACCESS TI A High-Density Genome-Wide Association Study by the Sjogren's Genetics Network Identifies Five Novel Susceptibility Loci for Primary Sjogren's Syndrome and Confirms Association with MHC, IRF5, and BLK SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Lessard, Christopher J.; Ice, John A.; Adrianto, Indra; Kelly, Jennifer A.; Scofield, R. Hal; Montgomery, Courtney G.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Mariette, Xavier; Miceli-Richard, Corinne] Bicetre Univ Hosp, Le Kremlin Bicetre, France. [Herlenius, Marie Wahren] Karolinska Inst, Stockholm, Sweden. [Witte, Torsten] Hannover Med Sch, D-3000 Hannover, Germany. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Lessard, James A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Ng, Wan-Fai] Newcastle Univ, Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Benjamin A Rybicki ACCESS] Henry Ford Hosp, Detroit, MI 48202 USA. [Anaya, Juan-Manuel] Univ Rosario Corp Invest Biol, Bogota, Colombia. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Moser, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. RI Adrianto, Indra/D-4214-2013; Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016 OI Adrianto, Indra/0000-0002-9973-3057; Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 481 BP S184 EP S184 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500481 ER PT J AU Liu, Y Chen, YQ Ramot, Y Garcia, D Torrelo, A Sheikh, A Paller, A Reinhardt, A Stone, D Gadina, M Plass, P Chapelle, D Zlotogorski, Z Goldbach-Mansky, RT AF Liu, Yin Chen, Yongqing Ramot, Yuval Garcia, Damaris Torrelo, Antonio Sheikh, Afzal Paller, Amy Reinhardt, Adam Stone, Deborah Gadina, Massimo Plass, Plass Chapelle, Dawn Zlotogorski, Zlotogorski Goldbach-Mansky, Raphaela T. TI A Novel Autoinflammatory Syndrome Presenting with Chronic Atypical Neutrophilic Dermatitis, Lipodystrophy and Elevated Temperatures (CANDLE syndrome) Caused by Mutation in the Immunoproteasome SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Liu, Yin; Chen, Yongqing; Garcia, Damaris; Stone, Deborah; Plass, Plass; Chapelle, Dawn] Off Clin Director NIAMS, Translat Autoinflammatory Dis Sect, Bethesda, MD USA. [Ramot, Yuval; Zlotogorski, Zlotogorski] Hadassah Hebrew Univ, Dept Dermatol, Med Ctr, Jerusalem, Israel. [Torrelo, Antonio] Hosp Nino Jesus, Dept Pediat Dermatol, Madrid, Spain. [Sheikh, Afzal] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Paller, Amy] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Paller, Amy] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Reinhardt, Adam] Univ Nebraska Med Ctr, Fac Phys, Coll Med, Omaha, NE USA. [Gadina, Massimo] NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 818 BP S322 EP S322 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501016 ER PT J AU Miller, FW Cooper, RG Vencovsky, J Rider, LG Danko, K Wedderburn, LR Lundberg, IE Pachman, LM Reed, AM Ytterberg, SR Padyukov, L O'Callaghan, AS Radstake, T Isenberg, DA Chinoy, H Ollier, WE O'Hanlon, T Peng, B Scheet, P Lee, AT Lamb, J Chen, W Amos, C Gregersen, PK AF Miller, Frederick W. Cooper, Robert G. Vencovsky, Jiri Rider, Lisa G. Danko, Katalin Wedderburn, Lucy R. Lundberg, Ingrid E. Pachman, Lauren M. Reed, Ann M. Ytterberg, Steven R. Padyukov, Leonid Selva O'Callaghan, Albert Radstake, Timothy Isenberg, David A. Chinoy, Hector Ollier, William E. O'Hanlon, Terrance Peng, Bo Scheet, Paul Lee, Annette T. Lamb, Janine Chen, Wei Amos, Christopher Gregersen, Peter K. CA Myositis Genetics Consortium TI Genome-Wide Association Study of Dermatomyositis Reveals Shared Genetic Risk Factors with Other Autoimmune Diseases SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Miller, Frederick W.; Rider, Lisa G.] NIEHS, NIH, Bethesda, MD USA. [Cooper, Robert G.] Hope Hosp, Salford M6 8HD, Lancs, England. [Vencovsky, Jiri] Inst Rheumatol, Prague 2, Czech Republic. [Danko, Katalin] Univ Debrecen, Debrecan, Hungary. [Wedderburn, Lucy R.] UCL, London WC1E 6BT, England. [Pachman, Lauren M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Reed, Ann M.; Ytterberg, Steven R.] Mayo Clin, Rochester, MN USA. [Padyukov, Leonid] Karolinska Inst, Rheumatol Unit, Stockholm, Sweden. [Selva O'Callaghan, Albert] Hosp Univ Gen Vall dHebron, Barcelona, Spain. [Isenberg, David A.] UCL, London WC1E 6JF, England. [Ollier, William E.] Univ Manchester, Sch Med, Manchester, Lancs, England. [Lee, Annette T.] Feinstein Inst Med Rsch, Manhasset, NY USA. [Gregersen, Peter K.] Feinstein Inst Med Reschearch, Manhasset, NY USA. NR 0 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1678 BP S656 EP S656 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502064 ER PT J AU Monach, PA Warner, RL Tomasson, G Specks, U Stone, JH Ding, L Fervenza, F Fessler, BJ Hoffman, GS Ikle, D Kallenberg, CGM Krischer, J Langford, CA Mueller, M Seo, P St Clair, EW Spiera, R Tchao, N Ytterberg, SR Johnson, KJ Merkel, PA AF Monach, Paul A. Warner, Roscoe L. Tomasson, Gunnar Specks, Ulrich Stone, John H. Ding, Linna Fervenza, Fernando Fessler, Barri J. Hoffman, Gary S. Ikle, David Kallenberg, Cees G. M. Krischer, Jeffrey Langford, Carol A. Mueller, Mark Seo, Philip St Clair, E. William Spiera, Robert Tchao, Nadia Ytterberg, Steven R. Johnson, Kent J. Merkel, Peter A. TI Serum Proteins Reflecting Inflammation, Injury, and Repair As Biomarkers of Disease Activity in ANCA-Associated Vasculitis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Tomasson, Gunnar; Merkel, Peter A.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Warner, Roscoe L.; Johnson, Kent J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Specks, Ulrich; Fervenza, Fernando; Ytterberg, Steven R.] Mayo Clin, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Fessler, Barri J.] Univ Alabama Birmingham, Birmingham, AL USA. [Hoffman, Gary S.] Cleveland Clin Found A50, Cleveland, OH USA. [Ikle, David] Rho, Chapel Hill, NC USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Krischer, Jeffrey] Univ S Florida, Tampa, FL USA. [Langford, Carol A.] Cleveland Clin, Cleveland, OH 44106 USA. [Mueller, Mark] US FDA, Bethesda, MD 20014 USA. [Seo, Philip] Johns Hopkins Vasculitis Ctr, Baltimore, MD USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Tchao, Nadia] Immune Tolerance Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 792 BP S312 EP S312 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500788 ER PT J AU Nikolov, NP Pillemer, SR Bakalov, V Bebris, L Colombo, J Illei, GG AF Nikolov, Nikolay P. Pillemer, Stanley R. Bakalov, Vladimir Bebris, Lolita Colombo, Joe Illei, Gabor G. TI Sympathetic and Parasympathetic Abnormalities in Primary Sjogren's Syndrome (pSS) Patients Assessed in Outpatients Using Real-Time Digital Autonomic Nervous System (ANS) Monitoring SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Nikolov, Nikolay P.; Pillemer, Stanley R.; Bebris, Lolita; Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Colombo, Joe] Ansar Med Technol Inc, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 482 BP S184 EP S185 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500482 ER PT J AU Ombrello, MJ Remmers, E Grom, AA Thomson, W Martini, A Gattorno, M Ozen, S Gul, A Bohnsack, JF Prahalad, S Zeft, AS Mellins, ED Satorius, C Park, JL Langefeld, CD Zeggini, E Glass, DN Thompson, SD Kastner, DL Woo, P AF Ombrello, Michael J. Remmers, Elaine Grom, Alexei A. Thomson, Wendy Martini, Alberto Gattorno, Marco Ozen, Seza Gul, Ahmet Bohnsack, John F. Prahalad, Sampath Zeft, Andrew S. Mellins, Elizabeth D. Satorius, Colleen Park, Jane L. Langefeld, Carl D. Zeggini, Eleftheria Glass, David N. Thompson, Susan D. Kastner, Daniel L. Woo, Patricia CA Int Childhood Arthrit Genetics Con TI Major Histocompatibility Complex Class II Gene Cluster Harbors Systemic Juvenile Idiopathic Arthritis Susceptibility Locus SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Ombrello, Michael J.; Remmers, Elaine; Satorius, Colleen; Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Grom, Alexei A.; Glass, David N.; Thompson, Susan D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Thomson, Wendy] Univ Manchester, Sch Med, Manchester, Lancs, England. [Martini, Alberto] IRCCS G Gaslini, Genoa, Italy. [Gattorno, Marco] Ist Ricovero & Cura Carattere Sci G Gaslini, Genoa, Italy. [Ozen, Seza] Hacettepe Univ, Fac Med, TR-06100 Ankara, Turkey. [Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey. [Bohnsack, John F.; Zeft, Andrew S.] Univ Utah, Salt Lake City, UT USA. [Prahalad, Sampath] Emory Childrens Ctr, Atlanta, GA USA. [Mellins, Elizabeth D.; Park, Jane L.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Winston Salem, NC USA. [Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Cambridge, England. [Woo, Patricia] UCL, Sch Med, London W1N 8AA, England. NR 0 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1686 BP S659 EP S660 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502072 ER PT J AU Ombrello, MJ Remmers, EF Sun, G Komarow, H Aksentijevich, I Datta, S Torabi-Parizi, P Subramanian, N Romberg, N Bunney, TD Baxendale, RW Kim, HS Ho, JS Douek, DC Gandhi, C Wanderer, AA Lee, H Nelson, S Long, E Moir, S Meffre, E Katan, M Kastner, DL Hoffman, HM Milner, JD AF Ombrello, Michael J. Remmers, Elaine F. Sun, Guangping Komarow, Hirsh Aksentijevich, Ivona Datta, Shrimati Torabi-Parizi, Parizad Subramanian, Naeha Romberg, Neil Bunney, Tom D. Baxendale, Rhona W. Kim, Hun Sik Ho, Jason Douek, Daniel C. Gandhi, Chhavi Wanderer, Alan A. Lee, Hane Nelson, Stanley Long, Eric Moir, Susan Meffre, Eric Katan, Matilda Kastner, Daniel L. Hoffman, Hal M. Milner, Joshua D. TI Genomic Deletions in Phospholipase C gamma 2 define a New Syndrome of Cold Urticaria, Antibody Deficiency and Susceptibility to Both Autoimmunity and Infection SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Ombrello, Michael J.; Remmers, Elaine F.; Aksentijevich, Ivona; Kastner, Daniel L.] Natl Human Genome Res Inst, NIH, Bethesda, MD USA. [Sun, Guangping; Komarow, Hirsh; Datta, Shrimati; Torabi-Parizi, Parizad; Subramanian, Naeha; Kim, Hun Sik; Ho, Jason; Douek, Daniel C.; Long, Eric; Moir, Susan; Milner, Joshua D.] NIAID, NIH, Bethesda, MD 20892 USA. [Romberg, Neil; Meffre, Eric] Yale Univ, Sch Med, New Haven, CT USA. [Bunney, Tom D.; Baxendale, Rhona W.; Katan, Matilda] Inst Canc Res, Chester Beatty Labs, London SW3 6JB, England. [Gandhi, Chhavi; Hoffman, Hal M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Wanderer, Alan A.] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Lee, Hane; Nelson, Stanley] Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 170 BP S62 EP S62 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500170 ER PT J AU Parks, CG D'Aloisio, A DeRoo, L Sandler, D AF Parks, Christine G. D'Aloisio, Aimee DeRoo, Lisa Sandler, Dale TI Childhood Residential Pesticides and Other Environmental Exposures in Relation to Rheumatoid Arthritis (RA) in Adulthood. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Parks, Christine G.; D'Aloisio, Aimee; DeRoo, Lisa; Sandler, Dale] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2173 BP S846 EP S847 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502559 ER PT J AU Parks, CG Vines, AI Eudy, A AF Parks, Christine G. Vines, Anissa I. Eudy, Amanda CA Carolina Lupus Study Investigators TI Stressful Life Experiences and Inflammation in the Carolina Lupus Study: An Open-Ended Query on Stress SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Parks, Christine G.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Vines, Anissa I.] Univ N Carolina, Chapel Hill, NC USA. [Eudy, Amanda] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1858 BP S724 EP S724 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502244 ER PT J AU Patel, PN Sharif, R Assassi, S Gensler, LS Diekman, LA Learch, TJ Weisman, MH Ward, MM Reveille, JD AF Patel, Pooja N. Sharif, Roozbeh Assassi, Shervin Gensler, Lianne S. Diekman, Laura A. Learch, Thomas J. Weisman, Michael H. Ward, Michael M. Reveille, John D. TI Gender Differences in the Correlation of Self-Reported Functional Status with Spinal Mobility in Patients with Ankylosing Spondylitis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Patel, Pooja N.] Univ Texas Houston, Houston, TX USA. [Sharif, Roozbeh; Reveille, John D.] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Assassi, Shervin] Univ Texas Hlth Sci, Houston, TX USA. [Gensler, Lianne S.] UCSF, San Francisco, CA USA. [Diekman, Laura A.] UT Hlth Sci Ctr, Houston, TX USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 505 BP S193 EP S193 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500505 ER PT J AU Rider, LG Lee, JA Jansen, AV Ruperto, N Huber, AM Oddis, CV Feldman, BM Lachenbruch, PA Aggarwal, R Miller, FW AF Rider, Lisa G. Lee, Julia A. Jansen, Anna V. Ruperto, Nicola Huber, Adam M. Oddis, Chester V. Feldman, Brian M. Lachenbruch, Peter A. Aggarwal, Rohit Miller, Frederick W. CA IMACS PRINTO TI Defining Clinically Relevant Changes in Core Set Activity Measures for Adult and Juvenile Idiopathic Inflammatory Myopathies (IIM) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Rider, Lisa G.; Lee, Julia A.; Jansen, Anna V.; Miller, Frederick W.] NIEHS, NIH, Bethesda, MD USA. [Ruperto, Nicola] PRINTO IRCCS, Genoa, Italy. [Huber, Adam M.] Dalhousie Univ, Halifax, NS, Canada. [Aggarwal, Rohit] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Feldman, Brian M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NR 0 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 240 BP S89 EP S89 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500240 ER PT J AU Rosenzweig, HL Clowers, JS Allensworth, J Vance, EE Planck, SR Davey, MP Chae, JJ Kastner, DL Rosenbaum, JT AF Rosenzweig, Holly L. Clowers, Jenna S. Allensworth, Jordan Vance, Emily E. Planck, Stephen R. Davey, Michael P. Chae, Jae Jin Kastner, Daniel L. Rosenbaum, James T. TI Dysregulation of Pyrin, the Familial Mediterranean Fever Protein, Exacerbates Endotoxin-Induced Uveitis in Mice SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Clowers, Jenna S.; Davey, Michael P.] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. [Chae, Jae Jin] NHGRI, Med Genet Branch, Bethesda, MD USA. [Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 986 BP S386 EP S386 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501181 ER PT J AU Rowzee, A Tandon, M Gallo, A Routsias, J Tzioufas, AG Alevizos, I AF Rowzee, Anne Tandon, Mayank Gallo, Alessia Routsias, John Tzioufas, Athanasios G. Alevizos, Ilias TI MicroRNA Expression in Vault Particles SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Alevizos, Ilias] NIDCR, NIH 10, Bethesda, MD USA. [Tzioufas, Athanasios G.] Natl Tech Univ Athens, Sch Med, Athens, Greece. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1937 BP S754 EP S755 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502323 ER PT J AU Sharif, R Patel, PN Assassi, S Gensler, LS Diekman, LA Learch, TJ Weisman, MH Ward, MM Reveille, JD AF Sharif, Roozbeh Patel, Pooja N. Assassi, Shervin Gensler, Lianne S. Diekman, Laura A. Learch, Thomas J. Weisman, Michael H. Ward, Michael M. Reveille, John D. TI How Does Disease Duration Modify the Association of Radiographic Damage with Ankylosing Spondylitis Metrology? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Sharif, Roozbeh; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Patel, Pooja N.] Univ Texas, Houston, TX USA. [Assassi, Shervin] Univ Texas Hlth Sci, Houston, TX USA. [Gensler, Lianne S.] UCSF, San Francisco, CA USA. [Diekman, Laura A.] UT Hlth Sci Ctr, Houston, TX USA. [Learch, Thomas J.] Cedars Sinai, Los Angeles, CA USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2531 BP S990 EP S991 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503108 ER PT J AU Sibley, CH Plass, N Brewer, C King, K Zalewski, C Kim, HJ Bishop, R Kicker, P Phillips, Z Dolan, JG Stone, D Neal, DCC Snyder, C Butman, J Wesley, R Goldbach-Mansky, RT AF Sibley, Cailin H. Plass, Nicole Brewer, Carmen King, Kelly Zalewski, Christopher Kim, H. Jeffrey Bishop, Rachel Kicker, Patrick Phillips, Zachary Dolan, Joseph G. Stone, Deborah Neal, Dawn C. Chapelle Snyder, Christopher Butman, John Wesley, Robert Goldbach-Mansky, Raphaela T. TI Predictors of Organ Damage Despite Serologic Remission in a Subset of Patients with Neonatal-Onset Multisystem Inflammatory Disease (NOMID). SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Sibley, Cailin H.; Plass, Nicole; Kicker, Patrick; Phillips, Zachary; Dolan, Joseph G.; Neal, Dawn C. Chapelle; Snyder, Christopher; Goldbach-Mansky, Raphaela T.] NIAMS, NIH, Bethesda, MD USA. [Brewer, Carmen; King, Kelly; Zalewski, Christopher; Kim, H. Jeffrey] NIDCD, NIH, Bethesda, MD USA. [Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Stone, Deborah] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2451 BP S954 EP S955 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503022 ER PT J AU Specks, U Merkel, PA Seo, P Spiera, RF Langford, CA Hoffman, GS Kallenberg, CGM Clair, EWS Tole, S Brunetta, P Shen, SY Tchao, N Fessler, BJ Webber, L Ding, L Sejismundo, LP Mieras, K Phippard, DJ Asare, A Lim, N Ikle, D Jepson, B Lail, A Mueller, M AF Specks, Ulrich Merkel, Peter A. Seo, Philip Spiera, Robert F. Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. Clair, E. William St. Tole, Swati Brunetta, Paul Shen, Shuyi Tchao, Nadia Fessler, Barri J. Webber, Lisa Ding, Linna Sejismundo, Lourdes P. Mieras, Kathleen Phippard, Deborah J. Asare, Adam Lim, Noha Ikle, David Jepson, Brett Lail, Alice Mueller, Mark TI Immunoglobulin Concentrations and Infection Risk Among Patients with ANCA-Associated Vasculitis Treated with Rituximab or Cyclophosphamide. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Specks, Ulrich; Mieras, Kathleen] Mayo Clin, Rochester, MN USA. [Merkel, Peter A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Seo, Philip] Johns Hopkins Vasculitis Ctr, Baltimore, MD USA. [Spiera, Robert F.] Hosp Special Surg, New York, NY 10021 USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Clair, E. William St.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Tole, Swati; Shen, Shuyi] Genentech Inc, San Francisco, CA USA. [Brunetta, Paul] Genentech Inc, So San Francisco, CA USA. [Tchao, Nadia; Phippard, Deborah J.; Asare, Adam; Lim, Noha] Immune Tolerance Network, Bethesda, MD USA. [Fessler, Barri J.] Univ Alabama Birmingham, Birmingham, AL USA. [Webber, Lisa; Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Sejismundo, Lourdes P.] Johns Hopkins Univ, Baltimore, MD USA. [Ikle, David; Jepson, Brett; Lail, Alice] Rho, Chapel Hill, NC USA. [Mueller, Mark] US FDA, Bethesda, MD 20014 USA. NR 0 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 789 BP S310 EP S311 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500785 ER PT J AU Srinivasalu, H Barnes, M Layh-Schmitt, G Ward, MM Colbert, RA AF Srinivasalu, Hemalatha Barnes, Michael Layh-Schmitt, Gerlinde Ward, Michael M. Colbert, Robert A. TI Early Disease Characteristics of Enthesitis-Related Arthritis Reveals Elevated TGF-Beta SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Srinivasalu, Hemalatha] Nemours Alfred I duPont Hosp Children, NIAMS, NIH, Bethesda, MD USA. [Barnes, Michael] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 511 BP S196 EP S196 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500511 ER PT J AU Stone, JH Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Fessler, BJ Tchao, N Webber, L Ding, LN Sejismundo, LP Mieras, K Ikle, D Phippard, DJ Jepson, B Lail, A Asare, A Lim, N Mueller, M Brunetta, P Allen, NB Fervenza, F Geetha, D Keogh, K Kissin, EY Monach, PA Peikert, T Stegeman, C Ytterberg, SR Specks, U AF Stone, John H. Merkel, Peter A. Seo, Philip Spiera, Robert Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. St Clair, E. William Fessler, Barri J. Tchao, Nadia Webber, Lisa Ding, Linna Sejismundo, Lourdes P. Mieras, Kathleen Ikle, David Phippard, Deborah J. Jepson, Brett Lail, Alice Asare, Adam Lim, Noha Mueller, Mark Brunetta, Paul Allen, Nancy B. Fervenza, Fernando Geetha, Duvuru Keogh, Karina Kissin, Eugene Y. Monach, Paul A. Peikert, Tobias Stegeman, Coen Ytterberg, Steven R. Specks, Ulrich CA RAVE-ITN Res Grp TI Extended Follow-up of Treatment with Rituximab Versus Cyclophosphamide for Remission-Induction of ANCA-Associated Vasculitis: Which Subsets Are At Greatest Risk for Flare? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Seo, Philip] Johns Hopkins Vasculitis Ctr, Baltimore, MD USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, Cees G. M.; Stegeman, Coen] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [St Clair, E. William; Allen, Nancy B.] Duke Univ, Med Ctr, Durham, NC USA. [Fessler, Barri J.] Univ Alabama Birmingham, Birmingham, AL USA. [Tchao, Nadia; Phippard, Deborah J.; Asare, Adam; Lim, Noha] Immune Tolerance Network, Bethesda, MD USA. [Webber, Lisa; Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Sejismundo, Lourdes P.] Johns Hopkins Univ, Baltimore, MD USA. [Mieras, Kathleen; Fervenza, Fernando; Keogh, Karina; Peikert, Tobias; Ytterberg, Steven R.; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Ikle, David; Jepson, Brett; Lail, Alice] Rho, Chapel Hill, NC USA. [Mueller, Mark] US FDA, Bethesda, MD 20014 USA. [Brunetta, Paul] Genentech Inc, So San Francisco, CA USA. [Geetha, Duvuru] Johns Hopkins Univ, York, PA USA. NR 0 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2432 BP S946 EP S947 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503003 ER PT J AU Sun, XZ Agrawal, N Tanaka, L Hayden-Ledbetter, M Hudkins, KL Alpers, CE Bolland, S Ledbetter, JA Elkon, KB AF Sun, Xizhang Agrawal, Nalini Tanaka, Lena Hayden-Ledbetter, Martha Hudkins, Kelly L. Alpers, Charles E. Bolland, Silvia Ledbetter, Jeffrey A. Elkon, Keith B. TI Increased Expression of Ribonuclease Prolongs Survival in Murine Lupus SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Sun, Xizhang; Agrawal, Nalini; Tanaka, Lena; Hayden-Ledbetter, Martha; Hudkins, Kelly L.; Alpers, Charles E.; Ledbetter, Jeffrey A.; Elkon, Keith B.] Univ Washington, Seattle, WA 98195 USA. [Bolland, Silvia] NIAID, NIH, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 559 BP S213 EP S214 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500555 ER PT J AU Tan, S Yao, JH Flynn, JA Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Flynn, John A. Yao, Lawrence Ward, Michael M. TI Fully Quantitative Syndesmophyte Measurement in Ankylosing Spondylitis Using Computed Tomography: Validity of Volume and Height Measures SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Tan, Sovira; Yao, Jianhua; Yao, Lawrence; Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. [Flynn, John A.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1298 BP S508 EP S509 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501492 ER PT J AU Tan, S Yao, JH Flynn, JA Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Flynn, John A. Yao, Lawrence Ward, Michael M. TI Fully Quantitative Syndesmophyte Measurement in Ankylosing Spondylitis Using Computed Tomography: Reliability of Volume and Height Measures SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Tan, Sovira; Yao, Jianhua; Yao, Lawrence; Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. [Flynn, John A.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1297 BP S508 EP S508 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501491 ER PT J AU Tandon, M Gallo, A Illei, GG Alevizos, I AF Tandon, Mayank Gallo, Alessia Illei, Gabor G. Alevizos, Ilias TI Deep Sequencing of Small RNAs Reveals Novel MicroRNAs in Minor Salivary Glands of Sjogren's Syndrome Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Illei, Gabor G.; Alevizos, Ilias] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 498 BP S190 EP S190 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500498 ER PT J AU Tjarnlund, A Rider, LG Miller, FW Werth, VP Pilkington, CA de Visser, M Forslund, E Amato, AA Barohn, RJ Bottai, M Finkel, R Paulus, HE Hengstman, GJD Liang, MH Singh, J Lundberg, IE AF Tjarnlund, Anna Rider, Lisa G. Miller, Frederick W. Werth, Victoria P. Pilkington, Clarissa A. de Visser, Marianne Forslund, Elin Amato, Anthony A. Barohn, Richard J. Bottai, Matteo Finkel, Richard Paulus, Harold E. Hengstman, Gerald J. D. Liang, Matthew H. Singh, Jasvinder Lundberg, Ingrid E. TI Ethnic but not Gender Differences in Disease Manifestations in Dermatomyositis Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Bottai, Matteo] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Rider, Lisa G.; Miller, Frederick W.] NIEHS, NIH, Bethesda, MD USA. [Werth, Victoria P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Pilkington, Clarissa A.] Great Ormond St Hosp Sick Children, Dept Rheumatol, London WC1N 3JH, England. [de Visser, Marianne] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Amato, Anthony A.; Liang, Matthew H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Amato, Anthony A.] Harvard Univ, Sch Med, Boston, MA USA. [Barohn, Richard J.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, MO USA. [Finkel, Richard] Univ Penn, Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. [Paulus, Harold E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Hengstman, Gerald J. D.] Catharina Hosp, Dept Neurol, Eindhoven, Netherlands. [Singh, Jasvinder] Univ Alabama, Birmingham, AL USA. [Singh, Jasvinder] VA Med Ctr, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 235 BP S87 EP S87 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500235 ER PT J AU Ward, MM Guthrie, LC Alba, MI AF Ward, Michael M. Guthrie, Lori C. Alba, Maria I. TI Patients' Ratings of Clinically Important Improvement in Pain, Global Assessment, and Physical Function in Rheumatoid Arthritis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Ward, Michael M.; Guthrie, Lori C.; Alba, Maria I.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 143 BP S51 EP S52 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500144 ER PT J AU Wei, CW Jung, J Marian, V Hardwick, DF Souto-Adeva, G Huang, YQ Neary, B Illei, GG Sanz, I AF Wei, Chungwen Jung, John Marian, Valentin Hardwick, Donna F. Souto-Adeva, Gema Huang, Youqun Neary, Bridget Illei, Gabor G. Sanz, Inaki TI Effect of Intravenous Cyclophosphamide Treatment on B Cells in SLE Nephritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Wei, Chungwen; Jung, John; Marian, Valentin; Huang, Youqun; Neary, Bridget; Sanz, Inaki] Univ Rochester, Rochester, NY USA. [Hardwick, Donna F.] NIH MSC 1616, Bethesda, MD USA. [Souto-Adeva, Gema; Illei, Gabor G.] NIDCR NIH 10 1N110, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2498 BP S977 EP S977 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503075 ER PT J AU Weiss, P Beukelman, T Schanberg, LE Kimura, Y Colbert, RA AF Weiss, Pamela Beukelman, Timothy Schanberg, Laura E. Kimura, Yukiko Colbert, Robert A. CA CARRANet Investigators TI Enthesitis Is a Significant Predictor of Decreased Quality of Life, Function, and Arthritis-Specific Pain Across Juvenile Idiopathic Arthritis (JIA) Categories: Preliminary Analyses From the CARRAnet Registry. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Weiss, Pamela] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Beukelman, Timothy] Univ Alabama, Birmingham, AL USA. [Schanberg, Laura E.] Duke Univ, Med Ctr, Durham, NC USA. [Kimura, Yukiko] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Colbert, Robert A.] NIAMS NIH, Bethesda, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 280 BP S105 EP S105 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500280 ER PT J AU Wright, NC Walitt, BT Curtis, JR Pettinger, M Parks, CG De Roos, AJ Wactawksi-Wende, J Mackey, R Jackson, RD Melamed, ML Howard, BV AF Wright, Nicole C. Walitt, Brian T. Curtis, Jeffery R. Pettinger, Mary Parks, Christine G. De Roos, Anneclaire J. Wactawksi-Wende, Jean Mackey, Rachel Jackson, Rebecca D. Melamed, Michal L. Howard, Barbara V. TI Is Sunlight Exposure and Vitamin D Intake Associated with Rheumatoid Arthritis? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Wright, Nicole C.; Curtis, Jeffery R.] Univ Alabama, Birmingham, AL USA. [Walitt, Brian T.] Washington Hosp Ctr, Washington, DC 20010 USA. [Pettinger, Mary; De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Parks, Christine G.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Wactawksi-Wende, Jean] SUNY Buffalo, Buffalo, NY 14260 USA. [Mackey, Rachel] Univ Pittsburgh, Pittsburgh, PA USA. [Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA. [Melamed, Michal L.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Howard, Barbara V.] Medstar Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 102 BP S35 EP S35 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500103 ER PT J AU Yin, HG Kosa, P Liu, XB Swaim, B Cabrera-Perez, J Lai, ZN Ambudka, I Bugge, T Chiorini, JA AF Yin, Hongen Kosa, Peter Liu, Xibao Swaim, Bill Cabrera-Perez, Javier Lai, Zhennan Ambudka, Indu Bugge, Thomas Chiorini, John A. TI Matriptase Dificency and Primary Sjogren Syndrome Induction: From Patients to Mice SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Yin, Hongen; Kosa, Peter; Liu, Xibao; Swaim, Bill; Cabrera-Perez, Javier; Lai, Zhennan; Ambudka, Indu; Bugge, Thomas; Chiorini, John A.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 776 BP S304 EP S305 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500772 ER PT J AU Zhou, H Souto-Adeva, G Hardwick, D Illei, GG AF Zhou, Hua Souto-Adeva, Gema Hardwick, Donna Illei, Gabor G. TI Urinary Exosomal Microrna-192 and-195 As Potential Biomarkers of Renal Disease Activity in Lupus Nephritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Zhou, Hua; Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Souto-Adeva, Gema; Hardwick, Donna] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2287 BP S894 EP S894 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502673 ER PT J AU Zhou, H Hasni, SA Tandon, M Alevizos, I Austin, HA Balow, JE Illei, GG AF Zhou, Hua Hasni, Sarfaraz A. Tandon, Mayank Alevizos, Ilias Austin, Howard A. Balow, James E. Illei, Gabor G. TI Renal Mir-150 As Potential Biomarker of Chronicity in Lupus Nephritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Zhou, Hua; Tandon, Mayank; Alevizos, Ilias; Illei, Gabor G.] NIDCR, Bethesda, MD USA. [Hasni, Sarfaraz A.] NIAMS, NIH, Bethesda, MD USA. [Austin, Howard A.; Balow, James E.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1382 BP S541 EP S541 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501576 ER PT J AU Stoddard, J Leibowitz, SF Ton, H Snowdon, S AF Stoddard, Joel Leibowitz, Scott F. Ton, Hendry Snowdon, Shane TI Improving Medical Education About Gender-Variant Youth and Transgender Adolescents SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Gender identity; Gender nonconformity; Gender disorders; Medical education; Continuing medical education ID RISK BEHAVIORS; HIV PREVALENCE; SEX WORK; DISCRIMINATION; VICTIMIZATION; CARE; GAY AB Gender minority children and adolescents present to a wide variety of health professionals for gender-related care and other care. However, few professionals may be prepared to meet their needs. Unprepared clinicians risk developing insufficient therapeutic rapport, missing salient information, and inadvertently contributing to risk. In this article the authors outline ways to address these gaps at all training levels to meet the needs of gender minority children and adolescents. They provide practical resources for colleagues interested in expanding education opportunities in their own community. In the end, competency in gender minority health should improve access to care for these youths. C1 [Stoddard, Joel; Ton, Hendry] Univ Calif Davis, Dept Psychiat & Behav Sci, Sacramento, CA 95818 USA. [Stoddard, Joel] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. [Leibowitz, Scott F.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Psychiat, Boston, MA 02115 USA. [Snowdon, Shane] Univ Calif San Francisco, Ctr LGBT Hlth & Equ, San Francisco, CA 94143 USA. RP Stoddard, J (reprint author), Univ Calif Davis, Dept Psychiat & Behav Sci, 2230 Stockton Blvd, Sacramento, CA 95818 USA. EM leoj@alum.mit.edu NR 28 TC 2 Z9 2 U1 3 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 1056-4993 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD OCT PY 2011 VL 20 IS 4 BP 779 EP + DI 10.1016/j.chc.2011.07.008 PG 14 WC Psychiatry SC Psychiatry GA 852SX UT WOS:000297378900016 PM 22051013 ER PT J AU Auchincloss, H Turka, LA AF Auchincloss, Hugh Turka, Laurence A. TI CTLA-4: Not All Costimulation Is Stimulatory SO JOURNAL OF IMMUNOLOGY LA English DT Editorial Material ID T-CELL-ACTIVATION; ANTIGEN RECEPTOR; CD28 C1 [Auchincloss, Hugh] NIAID, NIH, Bethesda, MD 20892 USA. [Turka, Laurence A.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Auchincloss, H (reprint author), NIAID, NIH, Bldg 31,7A-03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM auchinclossh@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 14 TC 5 Z9 6 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2011 VL 187 IS 7 BP 3457 EP 3458 DI 10.4049/jimmunol.1102316 PG 2 WC Immunology SC Immunology GA 822IB UT WOS:000295036400001 PM 21934096 ER PT J AU Choi, SC Simhadri, VR Tian, LJ Gil-Krzewska, A Krzewski, K Borrego, F Coligan, JE AF Choi, Seung-Chul Simhadri, Venkateswara R. Tian, Linjie Gil-Krzewska, Aleksandra Krzewski, Konrad Borrego, Francisco Coligan, John E. TI Cutting Edge: Mouse CD300f (CMRF-35-Like Molecule-1) Recognizes Outer Membrane-Exposed Phosphatidylserine and Can Promote Phagocytosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEGATIVE REGULATION; RECEPTOR; CELLS; CLEARANCE; FAMILY; LMIR3 AB Reportedly, CD300f negatively regulates interactions between dendritic and T cells and acts as an anti-inflammatory molecule in a multiple sclerosis mouse model. We found that a CD300f/Fc chimeric protein specifically binds to apoptotic/dead splenocytes and to apoptotic cells from starved or irradiated lymphocytic cell lines, an observation extended to insect cells. CD300f also binds PMA/ionomycin-activated splenocytes and Ag-stimulated T cells, an interaction inhibited by Annexin V. By ELISA, cosedimentation, and surface plasmon resonance using phospholipid-containing liposomes, we show that CD300f preferentially binds phosphatidylserine and requires a metal ion. Exogenous expression of CD300f in cell lines results in enhanced phagocytosis of apoptotic cells. We conclude that expression of CD300f conveys additional capacity to recognize phosphatidylserine to myeloid cells. The result of this recognition may vary with the overall qualitative and quantitative receptor content, as well as signaling capacity of the expressing effector cell, but enhanced phagocytosis is one measurable outcome. The Journal of Immunology, 2011, 187: 3483-3487. C1 [Choi, Seung-Chul; Tian, Linjie; Gil-Krzewska, Aleksandra; Krzewski, Konrad; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Simhadri, Venkateswara R.; Borrego, Francisco] US FDA, Div Monoclonal Antibodies, Lab Mol & Dev Immunol, Off Biotechnol Prod,Ctr Drug Evaluat & Review, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 205, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov RI Tian, Linjie/E-6878-2014 FU Food and Drug Administration; National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural programs of the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases. NR 15 TC 29 Z9 29 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2011 VL 187 IS 7 BP 3483 EP 3487 DI 10.4049/jimmunol.1101549 PG 5 WC Immunology SC Immunology GA 822IB UT WOS:000295036400005 PM 21865548 ER PT J AU Enqvist, M Nilsonne, G Hammarfjord, O Wallin, RPA Bjorkstrom, NK Bjornstedt, M Hjerpe, A Ljunggren, HG Dobra, K Malmberg, KJ Carlsten, M AF Enqvist, Monika Nilsonne, Gustav Hammarfjord, Oscar Wallin, Robert P. A. Bjoerkstroem, Niklas K. Bjornstedt, Mikael Hjerpe, Anders Ljunggren, Hans-Gustaf Dobra, Katalin Malmberg, Karl-Johan Carlsten, Mattias TI Selenite Induces Posttranscriptional Blockade of HLA-E Expression and Sensitizes Tumor Cells to CD94/NKG2A-Positive NK Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; SEQUENCE-DERIVED PEPTIDES; LUNG-CANCER CELLS; MHC CLASS-I; THIOREDOXIN REDUCTASE; INHIBITORY RECEPTORS; MEDIATED LYSIS; MISSING SELF; OVARIAN-CARCINOMA; PERIPHERAL-BLOOD AB CD94/NKG2A is an inhibitory receptor that controls the activity of a large proportion of human NK cells following interactions with the nonclassical HLA class Ib molecule HLA-E expressed on target cells. In this study, we show that selenite (SeO(3)(2-)), an inorganic selenium compound, induces an almost complete loss of cell surface expression of HLA-E on tumor cells of various origins. Selenite abrogated the HLA-E expression at a posttranscriptional level, since selenite exposure led to a dose-dependent decrease in cellular HLA-E protein expression whereas the mRNA levels remained intact. The loss of HLA-E expression following selenite treatment was associated with decreased levels of intracellular free thiols in the tumor cells, suggesting that the reduced HLA-E protein synthesis was caused by oxidative stress. Indeed, HLA-E expression and the level of free thiols remained intact following treatment with selenomethionine, a selenium compound that does not generate oxidative stress. Loss of HLA-E expression, but not of total HLA class I expression, on tumor cells resulted in increased susceptibility to CD94/NK group 2A-positive NK cells. Our results suggest that selenite may be used to potentiate the anti-tumor cytotoxicity in settings of NK cell-based immunotherapies. The Journal of Immunology, 2011, 187: 3546-3554. C1 [Enqvist, Monika; Hammarfjord, Oscar; Wallin, Robert P. A.; Bjoerkstroem, Niklas K.; Ljunggren, Hans-Gustaf; Malmberg, Karl-Johan; Carlsten, Mattias] Karolinska Univ, Huddinge Hosp, Dept Med, Ctr Infect Med,Karolinska Inst, S-14186 Stockholm, Sweden. [Nilsonne, Gustav; Bjornstedt, Mikael; Hjerpe, Anders; Dobra, Katalin] Karolinska Univ, Huddinge Hosp, Div Pathol, Dept Lab Med, S-14186 Stockholm, Sweden. [Carlsten, Mattias] Karolinska Inst, Immune & Gene Therapy Lab, Dept Oncol & Pathol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden. [Carlsten, Mattias] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Carlsten, M (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr MSC 1230,Bldg 10-5E-3130, Bethesda, MD 20892 USA. EM kalle.malmberg@ki.se; mattias.carlsten@nih.gov OI Nilsonne, Gustav/0000-0001-5273-0150; Bjorkstrom, Niklas/0000-0002-0967-076X; Carlsten, Mattias/0000-0001-9815-0012; Malmberg, Karl-Johan/0000-0002-8718-9373 FU Swedish Foundation for Strategic Research; Swedish Society for Medical Research; Swedish Research Council; Swedish Cancer Society; Swedish Children's Cancer Foundation; Cancer Society of Stockholm; Royal Swedish Academy of Science; Tobias Foundation; Mary Beve Foundation; David and Astrid Hagelens Foundation; Abney Foundation; Swedish Heart and Lung Foundation; AFA Insurance; Stockholm City Council FX This work was supported by grants from the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Swedish Research Council, the Swedish Cancer Society, the Swedish Children's Cancer Foundation, the Cancer Society of Stockholm, the Royal Swedish Academy of Science, the Tobias Foundation, the Mary Beve Foundation, the David and Astrid Hagelens Foundation, the Abney Foundation, the Swedish Heart and Lung Foundation, AFA Insurance, and "ALF-Project" grants from the Stockholm City Council. NR 69 TC 9 Z9 10 U1 2 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2011 VL 187 IS 7 BP 3546 EP 3554 DI 10.4049/jimmunol.1100610 PG 9 WC Immunology SC Immunology GA 822IB UT WOS:000295036400013 PM 21890659 ER PT J AU Karnell, JL Karnell, FG Stephens, GL Rajan, B Morehouse, C Li, Y Swerdlow, B Wilson, M Goldbach-Mansky, R Groves, C Coyle, AJ Herbst, R Ettinger, R AF Karnell, Jodi L. Karnell, Fredrick G., III Stephens, Geoffrey L. Rajan, Bhargavi Morehouse, Chris Li, Ying Swerdlow, Bonnie Wilson, Mildred Goldbach-Mansky, Raphaela Groves, Christopher Coyle, Anthony J. Herbst, Ronald Ettinger, Rachel TI Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INOSINE 5'-MONOPHOSPHATE DEHYDROGENASE; T-LYMPHOCYTES; IN-VITRO; IMMUNOSUPPRESSIVE DRUGS; AUTOIMMUNE-DISEASE; MURINE LUPUS; PLASMA-CELLS; MOFETIL; CYCLE AB Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs. The Journal of Immunology, 2011, 187: 3603-3612. C1 [Karnell, Jodi L.; Karnell, Fredrick G., III; Stephens, Geoffrey L.; Rajan, Bhargavi; Li, Ying; Swerdlow, Bonnie; Groves, Christopher; Coyle, Anthony J.; Herbst, Ronald; Ettinger, Rachel] MedImmune LLC, Gaithersburg, MD 20878 USA. [Morehouse, Chris; Wilson, Mildred; Goldbach-Mansky, Raphaela] NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Herbst, R (reprint author), MedImmune LLC, 1 MedImmune Way, Gaithersburg, MD 20878 USA. EM herbstr@medimmune.com FU Intramural NIH HHS [ZIA AR041138-11] NR 50 TC 18 Z9 18 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2011 VL 187 IS 7 BP 3603 EP 3612 DI 10.4049/jimmunol.1003319 PG 10 WC Immunology SC Immunology GA 822IB UT WOS:000295036400019 PM 21873529 ER PT J AU Zelinskyy, G Myers, L Dietze, KK Gibbert, K Roggendorf, M Liu, J Lu, MJ Kraft, AR Teichgraber, V Hasenkrug, KJ Dittmer, U AF Zelinskyy, Gennadiy Myers, Lara Dietze, Kirsten K. Gibbert, Kathrin Roggendorf, Michael Liu, Jia Lu, Mengji Kraft, Anke R. Teichgraeber, Volker Hasenkrug, Kim J. Dittmer, Ulf TI Virus-Specific CD8(+) T Cells Upregulate Programmed Death-1 Expression during Acute Friend Retrovirus Infection but Are Highly Cytotoxic and Control Virus Replication SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MULTIPLE INHIBITORY RECEPTORS; PREMATURE TERMINAL EXHAUSTION; CHRONIC VIRAL-INFECTION; PD-1 EXPRESSION; RAPID INDUCTION; HIV-INFECTION; RESPONSES; MICE; IDENTIFICATION; CD4(+) AB It was recently reported that inhibitory molecules such as programmed death-1 (PD-1) were upregulated on CD8(+) T cells during acute Friend retrovirus infection and that the cells were prematurely exhausted and dysfunctional in vitro. The current study confirms that most activated CD8(+) T cells upregulated expression of PD-1 during acute infection and revealed a dichotomy of function between PD-1(hi) and PD-1(lo) subsets. More PD-1(lo) cells produced antiviral cytokines such as IFN-gamma and TNF-alpha, whereas more PD-1(hi) cells displayed characteristics of cytotoxic effectors such as production of granzymes and surface expression of CD107a. Importantly, CD8(+) T cells mediated rapid in vivo cytotoxicity and were critical for control of acute Friend virus replication. Thus, direct ex vivo analyses and in vivo experiments revealed high CD8(+) T cell functionality and indicate that PD-1 expression during acute infection is not a marker of T cell exhaustion. The Journal of Immunology, 2011, 187: 3730-3737. C1 [Zelinskyy, Gennadiy; Dietze, Kirsten K.; Gibbert, Kathrin; Roggendorf, Michael; Liu, Jia; Lu, Mengji; Kraft, Anke R.; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, D-45122 Essen, Germany. [Myers, Lara; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Teichgraeber, Volker] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. RP Dittmer, U (reprint author), Univ Klinikum Essen, Inst Virol, D-45122 Essen, Germany. EM ulf.dittmer@uni-due.de FU Deutsche Forschungsgemeinschaft [TRR60, B4]; Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by a grant from the Deutsche Forschungsgemeinschaft (TRR60 project B4 to U.D. and G.Z.) and by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to K.J.H. and L.M.). NR 45 TC 31 Z9 31 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 OCT 1 PY 2011 VL 187 IS 7 BP 3730 EP 3737 DI 10.4049/jimmunol.1101612 PG 8 WC Immunology SC Immunology GA 822IB UT WOS:000295036400032 PM 21873525 ER PT J AU Verkoczy, L Chen, Y Bouton-Verville, H Zhang, JS Diaz, M Hutchinson, J Ouyang, YB Alam, SM Holl, TM Hwang, KK Kelsoe, G Haynes, BF AF Verkoczy, Laurent Chen, Yao Bouton-Verville, Hilary Zhang, Jinsong Diaz, Marilyn Hutchinson, Jennifer Ouyang, Ying-Bin Alam, S. Munir Holl, T. Matt Hwang, Kwan-Ki Kelsoe, Garnett Haynes, Barton F. TI Rescue of HIV-1 Broad Neutralizing Antibody-Expressing B Cells in 2F5 V-H x V-L Knockin Mice Reveals Multiple Tolerance Controls SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; IMMUNOGLOBULIN-M IGM; HEAVY-CHAIN; GENE REPLACEMENT; BINDING; MEMBRANE; REGION; POLYSPECIFICITY; AUTOREACTIVITY AB The HIV-1 broadly neutralizing Ab (bnAb) 2F5 has been shown to be poly-/self-reactive in vitro, and we previously demonstrated that targeted expression of its VDJ rearrangement alone was sufficient to trigger a profound B cell developmental blockade in 2F5 V-H knockin (KI) mice, consistent with central deletion of 2F5 H chain-expressing B cells. In this study, we generate a strain expressing the entire 2F5 bnAb specificity, 2F5 V-H x V-L KI mice, and find an even higher degree of tolerance control than observed in the 2F5 V-H KI strain. Although B cell development was severely impaired in 2F5 V-H x V-L KI animals, we demonstrate rescue of their B cells when cultured in IL-7/BAFF. Intriguingly, even under these conditions, most rescued B cell hybridomas produced mAbs that lacked HIV-1 Envelope (Env) reactivity due to editing of the 2F5 L chain, and the majority of rescued B cells retained an anergic phenotype. Thus, when clonal deletion is circumvented, kappa editing and anergy are additional safeguards preventing 2F5 V-H/V-L expression by immature/transitional B cells. Importantly, 7% of rescued B cells retained 2F5 V-H/V-L expression and secreted Env-specific mAbs with HIV-1-neutralizing activity. This partial rescue was further corroborated in vivo, as reflected by the anergic phenotype of most rescued B cells in 2F5 V-H x V-L KI x E mu-Bcl-2 transgenic mice and significant (yet modest) enrichment of Env-specific B cells and serum Igs. The rescued 2F5 mAb-producing B cell clones in this study are the first examples, to our knowledge, of in vivo-derived bone marrow precursors specifying HIV-1 bnAbs and provide a starting point for design of strategies aimed at rescuing such B cells. The Journal of Immunology, 2011, 187: 3785-3797. C1 [Verkoczy, Laurent; Chen, Yao; Bouton-Verville, Hilary; Zhang, Jinsong; Hutchinson, Jennifer; Alam, S. Munir; Hwang, Kwan-Ki; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Dept Med, Durham, NC 27710 USA. [Diaz, Marilyn] NIEHS, Res Triangle Pk, NC 27709 USA. [Ouyang, Ying-Bin] Taconic Biosci, Cranbury, NJ 08512 USA. [Holl, T. Matt; Kelsoe, Garnett; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP Verkoczy, L (reprint author), Duke Univ, Med Ctr, Duke Human Vaccine Inst, Dept Med, 2 Genome Court,Med Sci Res Bldg 2,Room 3015, Durham, NC 27710 USA. EM laurent.verkoczy@duke.edu RI ZHANG, JINSONG/E-1656-2011 OI ZHANG, JINSONG/0000-0002-2195-2997 FU Bill and Melinda Gates Foundation [38643]; National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI067854, AI081579, AI087202] FX This work was conducted as part of the Collaboration for AIDS Vaccine Discovery with support from Bill and Melinda Gates Foundation Grant 38643 (to B.F.H.) and National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants AI067854 (to B.F.H.), AI081579 (to G.K.), and AI087202 (to L.V.). NR 40 TC 46 Z9 46 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 OCT 1 PY 2011 VL 187 IS 7 BP 3785 EP 3797 DI 10.4049/jimmunol.1101633 PG 13 WC Immunology SC Immunology GA 822IB UT WOS:000295036400038 PM 21908739 ER PT J AU Shirreff, G Pellis, L Laeyendecker, O Fraser, C AF Shirreff, George Pellis, Lorenzo Laeyendecker, Oliver Fraser, Christophe TI Transmission Selects for HIV-1 Strains of Intermediate Virulence: A Modelling Approach SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMA VIRAL LOAD; CD4 CELL COUNTS; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; HETEROSEXUAL TRANSMISSION; REPLICATIVE FITNESS; AIDS-PREVENTION; COMMUNITY TRIAL; EARLY INFECTION AB Recent data shows that HIV-1 is characterised by variation in viral virulence factors that is heritable between infections, which suggests that viral virulence can be naturally selected at the population level. A trade-off between transmissibility and duration of infection appears to favour viruses of intermediate virulence. We developed a mathematical model to simulate the dynamics of putative viral genotypes that differ in their virulence. As a proxy for virulence, we use set-point viral load (SPVL), which is the steady density of viral particles in blood during asymptomatic infection. Mutation, the dependency of survival and transmissibility on SPVL, and host effects were incorporated into the model. The model was fitted to data to estimate unknown parameters, and was found to fit existing data well. The maximum likelihood estimates of the parameters produced a model in which SPVL converged from any initial conditions to observed values within 100150 years of first emergence of HIV-1. We estimated the 1) host effect and 2) the extent to which the viral virulence genotype mutates from one infection to the next, and found a trade-off between these two parameters in explaining the variation in SPVL. The model confirms that evolution of virulence towards intermediate levels is sufficiently rapid for it to have happened in the early stages of the HIV epidemic, and confirms that existing viral loads are nearly optimal given the assumed constraints on evolution. The model provides a useful framework under which to examine the future evolution of HIV-1 virulence. C1 [Shirreff, George; Pellis, Lorenzo; Fraser, Christophe] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. [Laeyendecker, Oliver] NIAID, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Shirreff, G (reprint author), Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. EM c.fraser@imperial.ac.uk RI Shirreff, George/A-3775-2013; Laeyendecker, Oliver/B-9331-2009; Fraser, Christophe/A-8109-2008; OI Fraser, Christophe/0000-0003-2399-9657; Laeyendecker, Oliver/0000-0002-6429-4760 FU School of Public Health; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Imperial College London; Medical Research Council Centre for Outbreak Analysis and Modelling; Royal Society FX This work was funded by the School of Public Health, Imperial College London, the Medical Research Council Centre for Outbreak Analysis and Modelling, and the Royal Society. Additional support was provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 20 Z9 21 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2011 VL 7 IS 10 AR e1002185 DI 10.1371/journal.pcbi.1002185 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 851IW UT WOS:000297262700019 PM 22022243 ER PT J AU Via, A De las Rivas, J Attwood, TK Landsman, D Brazas, MD Leunissen, JAM Tramontano, A Schneider, MV AF Via, Allegra De las Rivas, Javier Attwood, Teresa K. Landsman, David Brazas, Michelle D. Leunissen, Jack A. M. Tramontano, Anna Schneider, Maria Victoria TI Ten Simple Rules for Developing a Short Bioinformatics Training Course SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Via, Allegra; Tramontano, Anna] Univ Roma La Sapienza, Dept Phys, Biocomp Grp, I-00185 Rome, Italy. [De las Rivas, Javier] CSIC USAL, Canc Res Ctr IBMCC, Bioinformat & Funct Genom Res Grp, Salamanca, Spain. [Attwood, Teresa K.] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Attwood, Teresa K.] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Landsman, David] Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Brazas, Michelle D.] MaRS Ctr, Ontario Inst Canc Res, Toronto, ON, Canada. [Leunissen, Jack A. M.] Wageningen Univ, Lab Bioinformat, Wageningen, Netherlands. [Schneider, Maria Victoria] European Bioinformat Inst, EMBL Outstat, Outreach & Training Team, Hinxton, England. RP Via, A (reprint author), Univ Roma La Sapienza, Dept Phys, Biocomp Grp, I-00185 Rome, Italy. EM vicky@ebi.ac.uk RI Tramontano, anna/D-5378-2009; 2011, Secribsal/D-9425-2012; De Las Rivas, Javier/G-5936-2014; OI Tramontano, anna/0000-0002-5610-3338; De Las Rivas, Javier/0000-0002-0984-9946; Schneider, Maria Victoria/0000-0002-7114-2060; Landsman, David/0000-0002-9819-6675 FU Intramural NIH HHS NR 2 TC 13 Z9 14 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2011 VL 7 IS 10 AR e1002245 DI 10.1371/journal.pcbi.1002245 PG 3 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 851IW UT WOS:000297262700063 PM 22046119 ER PT J AU Shevtsova, NA Manzke, T Molkov, YI Bischoff, A Smith, JC Rybak, IA Richter, DW AF Shevtsova, Natalia A. Manzke, Till Molkov, Yaroslav I. Bischoff, Anne Smith, Jeffrey C. Rybak, Ilya A. Richter, Diethelm W. TI Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE Botzinger complex; glycinergic synapses; pre-Botzinger complex; rescue breathing; respiratory network; serotonin modulation ID PRE-BOTZINGER COMPLEX; RHYTHM GENERATION; EXPIRATORY NEURONS; IN-VIVO; PACEMAKER NEURONS; NEWBORN RATS; IMMUNOREACTIVE NEURONS; SYNAPTIC INHIBITION; PATTERN GENERATOR; NEURAL MECHANISMS AB Brainstem respiratory neurons express the glycine a3 receptor (Glya3R), which is a target of modulation by several serotonin (5-HT) receptor agonists. Application of the 5-HT1A receptor (5-HT1AR) agonist 8-OH-DPAT was shown (i) to depress cellular cAMP, leading to dephosphorylation of Glya3R and augmentation of postsynaptic inhibition of neurons expressing Glya3R (Manzke , 2010) and (ii) to hyperpolarize respiratory neurons through 5-HT-activated potassium channels. These processes counteract opioid-induced depression and restore breathing from apnoeas often accompanying pharmacotherapy of pain. The effect is postulated to rely on the enhanced Glya3R-mediated inhibition of inhibitory neurons causing disinhibition of their target neurons. To evaluate this proposal and investigate the neural mechanisms involved, an established computational model of the brainstem respiratory network (Smith , 2007), was extended by (i) incorporating distinct subpopulations of inhibitory neurons (glycinergic and GABAergic) and their synaptic interconnections within the Botzinger and pre-Botzinger complexes and (ii) assigning the 5-HT1AR-Glya3R complex to some of these inhibitory neuron types in the network. The modified model was used to simulate the effects of 8-OH-DPAT on the respiratory pattern and was able to realistically reproduce a number of experimentally observed responses, including the shift in the onset of post-inspiratory activity to inspiration and conversion of the eupnoeic three-phase rhythmic pattern into a two-phase pattern lacking the post-inspiratory phase. The model shows how 5-HT1AR activation can produce a disinhibition of inspiratory neurons, leading to the recovery of respiratory rhythm from opioid-induced apnoeas. C1 [Shevtsova, Natalia A.; Molkov, Yaroslav I.; Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. [Manzke, Till; Bischoff, Anne; Richter, Diethelm W.] Univ Gottingen, Dept Neuro & Sensory Physiol, Gottingen, Germany. [Manzke, Till; Bischoff, Anne; Richter, Diethelm W.] DFG Res Ctr Mol Physiol Brain, Gottingen, Germany. [Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD USA. RP Rybak, IA (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. EM rybak@drexel.edu OI Molkov, Yaroslav/0000-0002-0862-1974 FU NIH [R01 NS057815, R01 NS069220, R33 HL087379]; NIH, NINDS; DFG Research Center 'Molecular physiology of the brain' FX This study was supported in the USA by NIH grants R01 NS057815, R01 NS069220 and R33 HL087379, and in part by the Intramural Research Program of the NIH, NINDS, and in Germany by the DFG Research Center 'Molecular physiology of the brain'. NR 59 TC 15 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD OCT PY 2011 VL 34 IS 8 BP 1276 EP 1291 DI 10.1111/j.1460-9568.2011.07825.x PG 16 WC Neurosciences SC Neurosciences & Neurology GA 847ZC UT WOS:000297014000011 PM 21899601 ER PT J AU McDonald, SM Davis, K McAllen, JK Spiro, DJ Patton, JT AF McDonald, Sarah M. Davis, Kristin McAllen, John K. Spiro, David J. Patton, John T. TI Intra-genotypic diversity of archival G4P[8] human rotaviruses from Washington, DC SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Rotavirus; G4P[8]; Genetic diversity; Gene reassortment; Clade ID GROUP-A ROTAVIRUSES; CLASSIFICATION; STRAINS; PROTEIN; PORCINE; VACCINE; KENYA; VP4 AB Group A human rotaviruses (RVs) remain the most frequently detected viral agents associated with acute gastroenteritis in infants and young children. Despite their medical importance, relatively few complete genome sequences have been determined for commonly circulating G/P-type strains (i.e., G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]). In the current study, we sequenced the genomes of 11 G4P[8] isolates from stool specimens that were collected in Washington, DC during the years of 1974-1991. We found that the VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5/6-encoding genes of all 11 G4P[8] RVs have the genotypes of G4-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. By constructing phylogenetic trees for each gene, extensive intra-genotypic diversity was revealed among the G4P[8] RVs, and new subgenotype gene alleles were identified. Several of these alleles are nearly identical to those of G3P[8] isolates previously sequenced from this same Washington, DC collection, strongly suggesting that the RVs underwent gene reassortment. On the other hand, we observed that some G4P[8] RVs exhibit completely different allele-based genome constellations, despite being collected during the same epidemic season; there was no evidence of gene reassortment between these strains. This observation extends our previous findings and supports the notion that stable, genetically-distinct clades of human RVs with the same G/P-type can co-circulate in a community. Interestingly, the sub-genotype gene alleles found in some of the DC RVs share a close evolutionary relationship with genes of more contemporary human strains. Thus, archival human RVs sequenced in this study might represent evolutionary precursors to modern-day strains. Published by Elsevier B.V. C1 [McDonald, Sarah M.; Davis, Kristin; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [McAllen, John K.; Spiro, David J.] J Craig Venter Inst, Rockville, MD 20850 USA. RP McDonald, SM (reprint author), Virginia Tech, Virginia Tech Caril Res Inst, Dept Pathobiol & Biomed Sci, Coll Vet Med, 2 Riverside Circle, Roanoke, VA 24016 USA. EM mcdonaldsa@vtc.vt.edu RI Patton, John/P-1390-2014 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We would like to thank members of the Patton laboratory for scientific and editorial suggestions. S.M. McDonald, K. Davis, and J.T. Patton were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health during the time of this study. NR 26 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD OCT PY 2011 VL 11 IS 7 BP 1586 EP 1594 DI 10.1016/j.meegid.2011.05.023 PG 9 WC Infectious Diseases SC Infectious Diseases GA 849LK UT WOS:000297126800009 PM 21712102 ER PT J AU Goff, A Mucker, E Raymond, J Fisher, R Bray, M Hensley, L Paragas, J AF Goff, Arthur Mucker, Eric Raymond, Jolynne Fisher, Robert Bray, Mike Hensley, Lisa Paragas, Jason TI Infection of cynomolgus macaques with a recombinant monkeypox virus encoding green fluorescent protein SO ARCHIVES OF VIROLOGY LA English DT Article ID VACCINIA VIRUS; SMALLPOX; EFFICACY; ASSAY AB Monkeypox virus (MPXV) causes a vesiculopustular rash illness resembling smallpox in humans and produces a similar disease in nonhuman primates. To enhance the ability of researchers to study experimental MPXV infections, we inserted a gene encoding green fluorescent protein (GFP) into Monkeypox virus Zaire-79. Wild-type and MPXV-GFP replicated with similar kinetics in cell culture and caused a similar disease when injected intravenously into cynomolgus macaques. In MPXV-GFP-infected animals, examination under fluorescent light facilitated the identification of skin lesions during disease development and internal sites of replication at necropsy. MPXV-GFP could improve the quantitative assessment of antiviral therapy and vaccine efficacy. C1 [Goff, Arthur; Mucker, Eric; Hensley, Lisa] USA, Div Virol, Viral Therapeut Branch, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Raymond, Jolynne] Armed Forces Inst Pathol, Silver Spring, MD USA. [Fisher, Robert] US FDA, Lab Plasma Derivat, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Bray, Mike; Paragas, Jason] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. RP Goff, A (reprint author), USA, Div Virol, Viral Therapeut Branch, Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. EM arthur.goff@amedd.army.mil FU Defense Threat Reduction Agency; Department of Homeland Security's National Biodefense Analysis and Countermeasures Center (NBACC) FX The research described in this paper was funded by the Defense Threat Reduction Agency and The Department of Homeland Security's National Biodefense Analysis and Countermeasures Center (NBACC). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. NR 12 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD OCT PY 2011 VL 156 IS 10 BP 1877 EP 1881 DI 10.1007/s00705-011-1065-1 PG 5 WC Virology SC Virology GA 841KC UT WOS:000296510200022 PM 21814864 ER PT J AU Carney, EW Ellis, AL Tyl, RW Foster, PMD Scialli, AR Thompson, K Kim, J AF Carney, Edward W. Ellis, Amy L. Tyl, Rochelle W. Foster, Paul M. D. Scialli, Anthony R. Thompson, Kary Kim, James TI Critical Evaluation of Current Developmental Toxicity Testing Strategies: A Case of Babies and Their Bathwater SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Review DE safety testing; maternal toxicity; pharmacokinetics; alternatives to animal testing ID HUMAN RISK-ASSESSMENT; MATERNAL TOXICITY; FETAL MALFORMATIONS; ETHYLENE-GLYCOL; SCORING SYSTEM; WAVY RIBS; RABBIT; EMBRYO; REACH; RAT AB This review is the second in a series of four papers emanating from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the ILSI Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. The present review analyzes the strengths and weaknesses of current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e. g., large number of animals, high costs, low throughput, the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models relative to mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century. Birth Defects Res (Part B) 92:395-403, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Carney, Edward W.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Ellis, Amy L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Tyl, Rochelle W.] RTI Int, Discovery & Analyt Sci, Res Triangle Pk, NC USA. [Foster, Paul M. D.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [Scialli, Anthony R.] Tetra Tech Sci, Arlington, VA USA. [Thompson, Kary] Bristol Myers Squibb Co, Reprod Toxicol, New Brunswick, NJ USA. [Kim, James] ILSI Hlth & Environm Sci Inst HESI, Washington, DC USA. RP Carney, EW (reprint author), Dow Chem Co USA, Toxicol & Environm Res & Consulting, 1803 Bldg, Midland, MI 48674 USA. EM ecarney@dow.com NR 55 TC 7 Z9 7 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD OCT PY 2011 VL 92 IS 5 SI SI BP 395 EP 403 DI 10.1002/bdrb.20318 PG 9 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 842PT UT WOS:000296612100003 PM 21770028 ER PT J AU Brannen, KC Fenton, SE Hansen, DK Harrouk, W Kim, JH Shuey, D AF Brannen, Kimberly C. Fenton, Suzanne E. Hansen, Deborah K. Harrouk, Wafa Kim, James H. Shuey, Dana TI Developmental Toxicology-New Directions Workshop: Refining Testing Strategies and Study Designs SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE refined study designs; testing strategies; developmental toxicology; safety assessment AB In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration. Birth Defects Res (Part B) 92:404-412, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Brannen, Kimberly C.] Charles River Labs, Preclin Serv, Horsham, PA USA. [Fenton, Suzanne E.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [Hansen, Deborah K.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Harrouk, Wafa] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kim, James H.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Shuey, Dana] Endo Pharmaceut Inc, Chadds Ford, PA USA. RP Brannen, KC (reprint author), Charles River Labs, Preclin Serv, Horsham, PA USA. EM kimberly.brannen@crl.com FU Intramural NIH HHS [ZIA ES102785-02, ZIA ES102785-01] NR 13 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD OCT PY 2011 VL 92 IS 5 SI SI BP 404 EP 412 DI 10.1002/bdrb.20326 PG 9 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 842PT UT WOS:000296612100004 PM 22006510 ER PT J AU Ricart, AD Ashton, EA Cooney, MM Sarantopoulos, J Brell, JM Feldman, MA Ruby, KE Matsuda, K Munsey, MS Medina, G Zambito, A Tolcher, AW Remick, SC AF Ricart, Alejandro D. Ashton, Edward A. Cooney, Matthew M. Sarantopoulos, John Brell, Joanna M. Feldman, Maria A. Ruby, Kale E. Matsuda, Kazuko Munsey, Mark S. Medina, Gerardo Zambito, Angela Tolcher, Anthony W. Remick, Scot C. TI A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE MN-029; Vascular-disrupting agent; Phase I ID COMBRETASTATIN A4 PHOSPHATE; CIRCULATING ENDOTHELIAL-CELLS; TARGETING AGENT; CANCER-PATIENTS; 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID; PERFUSION ASSESSMENT; CLINICAL-TRIALS; A-4 PHOSPHATE; ZD6126; ANGIOGENESIS AB Purpose MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029. Methods Patients were treated with escalating doses of MN-029 (4.0-225 mg/m(2)) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6-8 h postdose. Results Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m(2) was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m(2), a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C(max) and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease >= 6 months. A significant linear correlation was found between reduction in K trans and exposure to MN-029. Conclusions MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m(2). C1 [Ricart, Alejandro D.] Pfizer Inc, Oncol Dev, San Diego, CA 92121 USA. [Ricart, Alejandro D.; Sarantopoulos, John; Medina, Gerardo; Tolcher, Anthony W.] Canc Therapy & Res Ctr S Texas, Inst Drug Dev, San Antonio, TX 78229 USA. [Ashton, Edward A.] VirtualScopics Inc, Rochester, NY USA. [Cooney, Matthew M.; Zambito, Angela; Remick, Scot C.] CASE Comprehens Canc Ctr, Dev Therapeut Program, Cleveland, OH USA. [Brell, Joanna M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Feldman, Maria A.; Ruby, Kale E.; Matsuda, Kazuko; Munsey, Mark S.] MediciNova Inc, San Diego, CA USA. RP Ricart, AD (reprint author), Pfizer Inc, Oncol Dev, 10646 Sci Ctr Dr, San Diego, CA 92121 USA. EM alejandro.d.ricart@pfizer.com FU MediciNova, Inc.; Abbott; Ambit; Amgen; Array BioPharma; Astellas; AVEO/Schering/Plough; Azaya Therapeutics; Bayer; Biogen Idec; BiPar; Bristol-Myers Squibb; Calando; Cougar; Dendreon; Eli Lilly; Enzon; Exelixis; Five Prime; Genentech; Genta; Glaxo Smith Kline; Hana Biosciences; HoffmanLa Roche; Merck; Merrimack; MethylGene; Myriad; Nektar; Nerviano; Proteolix; Sanofi-Aventis; Spectrum; Symphogen FX We thank Ana Ruiz-Garcia and Louis Lazo Radulovic for helpful discussions and technical assistance. This work was supported by MediciNova, Inc.; Alejandro D Ricart is compensated as an employee of Pfizer Inc and owns stock/stock options in Pfizer Inc. Edward A. Ashton, Matthew M. Cooney, John Sarantopoulos, Joanna M. Brell, Gerardo Medina, Angela Zambito: no disclosures. Maria A. Feldman, Kale E. Ruby, Kazuko Matsuda, Mark S. Munsey are compensated as employees of MediciNova Inc. Anthony W. Tolcher's institution has received research funding from Abbott, Ambit, Amgen, Array BioPharma, Astellas, AVEO/Schering/Plough, Azaya Therapeutics, Bayer, Biogen Idec, BiPar, Bristol-Myers Squibb, Calando, Cougar, Dendreon, Eli Lilly, Enzon, Exelixis, Five Prime, Genentech, Genta, Glaxo Smith Kline, Hana Biosciences, HoffmanLa Roche, Merck, Merrimack, MethylGene, Myriad, Nektar, Nerviano, Proteolix, Sanofi-Aventis, Spectrum, Symphogen; he has also received payment for consulting and advisory agreements from Abbott, Abgenomics, Abraxis, ACT Biotech, Actavis, Adnexus, Adventrx Pharmaceuticals, Ambit, Amgen, Ariad Pharmaceuticals, Arresto Biosciences, Astellas, AstraZeneca, AVEO, Bayer, Bind Bio, Biogen Idec, BiPar, Calando, Calistoga, Chemokine, Curis, Daiichi Sankyo, Dendreon, Dicerna, Eli Lilly, EMTx, Endo, Enzon, Exelixis, Five Prime, Genentech, Genta, Geron, Glaxo Smith Kline, HUYA Bioscience, Intellikine, Johnson & Johnson, Merck, MethylGene, Micromet, Myriad, Nektar, Nerviano, Neumedicines, Onyx, Otsuka, Pfizer, ProNai, Regeneron, Sanofi-Aventis, Santaris, Schering Plough, Seattle Genetics, Semophore, Spectrum, Supergen, Symphogen, Vaccinex, and Veeda. Scot C. Remick has received a clinical research grant from MediciNova Inc. NR 48 TC 12 Z9 13 U1 0 U2 6 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 OCT PY 2011 VL 68 IS 4 BP 959 EP 970 DI 10.1007/s00280-011-1565-4 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 849JR UT WOS:000297122300016 PM 21305290 ER PT J AU Liao, W Lin, JX Leonard, WJ AF Liao, Wei Lin, Jian-Xin Leonard, Warren J. TI IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID INTERLEUKIN-2-RECEPTOR BETA-CHAIN; TH2 DIFFERENTIATION; RECEPTOR-BETA; CYTOPLASMIC DOMAINS; SIGNALING PATHWAYS; IMMUNE-RESPONSES; EXPRESSION; GAMMA; GENE; LYMPHOCYTES AB Interleukin-2 (IL-2) is a pleiotropic cytokine that drives T-cell growth, augments NK cytolytic activity, induces the differentiation of regulatory T cells, and mediates activation-induced cell death. Along with IL-4, IL-7, IL-9, IL-15, and IL-21, IL-2 shares the common cytokine receptor gamma chain, gamma(c), which is mutated in humans with X-linked severe combined immunodeficiency. Herein, we primarily focus on the recently discovered complex roles of IL-2 in broadly modulating T cells for T helper cell differentiation. IL-2 does not specify the type of Th differentiation that occurs; instead, IL-2 modulates expression of receptors for other cytokines and transcription factors, thereby either promoting or inhibiting cytokine cascades that correlate with each Th differentiation state. In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells. C1 [Liao, Wei; Lin, Jian-Xin; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. We thank Dr. Rosanne Spolski, NHLBI, for critical comments. NR 58 TC 165 Z9 173 U1 3 U2 28 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2011 VL 23 IS 5 BP 598 EP 604 DI 10.1016/j.coi.2011.08.003 PG 7 WC Immunology SC Immunology GA 848EE UT WOS:000297032200006 PM 21889323 ER PT J AU DeGiorgis, JA Cavaliere, KR Burbach, JPH AF DeGiorgis, Joseph A. Cavaliere, Kimberly R. Burbach, J. Peter H. TI Identification of Molecular Motors in the Woods Hole Squid, Loligo pealei: An Expressed Sequence Tag Approach SO CYTOSKELETON LA English DT Article DE kinesin; dynein; squid; axonal transport; expressed sequence tag; transcriptome ID FAST AXONAL-TRANSPORT; GIANT-AXON; HEAVY-CHAIN; NEUROTRANSMITTER RELEASE; AXOPLASMIC ORGANELLES; CYTOPLASMIC DYNEIN; BINDING PROTEIN; HIGH-AFFINITY; NERVE-FIBERS; OPTIC LOBE AB The squid giant axon and synapse are unique systems for studying neuronal function. While a few nucleotide and amino acid sequences have been obtained from squid, large scale genetic and proteomic information is lacking. We have been particularly interested in motors present in axons and their roles in transport processes. Here, to obtain genetic data and to identify motors expressed in squid, we initiated an expressed sequence tag project by single-pass sequencing mRNAs isolated from the stellate ganglia of the Woods Hole Squid, Loligo pealei. A total of 22,689 high quality expressed sequence tag (EST) sequences were obtained and subjected to basic local alignment search tool analysis. Seventy six percent of these sequences matched genes in the National Center for Bioinformatics databases. By CAP3 analysis this library contained 2459 contigs and 7568 singletons. Mining for motors successfully identified six kinesins, six myosins, a single dynein heavy chain, as well as components of the dynactin complex, and motor light chains and accessory proteins. This initiative demonstrates that EST projects represent an effective approach to obtain sequences of interest. (C) 2011 Wiley Periodicals, Inc. C1 [DeGiorgis, Joseph A.; Cavaliere, Kimberly R.] Providence Coll, Dept Biol, Providence, RI 02918 USA. [DeGiorgis, Joseph A.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [DeGiorgis, Joseph A.; Burbach, J. Peter H.] Marine Biol Lab, Cellular Dynam Program, Woods Hole, MA 02543 USA. [Burbach, J. Peter H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, Utrecht, Netherlands. RP DeGiorgis, JA (reprint author), Providence Coll, Dept Biol, Providence, RI 02918 USA. EM jdegiorg@providence.edu FU NINDS; NIH; National Institutes of Neurological Disorders and Stroke, NIH; David de Wied Foundation; Hersenstichting Nederland; Baxter Postdoctoral Fellowship Fund; MBL Associates Fund; James A. and Faith Miller Memorial Fund; H.B. Steinbach Fund; National Center for Research Resources (NCRR), NIH [P20RR016457-10] FX The authors would like to thank Captain Henry Klimm, Captain Bill Klimm, Ed Enos, and the collecting staff at the Marine Resources Center, Marine Biological Laboratory, Woods Hole, Massachusetts for collecting and maintaining squid used in this research. We thank Gerard Bouffard and the NIH Intramural Sequencing Center at NHGRI for obtaining the expressed sequence tags. We thank Dr. Harish Pant and Dr. Philip Grant, NINDS, NIH, for support and hosting J.P.H.B., and Anita Hellemons for technical support. We are indebted to and give special thanks to Dr. Thomas S. Reese, NINDS, NIH for his support and comments on the manuscript. This research was supported by the National Institutes of Neurological Disorders and Stroke, NIH (J.A.D.); the David de Wied Foundation (J.P.H.B.), the Hersenstichting Nederland (J.P.H.B.); and by MBL Fellowships (J.P.H.B.) sponsored by the Baxter Postdoctoral Fellowship Fund, MBL Associates Fund, James A. and Faith Miller Memorial Fund, and the H.B. Steinbach Fund. The project described was also supported by the RI-INBRE Award # P20RR016457-10 from the National Center for Research Resources (NCRR), NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCRR or the NIH (J.A.D.). NR 65 TC 8 Z9 8 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1949-3584 EI 1949-3592 J9 CYTOSKELETON JI Cytoskeleton PD OCT PY 2011 VL 68 IS 10 BP 566 EP 577 DI 10.1002/cm.20531 PG 12 WC Cell Biology SC Cell Biology GA 847YH UT WOS:000297011300004 PM 21913340 ER PT J AU Wind, JJ Lonser, RR AF Wind, Joshua J. Lonser, Russell R. TI Management of von Hippel-Lindau disease-associated CNS lesions SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE endolymphatic sac tumor; hemangioblastoma; surgery; von Hippel-Lindau disease ID ENDOLYMPHATIC SAC TUMORS; CENTRAL-NERVOUS-SYSTEM; BRAIN-STEM HEMANGIOBLASTOMAS; MORBID HEARING-LOSS; NATURAL-HISTORY; SURGICAL-MANAGEMENT; PANCREATIC LESIONS; RADIATION-THERAPY; PHEOCHROMOCYTOMA; SURGERY AB Patients with von Hippel-Lindau disease (VHL) often harbor significant disease burden within the CNS, specifically craniospinal-axis hemangioblastomas and endolymphatic sac tumors (ELSTs). The majority (60-80%) of patients with VHL harbor hemangioblastomas, and 10-15% will develop ELSTs. Advances in the understanding of the natural history and outcomes associated with the surgical management of VHL-associated tumors have led to improved management of patients with VHL. Optimizing indications for surgical intervention and refining of surgical techniques for these lesions can reduce patient morbidity associated with the management of this syndrome. In this article, we review the various aspects of perioperative management of patients with VHL, surgical indications and general operative principles for the management of hemangioblastomas and ELSTs, and outcomes associated with the surgical treatment of these tumors. C1 [Wind, Joshua J.; Lonser, Russell R.] Natl Inst Neurol Disorders Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Wind, Joshua J.] George Washington Univ, Med Ctr, Dept Neurol Surg, Washington, DC 20037 USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Wind, Joshua/D-5480-2013 OI Wind, Joshua/0000-0003-3443-8476 NR 58 TC 17 Z9 19 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD OCT PY 2011 VL 11 IS 10 BP 1433 EP 1440 DI 10.1586/ERN.11.124 PG 8 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 838KO UT WOS:000296289300016 PM 21955200 ER PT J AU Martinelli, F Quinten, C Maringwa, JT Coens, C Vercauteren, J Cleeland, CS Flechtner, H Gotay, C Greimel, E King, M Mendoza, T Osoba, D Reeve, BB Ringash, J Schmucker-Von Koch, J Shi, QL Taphoorn, MJ Weis, J Bottomley, A AF Martinelli, Francesca Quinten, Chantal Maringwa, John T. Coens, Corneel Vercauteren, Jurgen Cleeland, Charles S. Flechtner, Henning Gotay, Carolyn Greimel, Eva King, Madeleine Mendoza, Tito Osoba, David Reeve, Bryce B. Ringash, Jolie Schmucker-Von Koch, Joseph Shi, Qiuling Taphoorn, Martin J. Weis, Joachim Bottomley, Andrew CA European Org Res Treatment Canc TI Examining the relationships among health-related quality-of-life indicators in cancer patients participating in clinical trials: a pooled study of baseline EORTC QLQ-C30 data SO EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH LA English DT Article DE cancer; clinical trials; cluster analysis; patient-reported outcomes; quality of life ID PHASE-III TRIAL; METASTATIC BREAST-CANCER; CELL LUNG-CANCER; EUROPEAN-ORGANIZATION; PROSTATE-CANCER; SYMPTOM CLUSTERS; COLORECTAL-CANCER; ADJUVANT THERAPY; RANDOMIZED-TRIAL; CHEMOTHERAPY AB Aims: Cancer patients experience multiple and concurrent health-related problems and symptoms due to their illness and therapies. The first objective of this analysis was to identify how health-related quality-of-life (HRQoL) indicators cluster among cancer patients and how possible clusters change across patients with different sociodemographic and clinical characteristics. The second objective of this study was to identify which HRQoL indicators are linked to patients' perception of overall quality of life. Methods: Retrospective pooling of 30 closed randomized European Organisation for Research and Treatment of Cancer (EORTC) clinical trials yielded baseline EORTC Quality of Life Core Questionnaire (QLQ-C30) HRQoL data for a total of 7417 patients. A cluster analysis was performed to determine how the 15 HRQoL indicators obtained with the QLQ-C30 cluster overall and by patient characteristics. Results: Three main clusters emerged from the overall dataset: a physical cluster, a psychological cluster and a gastrointestinal cluster. The same clusters were found in subgroups defined according to sociodemographic and clinical characteristics, while some differences emerged among cancer sites. The Global Health scale was found to be part of the physical cluster in the overall dataset. This result was consistent across different levels of disease severity, while divergent results were seen across some cancer sites. Conclusion: Our findings suggest that HRQoL indicators are interrelated. Understanding these relationships may aid clinicians in managing the symptom burden experienced by patients, as well as policy-makers, in defining psychosocial support plans. C1 [Martinelli, Francesca; Quinten, Chantal; Maringwa, John T.; Coens, Corneel; Vercauteren, Jurgen; Bottomley, Andrew] European Org Res Treatment Canc, Qual Life Dept, Brussels, Belgium. [Vercauteren, Jurgen] Katholieke Univ Leuven, Rega Inst, Louvain, Belgium. [Cleeland, Charles S.; Mendoza, Tito; Shi, Qiuling] Univ Texas Houston, MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Flechtner, Henning] Clin Child & Adolescent Psychiat & Psychotherapy, Magdeburg, Germany. [Gotay, Carolyn] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Greimel, Eva] Graz Univ, Dept Obstet & Gynecol, Graz, Austria. [King, Madeleine] Univ Sydney, Psychooncol Cooperat Res Grp, Sydney, NSW 2006, Australia. [Osoba, David] Qual Life Consulting, W Vancouver, BC, Canada. [Reeve, Bryce B.] NCI, Bethesda, MD 20892 USA. [Ringash, Jolie] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Schmucker-Von Koch, Joseph] Univ Regensburg, Med Eth Philosoph Fac, Regensburg, Germany. [Taphoorn, Martin J.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Taphoorn, Martin J.] Med Ctr Haaglanden, The Hague, Netherlands. [Weis, Joachim] Univ Freiburg, Dept Psychooncol, Freiburg, Germany. RP Martinelli, F (reprint author), European Org Res Treatment Canc, Qual Life Dept, Brussels, Belgium. EM francesca.martinelli@eortc.be RI van Zandwijk, Nico/E-4177-2012 OI van Zandwijk, Nico/0000-0002-8405-9688 FU Pfizer Foundation FX This study was funded by an unrestricted academic grant from the Pfizer Foundation, administered through the King Baudouin Foundation, for the EORTC PROBE group. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 55 TC 5 Z9 6 U1 2 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7167 J9 EXPERT REV PHARM OUT JI Expert Rev. Pharmacoecon. Outcomes Res. PD OCT PY 2011 VL 11 IS 5 BP 587 EP 599 DI 10.1586/ERP.11.51 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA 848BP UT WOS:000297022200016 PM 21958103 ER PT J AU Qiu, P Li, Y Ding, Y Weng, J Banks, SM Kern, S Fitz, Y Suffredini, AF Eichacker, PQ Cui, XZ AF Qiu, Ping Li, Yan Ding, Yi Weng, Jia Banks, Steven M. Kern, Steven Fitz, Yvonne Suffredini, Anthony F. Eichacker, Peter Q. Cui, Xizhong TI The individual survival benefits of tumor necrosis factor soluble receptor and fluid administration are not additive in a rat sepsis model SO INTENSIVE CARE MEDICINE LA English DT Article DE Sepsis; Bacterial infection; Pneumonia; TNF soluble receptor; Fluid support; Rat ID ESCHERICHIA-COLI SEPSIS; HUMAN SEPTIC SHOCK; LUNG INJURY; MONOCLONAL-ANTIBODY; WORSENS SURVIVAL; RENAL-FAILURE; FACTOR-ALPHA; INHIBITION; TNF; MICROCIRCULATION AB Background: Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support-itself beneficial-is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit. Methods and results: Antibiotic-treated rats (n = 156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24 h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln +/- standard error (SE): -0.65 +/- 0.30 and -0.62 +/- 0.30, respectively, p <= 0.05], together they did not (p = 0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (-0.37 +/- 0.29 versus -1.27 +/- 0.43, respectively, p = 0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24 h, the observed effects of the combination were also less than estimated ones (p <= 0.0005). Conclusions: The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative. C1 [Qiu, Ping; Li, Yan; Ding, Yi; Weng, Jia; Banks, Steven M.; Kern, Steven; Fitz, Yvonne; Suffredini, Anthony F.; Eichacker, Peter Q.; Cui, Xizhong] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU NIH FX This work was supported by NIH intramural fund. NR 30 TC 4 Z9 4 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD OCT PY 2011 VL 37 IS 10 BP 1688 EP 1695 DI 10.1007/s00134-011-2324-z PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 849WN UT WOS:000297156100017 PM 21922303 ER PT J AU Zernant, J Schubert, C Im, KM Burke, T Brown, CM Fishman, GA Tsang, SH Gouras, P Dean, M Allikmets, R AF Zernant, Jana Schubert, Carl Im, Kate M. Burke, Tomas Brown, Carolyn M. Fishman, Gerald A. Tsang, Stephen H. Gouras, Peter Dean, Michael Allikmets, Rando TI Analysis of the ABCA4 Gene by Next-Generation Sequencing SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CONE-ROD DYSTROPHY; STARGARDT-DISEASE; RETINITIS-PIGMENTOSA; MACULAR DYSTROPHY; PATTERN DYSTROPHY; TRANSPORTER GENE; MUTATIONS; DEGENERATION; PHENOTYPE; FAMILIES AB PURPOSE. To find all possible disease-associated variants in coding sequences of the ABCA4 gene in a large cohort of patients diagnosed with ABCA4-associated diseases. METHODS. One hundred sixty-eight patients who had been clinically diagnosed with Stargardt disease, cone-rod dystrophy, and other ABCA4-associated phenotypes were pre-screened for mutations in ABCA4 with the ABCA4 microarray, resulting in finding 1 of 2 expected mutations in 111 patients and 0 of 2 mutations in 57 patients. The next-generation sequencing (NGS) strategy was applied to these patients to sequence the entire coding region and the splice sites of the ABCA4 gene. Identified new variants were confirmed or rejected by Sanger sequencing and analyzed for possible pathogenicity by in silico programs and, where possible, by segregation analyses. RESULTS. Sequencing was successful in 159 of 168 patients and identified the second disease-associated allele in 49 of 103 (similar to 48%) of patients with one previously identified mutation. Among those with no mutations, both disease-associated alleles were detected in 4 of 56 patients, and one mutation was detected in 10 of 56 patients. The authors detected a total of 57 previously unknown, possibly pathogenic, variants: 29 missense, 4 nonsense, 9 small deletions and 15 splice-site-altering variants. Of these, 55 variants were deemed pathogenic by a combination of predictive methods and segregation analyses. CONCLUSIONS. Many mutations in the coding sequences of the ABCA4 gene are still unknown, and many possibly reside in noncoding regions of the ABCA4 locus. Although the ABCA4 array remains a good first-pass screening option, the NGS platform is a time-and cost-efficient tool for screening large cohorts. (Invest Ophthalmol Vis Sci. 2011;52:8479-8487) DOI: 10.1167/iovs.11-8182 C1 [Zernant, Jana; Schubert, Carl; Burke, Tomas; Brown, Carolyn M.; Tsang, Stephen H.; Gouras, Peter; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Tsang, Stephen H.; Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Im, Kate M.; Dean, Michael] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Fishman, Gerald A.] Pangere Ctr Hereditary Retinal Dis, Chicago, IL USA. RP Allikmets, R (reprint author), Columbia Univ, Dept Ophthalmol, 630 W 168th St, New York, NY 10032 USA. EM rla22@columbia.edu RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU National Eye Institute/National Institutes of Health [EY021163, EY013435, EY019861, EY019007]; Foundation Fighting Blindness; Research to Prevent Blindness (Department of Ophthalmology, Columbia University); National Institutes of Health, National Cancer Institute, Center for Cancer Research; SAIC-Frederick [NO1-NO1-CO-12400] FX Supported in part by National Eye Institute/National Institutes of Health Grants EY021163, EY013435, EY019861, and EY019007 (Core Support for Vision Research); Foundation Fighting Blindness; unrestricted funds from Research to Prevent Blindness (Department of Ophthalmology, Columbia University); Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; and SAIC-Frederick under Contract NO1-NO1-CO-12400. NR 32 TC 61 Z9 64 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2011 VL 52 IS 11 BP 8479 EP 8487 DI 10.1167/iovs.11-8182 PG 9 WC Ophthalmology SC Ophthalmology GA 846MN UT WOS:000296907700034 PM 21911583 ER PT J AU Matendo, RM Engmann, CM Ditekemena, JD Gado, J Tshefu, A McClure, EM Moore, J Boelaert, M Carlo, WA Wright, LL Bose, CL AF Matendo, Richard M. Engmann, Cyril M. Ditekemena, John D. Gado, Justin Tshefu, Antoinette McClure, Elizabeth M. Moore, Janet Boelaert, Marleen Carlo, Waldemar A. Wright, Linda L. Bose, Carl L. TI Challenge of Reducing Perinatal Mortality in Rural Congo: Findings of a Prospective, Population-based Study SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Article DE Neonatal mortality; Observational studies; Perinatal mortality; Population-based studies; Prospective studies; Stillbirths; Congo ID NEONATAL DEATHS; DEVELOPING-COUNTRIES; RISK-FACTORS; PARTICIPATORY INTERVENTION; NEWBORN-CARE; STILLBIRTHS; OUTCOMES; BIRTH; NEPAL; DISEASE AB Each year, an estimated six million perinatal deaths occur worldwide, and 98% of these deaths occur in low-and middle-income countries. These estimates are based on surveys in both urban and rural areas, and they may underrepresent the problem in rural areas. This study was conducted to quantify perinatal mortality, to identify the associated risk factors, and to determine the most common causes of early neonatal death in a rural area of the Democratic Republic of the Congo (DRC). Data were collected on 1,892 births. Risk factors associated with perinatal deaths were identified using multivariate analysis with logistic regression models. Causes of early neonatal deaths were determined by physician-review of information describing death. The perinatal mortality rate was 61 per 1,000 births; the stillbirth rate was 30 per 1,000 births; and the early neonatal death rate was 32 per 1,000 livebirths. Clinically-relevant factors independently associated with perinatal death included: low birthweight [odds ratio (OR)=13.51, 95% confidence interval (CI) 7.82-23.35], breech presentation (OR)=12.41; 95% CI 4.62-33.33), lack of prenatal care (OR=2.70, 95% CI 1.81-4.02), and parity greater than 4 (OR=1.93 95% CI 1.11-3.37). Over one-half of early neonatal deaths (n=37) occurred during the first two postnatal days, and the most common causes were low birthweight/prematurity (47%), asphyxia (34%), and infection (8%). The high perinatal mortality rate in rural communities in the DRC, approximately one-half of which is attributable to early neonatal death, may be modifiable. Specifically, deaths due to breech presentation, the second most common risk factor, may be reduced by making available emergency obstetric care. Most neonatal deaths occur soon after birth, and nearly three-quarters are caused by low birthweight/prematurity or asphyxia. Neonatal mortality might be reduced by targeting interventions to improve neonatal resuscitation and care of larger preterm infants. C1 [Matendo, Richard M.] Hop Gen Reference Kinshasa Ex Mama Yemo, Kinshasa Sch Publ Hlth, UNC KSPH Program, Kinshasa, Zaire. [Engmann, Cyril M.; Bose, Carl L.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [McClure, Elizabeth M.; Moore, Janet] Res Triangle Inst, Durham, NC USA. [Boelaert, Marleen] Prince Leopold Inst Trop Med, Epidemiol Unit, Antwerp, Belgium. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Wright, Linda L.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD USA. RP Matendo, RM (reprint author), Hop Gen Reference Kinshasa Ex Mama Yemo, Kinshasa Sch Publ Hlth, UNC KSPH Program, Pavillon 27,Ave Tombalbaye, Kinshasa, Zaire. EM rmatendo@yahoo.fr RI Boelaert, Marleen/E-2698-2012 OI Boelaert, Marleen/0000-0001-8051-6776 FU NICHD NIH HHS [U01 HD040636] NR 38 TC 0 Z9 1 U1 0 U2 2 PU ICDDR B PI DHAKA PA MOHAKHALI, 1212 DHAKA, BANGLADESH SN 1606-0997 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD OCT PY 2011 VL 29 IS 5 BP 532 EP 540 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 846NK UT WOS:000296910300014 PM 22106760 ER PT J AU Jahouh, F Hou, SJ Kovac, P Banoub, JH AF Jahouh, Farid Hou, Shu-jie Kovac, Pavol Banoub, Joseph H. TI Determination of the glycation sites of Bacillus anthracis neoglycoconjugate vaccine by MALDI-TOF/TOF-CID-MS/MS and LC-ESI-QqTOF-tandem mass spectrometry SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE neoglycoconjugate; proteinases; glycated peptides; MALDI-TOF/TOF-CID-MS/MS; LC-ESI-QqTOF-CID-MS/MS ID ELECTRON-CAPTURE DISSOCIATION; COLLISION-INDUCED DISSOCIATION; TETRASACCHARIDE SIDE-CHAIN; VIBRIO-CHOLERAE O1; PEPTIDES; PROTEIN; EXOSPORIUM; SPECTRA; LIPOPOLYSACCHARIDE; IMMUNOGENICITY AB We present herein an efficient mass spectrometric method for the localization of the glycation sites of a model neoglycoconjugate vaccine formed by a construct of the tetrasaccharide side chain of the Bacillus anthracis exosporium and the protein carrier bovine serum albumin. The glycoconjugate was digested with both trypsin and GluC V8 endoproteinases, and the digests were then analyzed by MALDI-TOF/TOF-CID-MS/MS and nano-LC-ESI-QqTOF-CID-MS/MS. The sequences of the unknown peptides analyzed by MALDI-TOF/TOF-CID-MS/MS, following digestion with the GluC V8 endoproteinase, allowed us to recognize three glycopeptides whose glycation occupancies were, respectively, on Lys 235, Lys 420, and Lys 498. Similarly, the same analysis was performed on the tryptic digests, which permitted us to recognize two glycation sites on Lys 100 and Lys 374. In addition, we have also used LC-ESI-QqTOF-CID-MS/MS analysis for the identification of the tryptic digests. However, this analysis identified a higher number of glycopeptides than would be expected from a glycoconjugate composed of a carbohydrate-protein ratio of 5.4:1, which would have resulted in glycation occupancies of 18 specific sites. This discrepancy was due to the large number of glycoforms formed during the synthetic carbohydrate-spacer-carrier protein conjugation. Likewise, the LC-ESI-QqTOF-MS/MS analysis of the GluC V8 digest also identified 17 different glycation sites on the synthetic glycoconjugate. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Banoub, Joseph H.] Dept Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. [Jahouh, Farid; Banoub, Joseph H.] Mem Univ Newfoundland, Dept Chem, St John, NF A1B 3X7, Canada. [Hou, Shu-jie; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Banoub, JH (reprint author), Dept Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. EM banoubjo@dfo-mpo.gc.ca FU Intramural NIH HHS [ZIA DK059701-38] NR 44 TC 9 Z9 9 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-5174 EI 1096-9888 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2011 VL 46 IS 10 BP 993 EP 1003 DI 10.1002/jms.1980 PG 11 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 848DC UT WOS:000297028200004 PM 22012665 ER PT J AU Delvolve, AM Woods, AS AF Delvolve, Alice M. Woods, Amina S. TI Optimization of automated matrix deposition for biomolecular mapping using a spotter SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE imaging; mass spectrometry; lipids; chemical ink jet printer ID IMAGING MASS-SPECTROMETRY; BRAIN-TISSUE-SECTIONS; MALDI; TOFMS; MS/MS; LOCALIZATION; LIPIDS AB Imaging mass spectrometry using matrix-assisted laser desorption/ionization allows the detailed mapping of biomolecules directly from tissue. Matrix deposition is the key step for successful imaging. The appropriate concentration and deposition of matrix is critical for extraction, desorption, and ionization of molecules from tissue without losing molecular localization. The main challenge to meet these criteria is to deposit matrix droplets homogeneously on the tissue section. This work shows how a chemical inkjet printer was used for this purpose resulting in the imaging of phosphatidylcholines and sulfatides. The intricacies involved in effective matrix deposition are discussed. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Delvolve, Alice M.; Woods, Amina S.] NIDA IRP, NIH, Baltimore, MD USA. RP Woods, AS (reprint author), NIDA IRP, NIH, 333 Cassell Dr,Room 1120, Baltimore, MD USA. EM awoods@mail.nih.gov FU National Institute on Drug Abuse, NIH FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors acknowledge Steve M. Wishnies and Brian J. Feild of the Shimadzu Corporation for technical advices. NR 19 TC 8 Z9 8 U1 0 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2011 VL 46 IS 10 BP 1046 EP 1050 DI 10.1002/jms.1986 PG 5 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 848DC UT WOS:000297028200010 PM 22012671 ER PT J AU Taylor, RT Best, SM AF Taylor, R. Travis Best, Sonja M. TI Assessing ubiquitination of viral proteins: Lessons from flavivirus NS5 SO METHODS LA English DT Article DE Flavivirus; NS5; Ubiquitin; Langat; Biotin; Streptavidin ID TICK-BORNE FLAVIVIRUS; LYSINE; DEGRADATION; DEUBIQUITINATION; IDENTIFICATION; UBIQUITYLATION; REPLICATION; RESIDUES; IMMUNITY; SYSTEM AB Ubiquitin (Ub) conjugation to a substrate protein is a widely used cellular mechanism for control of protein stability and function, modulation of signal transduction pathways and antiviral responses. Identification and characterization of ubiquitinated viral proteins is an important step in understanding novel mechanisms of viral protein regulation as well as elucidating cellular antiviral strategies. Here we describe a protocol to easily detect and characterize the ubiquitination status of a viral substrate protein expressed either during infection or ectopically expressed as a fusion with a biotinylatable epitope tag. This tag provides advantages over current immunoprecipitation techniques by making use of the extremely tight biotin-streptavidin interaction. We provide an example of this protocol using the nonstructural protein 5 (NS5) from Langat virus (LGTV), a member of the tick-borne encephalitis virus (TBEV) serocomplex within the Flavivirus genus. Using the protocols outlined here, we describe some of the pitfalls inherent in determination of Ub linkage and demonstrate that NS5 is modified by at least two distinct ubiquitination types, multiubiquitination and K48-linked polyubiquitin chains. Published by Elsevier Inc. C1 [Taylor, R. Travis; Best, Sonja M.] NIAID, Innate Immun & Pathogenesis Unit, Virol Lab, Rocky Mt Labs,DIR,NIH, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Innate Immun & Pathogenesis Unit, Virol Lab, Rocky Mt Labs,DIR,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) FX We thank Dr. Heinz Feldmann, Dr. Shelly Robertson, and Kirk Lubick for critical reviews of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). NR 38 TC 3 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD OCT PY 2011 VL 55 IS 2 BP 166 EP 171 DI 10.1016/j.ymeth.2011.08.003 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846WL UT WOS:000296933800010 PM 21855635 ER PT J AU Leinisch, F Jiang, JJ Deterding, LJ Mason, RP AF Leinisch, Fabian Jiang, JinJie Deterding, Leesa J. Mason, Ronald P. TI Simplified Synthesis of Isotopically Labeled 5,5-Dimethyl-pyrroline N-Oxide SO MOLECULES LA English DT Article DE spin trap; isotopic labeling; DMPO ID BIOLOGICAL APPLICATIONS; FREE-RADICALS; SPIN-TRAPS; 1-OXIDES AB 5,5-Dimethylpyrroline N-oxide ((15)N) and 5,5-di(trideuteromethyl)pyrroline N-oxide were synthesized from the respective isotopically labeled 2-nitropropane analogs obtained from the reaction of sodium nitrate with 2-halopropanes. This facile, straightforward process allows synthesizing isotopically labeled DMPO analogs in a 4-step reaction without special equipment. C1 [Leinisch, Fabian; Jiang, JinJie; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Deterding, Leesa J.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Leinisch, F (reprint author), Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM leinischf@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX We would like to thank Ann G. Motten, Jean Corbett, Fiona A. Summers and Mary J. Mason for their help with the manuscript and Eugene DeRose for the NMR measurements. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 17 TC 0 Z9 0 U1 0 U2 3 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD OCT PY 2011 VL 16 IS 10 BP 8428 EP 8436 DI 10.3390/molecules16108428 PG 9 WC Chemistry, Organic SC Chemistry GA 847KY UT WOS:000296973000021 PM 21986521 ER PT J AU Fujimori, N Oono, T Igarashi, H Ito, T Nakamura, T Uchida, M Coy, DH Jensen, RT Takayanagi, R AF Fujimori, Nao Oono, Takamasa Igarashi, Hisato Ito, Tetsuhide Nakamura, Taichi Uchida, Masahiko Coy, David H. Jensen, Robert T. Takayanagi, Ryoichi TI Vasoactive intestinal peptide reduces oxidative stress in pancreatic acinar cells through the inhibition of NADPH oxidase SO PEPTIDES LA English DT Article DE Vasoactive intestinal peptide; Reactive oxygen species; Antioxidant; NADPH oxidase ID PROTEIN-KINASE-A; STELLATE CELLS; FREE-RADICALS; TNF-ALPHA; ACTIVATION; VIP; DISEASE; MODEL; RATS; RECEPTORS AB Vasoactive intestinal peptide (VIP) attenuates experimental acute pancreatitis (AP) by inhibition of cytokine production from inflammatory cells. It has been suggested that reactive oxygen species (ROS) as well as cytokines play pivotal roles in the early pathophysiology of AP. This study aimed to clarify the effect of VIP on the oxidative condition in pancreas, especially pancreatic acinar cells (acini). Hydrogen peroxide (H(2)O(2))-induced intracellular ROS, assessed with CM-H(2)DCFDA, increased time- and dose-dependently in acini isolated from rats. Cell viability due to ROS-induced cellular damage, evaluated by MTS assay, was decreased with >= 100 mu mol/L H(2)O(2). VIP significantly inhibited ROS production from acini and increased cell viability in a dose-dependent manner. Expression of antioxidants including catalase, glutathione reductase, superoxide dismutase (SOD) 1 and glutathione peroxidase was not altered by VIP except for SOD2. Furthermore, Nox1 and Nox2, major components of NADPH oxidase, were expressed in pancreatic acini, and significantly increased after H(2)O(2) treatment. Also, NADPH oxidase activity was provoked by H(2)O(2). VIP decreased NADPH oxidase activity, which was abolished by PICA inhibitor H89. These results suggested that VIP affected the mechanism of ROS production including NADPH oxidase through induction of a cAMP/PKA pathway. In conclusion, VIP reduces oxidative stress in acini through the inhibition of NADPH oxidase. These results combined with findings of our previous study suggest that VIP exerts its protective effect in pancreatic damage, not only through an inhibition of cytokine production, but also through a reduction of the injury caused by oxidative stress. (C) 2011 Elsevier Inc. All rights reserved. C1 [Fujimori, Nao; Oono, Takamasa; Igarashi, Hisato; Ito, Tetsuhide; Nakamura, Taichi; Uchida, Masahiko; Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan. [Coy, David H.] Tulane Univ, Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. [Jensen, Robert T.] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Pancreas Research Foundation of Japan; Ministry of Education, Culture, Sports, Science, and Technology, Japan; Research Committee of Intractable Diseases of the Pancreas by the Ministry of Health, Labour, and Welfare Japan [50253448] FX This study was supported in part by the project of "Creation of Innovation Centers for Advanced Interdisciplinary Research Areas" based on the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Igarashi H.), by the Pancreas Research Foundation of Japan (Igarashi H.), by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20590808, Ito T.) and by the Research Committee of Intractable Diseases of the Pancreas (Principal investigator: Tooru Shimosegawa) provided by the Ministry of Health, Labour, and Welfare Japan (50253448, Ito T.). NR 53 TC 9 Z9 9 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD OCT PY 2011 VL 32 IS 10 BP 2067 EP 2076 DI 10.1016/j.peptides.2011.08.027 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 848VS UT WOS:000297083800012 PM 21924308 ER PT J AU Ceballos, LA Piccinali, RV Marcet, PL Vazquez-Prokopec, GM Cardinal, MV Schachter-Broide, J Dujardin, JP Dotson, EM Kitron, U Gurtler, RE AF Ceballos, Leonardo A. Piccinali, Romina V. Marcet, Paula L. Vazquez-Prokopec, Gonzalo M. Victoria Cardinal, M. Schachter-Broide, Judith Dujardin, Jean-Pierre Dotson, Ellen M. Kitron, Uriel Guertler, Ricardo E. TI Hidden Sylvatic Foci of the Main Vector of Chagas Disease Triatoma infestans: Threats to the Vector Elimination Campaign? SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID RURAL NORTHWESTERN ARGENTINA; TRYPANOSOMA-CRUZI INFECTION; SANTIAGO-DEL-ESTERO; RHODNIUS-PROLIXUS; BOLIVIAN CHACO; ENTOMOLOGICAL SURVEILLANCE; PERIDOMESTIC POPULATIONS; AMERICAN TRYPANOSOMIASIS; PYRETHROID INSECTICIDES; REDUVIIDAE POPULATIONS AB Background: Establishing the sources of reinfestation after residual insecticide spraying is crucial for vector elimination programs. Triatoma infestans, traditionally considered to be limited to domestic or peridomestic (abbreviated as D/PD) habitats throughout most of its range, is the target of an elimination program that has achieved limited success in the Gran Chaco region in South America. Methodology/Principal Findings: During a two-year period we conducted semi-annual searches for triatomine bugs in every D/PD site and surrounding sylvatic habitats after full-coverage spraying of pyrethroid insecticides of all houses in a well-defined rural area in northwestern Argentina. We found six low-density sylvatic foci with 24 T. infestans in fallen or standing trees located 110-2,300 m from the nearest house or infested D/PD site detected after insecticide spraying, when house infestations were rare. Analysis of two mitochondrial gene fragments of 20 sylvatic specimens confirmed their species identity as T. infestans and showed that their composite haplotypes were the same as or closely related to D/PD haplotypes. Population studies with 10 polymorphic microsatellite loci and wing geometric morphometry consistently indicated the occurrence of unrestricted gene flow between local D/PD and sylvatic populations. Mitochondrial DNA and microsatellite sibship analyses in the most abundant sylvatic colony revealed descendents from five different females. Spatial analysis showed a significant association between two sylvatic foci and the nearest D/PD bug population found before insecticide spraying. Conclusions: Our study shows that, despite of its high degree of domesticity, T. infestans has sylvatic colonies with normal chromatic characters (not melanic morphs) highly connected to D/PD conspecifics in the Argentinean Chaco. Sylvatic habitats may provide a transient or permanent refuge after control interventions, and function as sources for D/PD reinfestation. The occurrence of sylvatic foci of T. infestans in the Gran Chaco may pose additional threats to ongoing vector elimination efforts. C1 [Ceballos, Leonardo A.; Piccinali, Romina V.; Victoria Cardinal, M.; Schachter-Broide, Judith; Guertler, Ricardo E.] Univ Buenos Aires, Dept Ecol Genet & Evolut, Lab Ecoepidemiol, Buenos Aires, DF, Argentina. [Marcet, Paula L.; Dotson, Ellen M.] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Atlanta, GA USA. [Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Dujardin, Jean-Pierre] Ctr Natl Rech Sci, Inst Rech Dev, Unite Mixte Rech, Montpellier, France. RP Ceballos, LA (reprint author), Univ Buenos Aires, Dept Ecol Genet & Evolut, Lab Ecoepidemiol, Buenos Aires, DF, Argentina. EM gurtler@ege.fcen.uba.ar OI Marcet, Paula/0000-0002-0676-3020 FU National Institutes of Health/National Science Foundation [R01 TW05836]; Fogarty International Center; National Institute of Environmental Health Sciences; Agencia Nacional de Promocion Cientifica y Tecnica (Argentina); University of Buenos Aires; UNDP/World Bank/WHO/TDR [A70596]; International Development Research Centre [103696-009] FX This work was supported by the National Institutes of Health/National Science Foundation Ecology of Disease program through NIH Research Grant R01 TW05836 funded by the Fogarty International Center and the National Institute of Environmental Health Sciences (to U.K., R.E.G. and Joel E. Cohen), Agencia Nacional de Promocion Cientifica y Tecnica (Argentina) and by the University of Buenos Aires (R.E.G.). The participation of R.E.G. was also supported by UNDP/World Bank/WHO/TDR (Grant No. A70596) and International Development Research Centre (Grant No. 103696-009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 37 Z9 37 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2011 VL 5 IS 10 AR e1365 DI 10.1371/journal.pntd.0001365 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 842FR UT WOS:000296579700035 PM 22039559 ER PT J AU Wahl-Jensen, V Kurz, S Feldmann, F Buehler, LK Kindrachuk, J DeFilippis, V Correia, JD Fruh, K Kuhn, JH Burton, DR Feldmann, H AF Wahl-Jensen, Victoria Kurz, Sabine Feldmann, Friedericke Buehler, Lukas K. Kindrachuk, Jason DeFilippis, Victor Correia, Jean da Silva Frueh, Klaus Kuhn, Jens H. Burton, Dennis R. Feldmann, Heinz TI Ebola Virion Attachment and Entry into Human Macrophages Profoundly Effects Early Cellular Gene Expression SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID VIRUS-INFECTED PATIENTS; DOUBLE-STRANDED-RNA; HEMORRHAGIC-FEVER; VP35 PROTEIN; IFN-ALPHA; RESPONSES; CELLS; PATHOGENESIS; ACTIVATION; MARBURG AB Zaire ebolavirus (ZEBOV) infections are associated with high lethality in primates. ZEBOV primarily targets mononuclear phagocytes, which are activated upon infection and secrete mediators believed to trigger initial stages of pathogenesis. The characterization of the responses of target cells to ZEBOV infection may therefore not only further understanding of pathogenesis but also suggest possible points of therapeutic intervention. Gene expression profiles of primary human macrophages exposed to ZEBOV were determined using DNA microarrays and quantitative PCR to gain insight into the cellular response immediately after cell entry. Significant changes in mRNA concentrations encoding for 88 cellular proteins were observed. Most of these proteins have not yet been implicated in ZEBOV infection. Some, however, are inflammatory mediators known to be elevated during the acute phase of disease in the blood of ZEBOV-infected humans. Interestingly, the cellular response occurred within the first hour of Ebola virion exposure, i.e. prior to virus gene expression. This observation supports the hypothesis that virion binding or entry mediated by the spike glycoprotein (GP(1,2)) is the primary stimulus for an initial response. Indeed, ZEBOV virions, LPS, and virus-like particles consisting of only the ZEBOV matrix protein VP40 and GP(1,2) (VLP(VP40-GP)) triggered comparable responses in macrophages, including pro-inflammatory and proapoptotic signals. In contrast, VLP(VP40) (particles lacking GP(1,2)) caused an aberrant response. This suggests that GP(1,2) binding to macrophages plays an important role in the immediate cellular response. C1 [Wahl-Jensen, Victoria; Kindrachuk, Jason; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Ft Detrick, MD USA. [Wahl-Jensen, Victoria; Feldmann, Friedericke; Feldmann, Heinz] Publ Hlth Agcy Canada, Canadian Sci Ctr Human & Anim Hlth, Natl Microbiol Lab, Winnipeg, MB, Canada. [Wahl-Jensen, Victoria; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Feldmann, Friedericke; Feldmann, Heinz] NIAID, Integrated Res Facil, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Buehler, Lukas K.] Southwestern Coll, Sch Math Sci & Engn, Chula Vista, CA USA. [DeFilippis, Victor; Frueh, Klaus] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Portland, OR 97201 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Wahl-Jensen, V (reprint author), NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Ft Detrick, MD USA. EM victoriajensen@nih.gov; feldmannh@mail.nih.gov RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Kindrachuk, Jason/0000-0002-3305-7084 FU Public Health Agency of Canada; National Institutes of Health [R01 AI048053]; Canadian Institutes of Health Research [MOP 43921]; National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200200016I] FX This work was supported by the Public Health Agency of Canada and grants from the National Institutes of Health (R01 AI048053) awarded to D.B. and the Canadian Institutes of Health Research (MOP 43921) awarded to H.F. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Authors VWJ and JHK performed this work as employees of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute's prime contract with the National Institute of Allergy and Infectious Diseases (NIAID), under Contract No. HHSN272200200016I. NR 53 TC 20 Z9 22 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2011 VL 5 IS 10 AR e1359 DI 10.1371/journal.pntd.0001359 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 842FR UT WOS:000296579700029 PM 22028943 ER PT J AU al Basatena, NKS MacNamara, A Vine, AM Thio, CL Astemborski, J Usuku, K Osame, M Kirk, GD Donfield, SM Goedert, JJ Bangham, CRM Carrington, M Khakoo, SI Asquith, B AF al Basatena, Nafisa-Katrin Seich MacNamara, Aidan Vine, Alison M. Thio, Chloe L. Astemborski, Jacquie Usuku, Koichiro Osame, Mitsuhiro Kirk, Gregory D. Donfield, Sharyne M. Goedert, James J. Bangham, Charles R. M. Carrington, Mary Khakoo, Salim I. Asquith, Becca TI KIR2DL2 Enhances Protective and Detrimental HLA Class I-Mediated Immunity in Chronic Viral Infection SO PLOS PATHOGENS LA English DT Article ID CD8(+) T-CELLS; HEPATITIS-C VIRUS; NATURAL-KILLER-CELLS; LEUKOCYTE RECEPTOR COMPLEX; ANTIGEN-CLASS-I; INHIBITORY RECEPTORS; FUNCTIONAL TRANSFER; TYPE-1 INFECTION; DENDRITIC CELLS; KIR EXPRESSION AB Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection. C1 [al Basatena, Nafisa-Katrin Seich; MacNamara, Aidan; Vine, Alison M.; Bangham, Charles R. M.; Khakoo, Salim I.; Asquith, Becca] Univ London Imperial Coll Sci Technol & Med, London, England. [Thio, Chloe L.; Astemborski, Jacquie; Kirk, Gregory D.] Johns Hopkins Univ, Baltimore, MD USA. [Usuku, Koichiro] Kumamoto Univ, Kumamoto, Japan. [Osame, Mitsuhiro] Kagoshima Univ, Kagoshima 890, Japan. [Donfield, Sharyne M.] Rho, Chapel Hill, NC USA. [Goedert, James J.] NCI, Rockville, MD USA. [Carrington, Mary] SAIC Frederick Inc, NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Carrington, Mary] MIT, Ragon Inst MGH, Boston, MA USA. [Carrington, Mary] Harvard Univ, Boston, MA 02115 USA. RP al Basatena, NKS (reprint author), Univ London Imperial Coll Sci Technol & Med, London, England. EM b.asquith@ic.ac.uk OI Khakoo, Salim/0000-0002-4057-9091; Asquith, Becca/0000-0002-5911-3160; MacNamara, Aidan/0000-0001-5958-2429; Bangham, Charles/0000-0003-2624-3599 FU Wellcome Trust; Medical Research Council; National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; National Institutes of Health, National Institute of Child Health and Human Development [1 R01 HD41224]; National Institute on Drug Abuse [R01-DA-04334, R01-DA-12568, R01-DA-16078] FX This work is supported by the Wellcome Trust, the Medical Research Council and the National Institutes of Health. Specifically, BA was supported by the MRC and NKS was supported by the Wellcome Trust. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The HGDS was funded by the National Institutes of Health, National Institute of Child Health and Human Development, 1 R01 HD41224. ALIVE was supported by the National Institute on Drug Abuse, grants R01-DA-04334, R01-DA-12568 and R01-DA-16078. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 23 Z9 23 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2011 VL 7 IS 10 AR e1002270 DI 10.1371/journal.ppat.1002270 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 844FY UT WOS:000296734300006 ER PT J AU Sashihara, J Hoshino, Y Bowman, JJ Krogmann, T Burbelo, PD Coffield, VM Kamrud, K Cohen, JI AF Sashihara, Junji Hoshino, Yo Bowman, J. Jason Krogmann, Tammy Burbelo, Peter D. Coffield, V. McNeil Kamrud, Kurt Cohen, Jeffrey I. TI Soluble Rhesus Lymphocryptovirus gp350 Protects against Infection and Reduces Viral Loads in Animals that Become Infected with Virus after Challenge SO PLOS PATHOGENS LA English DT Article ID EPSTEIN-BARR-VIRUS; ENVELOPE GLYCOPROTEIN GP340; T-CELL EPITOPES; COTTONTOP TAMARINS; LYMPHOPROLIFERATIVE DISEASE; RECOMBINANT VACCINIA; NEUTRALIZING ANTIBODIES; MALIGNANT-LYMPHOMA; NUCLEAR PROTEIN-2; MEMBRANE ANTIGEN AB Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine-immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e. g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans. C1 [Sashihara, Junji; Hoshino, Yo; Bowman, J. Jason; Krogmann, Tammy; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Coffield, V. McNeil; Kamrud, Kurt] AlphaVax Inc, Res Triangle Pk, NC USA. RP Sashihara, J (reprint author), Kansai Rousai Hosp, Dept Pediat, Osaka, Hyogo, Japan. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This research was supported by the intramural program of the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 17 Z9 17 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2011 VL 7 IS 10 AR e1002308 DI 10.1371/journal.ppat.1002308 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 844FY UT WOS:000296734300038 PM 22028652 ER PT J AU Smith, DS Guo, KJ Barrett, BS Heilman, KJ Evans, LH Hasenkrug, KJ Greene, WC Santiago, ML AF Smith, Diana S. Guo, Kejun Barrett, Bradley S. Heilman, Karl J. Evans, Leonard H. Hasenkrug, Kim J. Greene, Warner C. Santiago, Mario L. TI Noninfectious Retrovirus Particles Drive the Apobec3/Rfv3 Dependent Neutralizing Antibody Response SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; FRIEND-VIRUS; IN-VIVO; HIV-1 INFECTION; T-CELLS; CYTIDINE DEAMINASES; ENZYME APOBEC3G; EDITING ENZYME AB Members of the APOBEC3 family of deoxycytidine deaminases counteract a broad range of retroviruses in vitro through an indirect mechanism that requires virion incorporation and inhibition of reverse transcription and/or hypermutation of minus strand transcripts in the next target cell. The selective advantage to the host of this indirect restriction mechanism remains unclear, but valuable insights may be gained by studying APOBEC3 function in vivo. Apobec3 was previously shown to encode Rfv3, a classical resistance gene that controls the recovery of mice from pathogenic Friend retrovirus (FV) infection by promoting a more potent neutralizing antibody (NAb) response. The underlying mechanism does not involve a direct effect of Apobec3 on B cell function. Here we show that while Apobec3 decreased titers of infectious virus during acute FV infection, plasma viral RNA loads were maintained, indicating substantial release of noninfectious particles in vivo. The lack of plasma virion infectivity was associated with a significant post-entry block during early reverse transcription rather than G-to-A hypermutation. The Apobec3-dependent NAb response correlated with IgG binding titers against native, but not detergent-lysed virions. These findings indicate that innate Apobec3 restriction promotes NAb responses by maintaining high concentrations of virions with native B cell epitopes, but in the context of low virion infectivity. Finally, Apobec3 restriction was found to be saturable in vivo, since increasing FV inoculum doses resulted in decreased Apobec3 inhibition. By analogy, maximizing the release of noninfectious particles by modulating APOBEC3 expression may improve humoral immunity against pathogenic human retroviral infections. C1 [Smith, Diana S.; Guo, Kejun; Barrett, Bradley S.; Heilman, Karl J.; Santiago, Mario L.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Evans, Leonard H.; Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. [Evans, Leonard H.; Greene, Warner C.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94143 USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Microbiol, San Francisco, CA 94143 USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Immunol, San Francisco, CA 94143 USA. [Santiago, Mario L.] Univ Colorado Denver, Dept Immunol, Aurora, CO USA. [Santiago, Mario L.] Univ Colorado Denver, Dept Microbiol, Aurora, CO USA. RP Smith, DS (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO USA. EM mario.santiago@ucdenver.edu OI Santiago, Mario L./0000-0001-7792-2706 FU NIH [R01 AI090795]; UCSF-GIVI Center for AIDS Research; NIH, NIAID FX This work was supported by the NIH grant R01 AI090795 (M.L.S), UCSF-GIVI Center for AIDS Research "Outside the Box AIDS Vaccine" Award (W. C. G. and M. L. S.) and the Intramural Research Program of the NIH, NIAID (K.J.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 24 Z9 24 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2011 VL 7 IS 10 AR e1002284 DI 10.1371/journal.ppat.1002284 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 844FY UT WOS:000296734300014 PM 21998583 ER PT J AU Watanabe, S Zimmermann, M Goodwin, MB Sauer, U Barry, CE Boshoff, HI AF Watanabe, Shinya Zimmermann, Michael Goodwin, Michael B. Sauer, Uwe Barry, Clifton E., III Boshoff, Helena I. TI Fumarate Reductase Activity Maintains an Energized Membrane in Anaerobic Mycobacterium tuberculosis SO PLOS PATHOGENS LA English DT Article ID TRICARBOXYLIC-ACID CYCLE; ESCHERICHIA-COLI; SUCCINATE-DEHYDROGENASE; PULMONARY TUBERCULOSIS; HYPOXIC RESPONSE; EMISSION-TOMOGRAPHY; ALPHA-CRYSTALLIN; MALIC ENZYMES; METABOLISM; DORMANCY AB Oxygen depletion of Mycobacterium tuberculosis engages the DosR regulon that coordinates an overall down-regulation of metabolism while up-regulating specific genes involved in respiration and central metabolism. We have developed a chemostat model of M. tuberculosis where growth rate was a function of dissolved oxygen concentration to analyze metabolic adaptation to hypoxia. A drop in dissolved oxygen concentration from 50 mmHg to 0.42 mmHg led to a 2.3 fold decrease in intracellular ATP levels with an almost 70-fold increase in the ratio of NADH/NAD(+). This suggests that re-oxidation of this co-factor becomes limiting in the absence of a terminal electron acceptor. Upon oxygen limitation genes involved in the reverse TCA cycle were upregulated and this upregulation was associated with a significant accumulation of succinate in the extracellular milieu. We confirmed that this succinate was produced by a reversal of the TCA cycle towards the non-oxidative direction with net CO(2) incorporation by analysis of the isotopomers of secreted succinate after feeding stable isotope ((13)C) labeled precursors. This showed that the resulting succinate retained both carbons lost during oxidative operation of the TCA cycle. Metabolomic analyses of all glycolytic and TCA cycle intermediates from (13)C-glucose fed cells under aerobic and anaerobic conditions showed a clear reversal of isotope labeling patterns accompanying the switch from normoxic to anoxic conditions. M. tuberculosis encodes three potential succinate-producing enzymes including a canonical fumarate reductase which was highly upregulated under hypoxia. Knockout of frd, however, failed to reduce succinate accumulation and gene expression studies revealed a compensatory upregulation of two homologous enzymes. These major realignments of central metabolism are consistent with a model of oxygen-induced stasis in which an energized membrane is maintained by coupling the reductive branch of the TCA cycle to succinate secretion. This fermentative process may offer unique targets for the treatment of latent tuberculosis. C1 [Watanabe, Shinya; Goodwin, Michael B.; Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Zimmermann, Michael; Sauer, Uwe] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland. RP Watanabe, S (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hboshoff@niaid.nih.gov RI Watanabe, Shinya/B-7008-2009; Barry, III, Clifton/H-3839-2012 OI Watanabe, Shinya/0000-0001-6542-6502; FU NIH, NIAID; Bill and Melinda Gates Foundation; Wellcome Trust through the Grand Challenges in Global Health Initiative; EU FX This research was supported (in part) by the Intramural Research Program of the NIH, NIAID, and funded (in part) by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative to Imperial College, London (Douglas Young, PI) and financial support (to US and MZ) through the EU FP7 project SysteMTb. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 76 Z9 76 U1 4 U2 25 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2011 VL 7 IS 10 AR e1002287 DI 10.1371/journal.ppat.1002287 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 844FY UT WOS:000296734300017 PM 21998585 ER PT J AU Parascandola, M AF Parascandola, Mark TI Causes, risks, and probabilities: Probabilistic concepts of causation in chronic disease epidemiology SO PREVENTIVE MEDICINE LA English DT Article DE Epidemiology; Causation; Causal inference; Cancer; Prevention AB Identifying and understanding causes of disease is arguably the central aim of the discipline of epidemiology. However, while the discipline has matured over the past sixty years, developing a battery of quantitative tools and methods for data analysis, the discipline of epidemiology lacks an explicit, shared theoretical account of causation. Moreover, some epidemiologists exhibit discomfort with the concept of causation itself, concerned that it creates more confusion than clarity. This paper describes how, during the post-war period, epidemiologists began to think about causation in new ways as they encountered novel challenges in studying chronic diseases. The epidemiologic evidence linking cigarette smoking and lung cancer in the 1950s provided a focus for debates over causation. While some epidemiologists embraced probabilistic concepts of cause and effect, others maintained that causal mechanisms must ultimately be deterministic. The tension between probabilistic risk factors and deterministic causal mechanisms continues to haunt epidemiology today. Published by Elsevier Inc. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov NR 33 TC 5 Z9 6 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD OCT-NOV PY 2011 VL 53 IS 4-5 BP 232 EP 234 DI 10.1016/j.ypmed.2011.09.007 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 846WZ UT WOS:000296935200007 PM 21983603 ER PT J AU Strenziok, M Krueger, F Deshpande, G Lenroot, RK van der Meer, E Grafman, J AF Strenziok, Maren Krueger, Frank Deshpande, Gopikrishna Lenroot, Rhoshel K. van der Meer, Elke Grafman, Jordan TI Fronto-parietal regulation of media violence exposure in adolescents: a multi-method study SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE aggression; violence; functional magnetic resonance imaging; skin conductance response; Granger causality mapping ID HUMAN ORBITOFRONTAL CORTEX; GRANGER CAUSALITY ANALYSIS; DIRECTED TRANSFER-FUNCTION; VIDEO GAMES; SPATIAL ATTENTION; TELEVISION VIOLENCE; AGGRESSIVE-BEHAVIOR; LOBE CONTRIBUTIONS; PARIETAL CORTEX; WORKING-MEMORY AB Adolescents spend a significant part of their leisure time watching TV programs and movies that portray violence. It is unknown, however, how the extent of violent media use and the severity of aggression displayed affect adolescents' brain function. We investigated skin conductance responses, brain activation and functional brain connectivity to media violence in healthy adolescents. In an event-related functional magnetic resonance imaging experiment, subjects repeatedly viewed normed videos that displayed different degrees of aggressive behavior. We found a downward linear adaptation in skin conductance responses with increasing aggression and desensitization towards more aggressive videos. Our results further revealed adaptation in a fronto-parietal network including the left lateral orbitofrontal cortex (lOFC), right precuneus and bilateral inferior parietal lobules, again showing downward linear adaptations and desensitization towards more aggressive videos. Granger causality mapping analyses revealed attenuation in the left lOFC, indicating that activation during viewing aggressive media is driven by input from parietal regions that decreased over time, for more aggressive videos. We conclude that aggressive media activates an emotion-attention network that has the capability to blunt emotional responses through reduced attention with repeated viewing of aggressive media contents, which may restrict the linking of the consequences of aggression with an emotional response, and therefore potentially promotes aggressive attitudes and behavior. C1 [Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Strenziok, Maren; van der Meer, Elke] Humboldt Univ, Dept Cognit Psychol, D-12489 Berlin, Germany. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Deshpande, Gopikrishna] Emory Univ, Dept Biomed Engn, Atlanta, GA 30332 USA. [Deshpande, Gopikrishna] Georgia Inst Technol, Atlanta, GA 30332 USA. [Lenroot, Rhoshel K.] NIMH, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, 10 Ctr Dr,Bldg 10,Room 7D43,MSC1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Deshpande, Gopikrishna/0000-0001-7471-5357 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX The authors thank Dr Dimitrios Kapogiannis and Dr Edward Huey for performing the neurological examinations on our subjects. This research was funded by the intramural research program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 78 TC 16 Z9 16 U1 2 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD OCT PY 2011 VL 6 IS 5 BP 537 EP 547 DI 10.1093/scan/nsq079 PG 11 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 834BC UT WOS:000295931000001 PM 20934985 ER PT J AU Godwin, KM Wasserman, J Ostwald, SK AF Godwin, Kyler M. Wasserman, Joan Ostwald, Sharon K. TI Cost Associated with Stroke: Outpatient Rehabilitative Services and Medication SO TOPICS IN STROKE REHABILITATION LA English DT Article DE outpatient stroke medication costs; outpatient stroke rehabilitation AB Purpose: This study aimed to capture direct costs of outpatient rehabilitative stroke care and medications for a 1-year period after discharge from inpatient rehabilitation. Methods: Outpatient rehabilitative services and medication costs for 1 year, during the time period of 2001 to 2005, were calculated for 54 first-time stroke survivors. Costs for services were based on Medicare reimbursement rates. Medicaid reimbursement rates and average wholesale price were used to estimate medication costs. Results: Of the 54 stroke survivors, 40 (74.1%) were categorized as independent, 12 (22.2%) had modified dependence, and 2 (3.7%) were dependent at the time of discharge from inpatient rehabilitation. Average cost for outpatient stroke rehabilitation services and medications the first year post inpatient rehabilitation discharge was $17,081. The corresponding average yearly cost of medication was $5,392, while the average cost of yearly rehabilitation service utilization was $11,689. Cost attributed to medication remained relatively constant throughout the groups. Outpatient rehabilitation service utilization constituted a large portion of cost within each group: 69.7% (dependent), 72.5% (modified dependence), and 66.7% (independent). Conclusions: Stroke survivors continue to incur significant costs associated with their stroke for the first 12 months following discharge from an inpatient rehabilitation setting. Changing public policies affect the cost and availability of care. This study provides a snapshot of outpatient medication and therapy costs prior to the enactment of major changes in federal legislation and serves as a baseline for future studies. C1 [Godwin, Kyler M.; Ostwald, Sharon K.] Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Ctr Aging, Houston, TX USA. [Wasserman, Joan] NINR, Off Extramural Programs, NIH, Washington, DC USA. RP Godwin, KM (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Ctr Aging, Houston, TX USA. FU American Nurses Foundation [2004112]; National Institutes of Nursing Research/National Institutes of Health [NR035316] FX This study was supported by grants from the American Nurses Foundation (J. Wasserman, PI, ID 2004112) and the National Institutes of Nursing Research/National Institutes of Health (S. Ostwald, PI, NR035316). NR 16 TC 12 Z9 15 U1 0 U2 5 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1074-9357 J9 TOP STROKE REHABIL JI Top. Stroke Rehabil. PD OCT PY 2011 VL 18 SU 1 BP 676 EP 684 DI 10.1310/tsr18s01-676 PG 9 WC Rehabilitation SC Rehabilitation GA 850FD UT WOS:000297179600011 PM 22120036 ER PT J AU Scott, G Monceaux, B Mishina, Y Brown, T Ray, M AF Scott, Gregory Monceaux, Brittany Mishina, Yuji Brown, Tracy Ray, Manas TI EVC2/LIMBIN KO mice as a model for Ellis-van Creveld Syndrome and Bovine Chondrodysplastic Dwarfism SO TRANSGENIC RESEARCH LA English DT Meeting Abstract C1 [Scott, Gregory; Brown, Tracy; Ray, Manas] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Mishina, Yuji] Univ Michigan, Ann Arbor, MI 48109 USA. [Monceaux, Brittany] LSU Hlth Sci Ctr, Shreveport, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD OCT PY 2011 VL 20 IS 5 MA 43 BP 1157 EP 1157 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 844XS UT WOS:000296786900057 ER PT J AU Chen, ZD Mantha, R Chen, J Slivano, O Takahashi, H AF Chen, Zhidong Mantha, Rebecca Chen, Janice Slivano, Orazio Takahashi, Hideko TI Fecal DNA for genotyping transgenic animals SO TRANSGENIC RESEARCH LA English DT Meeting Abstract C1 [Chen, Zhidong] MultiTarget Pharmaceut LLC, Salt Lake City, UT USA. [Mantha, Rebecca] Atom Energy Canada Ltd, Chalk River, ON K0J 1J0, Canada. [Chen, Janice] Johns Hopkins Univ, Baltimore, MD USA. [Slivano, Orazio] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Takahashi, Hideko] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD OCT PY 2011 VL 20 IS 5 MA 56 BP 1162 EP 1163 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 844XS UT WOS:000296786900070 ER PT J AU Vasudevan, K Sztein, J AF Vasudevan, Kuzhilani Sztein, Jorge TI Optimizing the superovulation protocol for 129S1/SVImj mouse stain SO TRANSGENIC RESEARCH LA English DT Meeting Abstract C1 [Vasudevan, Kuzhilani; Sztein, Jorge] NIAID, ARTiC, CMB, NIH, Rockville, MD USA. RI Sztein, Jorge/B-7165-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD OCT PY 2011 VL 20 IS 5 MA 98 BP 1178 EP 1178 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 844XS UT WOS:000296786900112 ER PT J AU Chen, XY Gambhlr, SS Cheon, J AF Chen, Xiaoyuan Gambhlr, Sanjiv S. Cheon, Jinwoo TI Theranostic Nanomedicine SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Editorial Material C1 [Chen, Xiaoyuan] Natl Inst Hlth, Bethesda, MD 20892 USA. [Gambhlr, Sanjiv S.] Stanford Univ, Stanford, CA 94305 USA. [Cheon, Jinwoo] Yonsei Univ, Seoul 120749, South Korea. RP Chen, XY (reprint author), Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 58 Z9 59 U1 3 U2 43 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD OCT PY 2011 VL 44 IS 10 SI SI BP 841 EP 841 DI 10.1021/ar200231d PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 843OT UT WOS:000296682400001 PM 22004477 ER PT J AU Xie, J Liu, G Eden, HS Ai, H Chen, XY AF Xie, Jin Liu, Gang Eden, Henry S. Ai, Hua Chen, Xiaoyuan TI Surface-Engineered Magnetic Nanoparticle Platforms for Cancer Imaging and Therapy SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID IRON-OXIDE NANOPARTICLES; BIOMEDICAL APPLICATIONS; MNO NANOPARTICLES; TUMOR VASCULATURE; CONTRAST AGENT; GENE DELIVERY; QUANTUM DOTS; RGD PEPTIDES; MRI CONTRAST; PROBES AB Enormous efforts have been made toward the translation of nanotechnology into medical practice, including cancer management. Generally the applications have fallen into two categories: diagnosis and therapy. Because the targets are often the same, the development of separate approaches can miss opportunities to improve efficiency and effectiveness. The unique physical properties of nanomaterials enable them to serve as the basis for superior imaging probes to locate and report cancerous lesions and as vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nanotheranostics, nanoplatforms with both imaging and therapeutic functionalities. These new multimodal platforms are highly versatile and valuable components of the emerging trend toward personalized medicine, which emphasizes tailoring treatments to the biology of individual patients to optimize outcomes. The dose coupling of imaging and treatment within a theranostic agent and the data about the evolving course of an illness that these agents provide can facilitate informed decisions about modifications to treatment. Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened for this class of biomaterials. Such nanoparticles are not merely tiny magnetic crystals, but potential platforms with large surface-to-volume ratios. By taking advantage of the well-developed surface chemistry of these materials, researchers can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This versatility makes magnetic nanoparticles excellent scaffolds for the construction of theranostic agents, and many efforts have been launched toward this goal. In this Account, we introduce the surface engineering techniques that we and others have developed, with an emphasis on how these techniques affect the role of nanoparticles as imaging or therapeutic agents. We and others have developed a set of chemical methods to prepare magnetic nanoparticles that possess accurate sizes, shapes, compositions, magnetizations, relaxivities, and surface charges. These features, in turn, can be harnessed to adjust the toxicity and stability of the nanoparticles and, further, to load functionalities, via various mechanisms, onto the nanoparticle surfaces. C1 [Ai, Hua] Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. [Xie, Jin; Liu, Gang; Eden, Henry S.; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Liu, Gang] N Sichuan Med Coll, Affiliated Hosp, Dept Radiol, Sichuan Key Lab Med Imaging, Nanchong 637007, Peoples R China. [Ai, Hua] Sichuan Univ, W China Hosp, Dept Radiol, Chengdu 610041, Peoples R China. RP Ai, H (reprint author), Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. EM huaai@scu.edu.cn; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009]; Pathway to Independence Award [K99/R00]; Program for New Century Excellent Talents in University [NCET-06-0781]; Distinguished Young Scholars Project of Sichuan Province [06ZQ026-0027, 2011JQ0032]; NSFC [20974065, 50603015, 50830107] FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the International Cooperative Program of the National Science Foundation of China (NSFC) (Grant 81028009). Dr. Jin Xie was partially supported by a Pathway to Independence Award (Grant K99/R00). The work was also supported by Program for New Century Excellent Talents in University (Grant NCET-06-0781), Distinguished Young Scholars Project of Sichuan Province (Grants 06ZQ026-0027 and 2011JQ0032), and NSFC (Grants 20974065, 50603015, and 50830107). NR 49 TC 278 Z9 279 U1 30 U2 327 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD OCT PY 2011 VL 44 IS 10 SI SI BP 883 EP 892 DI 10.1021/ar200044b PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 843OT UT WOS:000296682400006 PM 21548618 ER PT J AU Puri, A Blumenthal, R AF Puri, Anu Blumenthal, Robert TI Polymeric Lipid Assemblies as Novel Theranostic Tools SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID DRUG-DELIVERY SYSTEMS; CELL-MEMBRANES; COLORIMETRIC DETECTION; PHOTOINDUCED DESTABILIZATION; SUPRAMOLECULAR ASSEMBLIES; DIACETYLENIC LIPOSOMES; PHOSPHOLIPID POLYMERS; MOLECULAR RECOGNITION; INFLUENZA-VIRUS; SMART MATERIALS AB Polymerizable lipids have been used in research and medical applications such as membrane models, imaging platforms, drug delivery systems, vaccine carriers, biosensors, and coating materials. The polymerization of these lipid molecules forms a covalent bond between lipid moieties, which improves the noncovalent interactions that maintain the lipid lamellar phase architecture and increases the stability of the polymerized system. Because such lipid molecules form nanoassemblies with modifiable structures that acquire the stability of polymers following covalent bond formation, these lipids are of considerable Interest in the emerging field of theranostics. In this Account, we summarize the biomedical applications of polymerizable lipids (primarily phospholipids) in the context of various nanoplatforms. We discuss stable nanoplatforms, which have been used in a variety of theranostics applications. In addition, we describe methods for assembling triggerable theranostics by combining appropriate nonpolymerizable lipids with polymerizable lipids. Polymeric lipids hold promise as nanotools in the field of medical imaging, targeting, and on-demand drug delivery. Because of their similarity to biological lipids, long-term toxicity issues from polymerizable lipid nanoplatforms are predicted to be minimal. Although the field of polymeric nanocapsules is still in development, intensive efforts are underway to produce systems which could be applied to disease diagnosis and treatment. We envision that nanoimaging platforms coupled with localized drug delivery technology will have a significant impact on cancer therapy and other related diseases. The existing wealth of clinical knowledge both in the photochemistry of imaging agents and/or drugs and modifications of these agents using light will prove valuable in the further development of polymeric theranostic lipid-based nanoparticles. C1 [Puri, Anu; Blumenthal, Robert] NCI, CCR Nanobiol Program, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, CCR Nanobiol Program, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 71 TC 35 Z9 36 U1 1 U2 54 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD OCT PY 2011 VL 44 IS 10 SI SI BP 1071 EP 1079 DI 10.1021/ar2001843 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 843OT UT WOS:000296682400024 PM 21919465 ER EF